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Volume 19, Number 4 October 2009

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Introduction: Locally Advanced Breast Cancer

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his is the most exciting time in the history of breastcancer research and treatment. Advances occurring in all

isciplines of breast cancer care have had the positive effect ofmproving survival and decreasing treatment side effects. Forxample, screening and public educational efforts have sig-ificantly decreased the percentage of breast cancer cases thatresent with locally advanced or metastatic disease. For thoseho do present with locally advanced breast cancer, ad-ances in surgical therapies have helped minimize treatment-elated morbidity and improved the quality of life for survi-ors. With respect to systemic therapies, new cytotoxichemotherapies, new dose scheduling, and the introductionf aromatase inhibitors have helped minimize the risk ofeath from subsequent development of metastatic disease.he understanding of breast cancer biology is also rapidlyhanging, which has led to new therapeutics directed againstelective molecular targets, such as the HER2/neu receptor.inally, radiation treatments, which have been an integralomponent of breast cancer management for over 6 decades,ave evolved. As a packet, these advances have made a realifference for breast cancer patients. Specifically, breast can-er death rates in the United States and the United Kingdomave shown a precipitous and consistent decline over the pastecade.1

Despite this background, there is still room for improve-ent. Over 40,000 women in the United States are predicted

o die of breast cancer each year.1 Many of the patients whoventually die originally presented with lymph node-positiveisease and/or locally advanced breast cancer. In countriesithout mammographic screening programs, the percentagef patients diagnosed with locally advanced breast cancer andhe percentage of patients dying of disease are even more of aressing issue.It is imperative that radiation oncologists and other spe-

ialists remain aware of the number of changes developing inhe understanding of locally advanced breast cancer and thatocally advanced breast cancer is a potentially curable dis-ase. Moreover, each new systemic treatment advance thatncreases the chance of eradicating micrometastases makeshe role of radiation for locally advanced breast cancer evenore critical. For example, patients treated for locally ad-

anced breast cancer before the development of effective sys-
emic treatments would often die of metastatic disease. Such r
053-4296/09/$-see front matter © 2009 Published by Elsevier Inc.oi:10.1016/j.semradonc.2009.05.002

atients received little benefit from radiation achieving erad-cation of persistent foci of local-regional disease after sur-ery. In contrast, with effective systemic treatment, failure ofradication of persistent local-regional disease has beenhown to increase the risk of subsequent distant failures.sing systemic therapy, radiation benefits can translate into

mproved survival and cure rates.2

This issue of Seminars in Radiation Oncology provides theeader with a broad overview of the current status of locallydvanced breast cancer. Newman updates the epidemiologyf locally advanced breast cancer and highlights how dispar-ties in health care can influence the incidence of this diseasend its treatment success. Huber et al review how the evolv-ng understanding of breast cancer biology is leading to anmproved classification of breast cancer. Locally advancedreast cancer represents a spectrum of different biologicaliseases that have distinct patterns of presentation, molecularhenotypes, treatment responses to various agents, and prog-oses. It is imperative that the radiation oncology communityecome familiar with the new molecular lexicon of breastancer classifications and incorporate molecular features intoheir therapeutic thought processes.

The optimal management of locally advanced breast can-er requires multidisciplinary care. As highlighted by Spechtnd Gralow, neoadjuvant chemotherapy is now consideredhe standard of care for these patients. This treatment is as-ociated with high response rates, which can convert inoper-ble disease to an operable status and can allow for someatients to be treated with breast conservation. With theove to sequence chemotherapy before surgery, accurateretreatment assessment of disease is critical. Whitman andtrom review the importance of a clear delineation of local-egional disease status with appropriate diagnostic imagingnd examination before embarking on a course of neoadju-ant chemotherapy. Of particular value is the use of ultra-ound with fine-needle aspiration to evaluate the extent andocation of regional adenopathy. The documentation of dis-ase in lymph nodes before neoadjuvant chemotherapy canrequently change clinical staging and affect subsequent lo-al-regional treatment decisions.

One major potential advantage that neoadjuvant chemo-herapy offers for selected patients with favorable disease
esponse is the opportunity of treating with breast-conserva-
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194 T.A. Buchholz

ion therapy. Breast conservation after neoadjuvant chemo-herapy requires close multidisciplinary coordination andareful selection criteria to achieve optimal results. In thisssue, Alm El-Din and Taghian review the published outcomeata regarding breast conservation after neoadjuvant chemo-herapy and help describe appropriate selection criteria foronsideration of this treatment approach.

Radiation treatments also play an important role as adju-ant therapy for patients treated with mastectomy. Postmas-ectomy radiation has been found to contribute to the sur-ival of patients with locally advanced disease, and, asystemic treatments improve, the benefits of local-regionalherapies on survival increase. Jagsi and Pierce review the rolef radiation after mastectomy and also discuss the publishedata regarding the use of postmastectomy radiation in pa-ients treated with neoadjuvant chemotherapy.

With survival probabilities increasing, it is critical that theong-term risks of normal tissue injuries associated with ra-iation be minimized. Data from the Early Breast Cancerrialists’ Collaborative Group meta-analysis clearly show thatadiation can be associated with an increased risk of deathrom cardiovascular disease.2 Modern treatment techniquesre available to minimize and potentially overcome this risk.urthermore, 3-dimensional image-guided radiation treat-ent planning can help ensure that the adequate dose iselivered to important targets, which should help to improvehe efficacy of treatment. Moran and Haffty review modernadiation treatment techniques to highlight some of these
dvances.
Finally, inflammatory breast cancer remains the most ag-ressive and malignant subcategory of locally advanced dis-ase. Inflammatory breast cancer has unique clinical presen-ations, biological features, and natural histories. Woodwardnd Cristofanilli highlight these unique features, discuss op-imal therapeutic approaches, and review future directions ofesearch.

Advances in the management of locally advanced breastancer have significantly improved the outcome for patients,nd radiation treatments for this disease continue to comple-ent the benefits of surgery and systemic therapy. The nu-erous advances in physics, imaging, and computer technol-

gies have permitted radiation treatments to be much morerecise, which has the real potential to overcome many of the

imitations of the past. In addition, radiation oncologistseed to continue contributing to the understanding of breastancer biology and remain educated about the continuingdvances in other subspecialties. It is with this aim that weedicate this issue of Seminars in Radiation Oncology.

Thomas A. Buchholz, MD, FACRGuest Editor

eferences. Cancer Facts & Figures 2008. Atlanta, GA, American Cancer Society,

2008, pp 2-8. Early Breast Cancer Trialists’ Collaborative Group: Effects of radiother-

apy and of differences in the extent of surgery for early breast cancer onlocal recurrence and 15-year survival: An overview of the randomised
trials. Lancet 366:2087-2106, 2005

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pidemiology of Locally Advanced Breast Cancerisa A. Newman, MD, MPH, FACS

Locally advanced breast cancer refers to patients diagnosed with bulky primary cancersand/or regional adenopathy. It’s frequency has diminished greatly because of screeningmammography and early detection. However, impoverished and minority racial/ethniccommunities continue to experience disproportionately high breast cancer mortality ratesbecause of their high risk for being diagnosed with locally advanced disease.Semin Radiat Oncol 19:195-203 © 2009 Published by Elsevier Inc.

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ocally advanced breast cancer (LABC) is a relatively non-specific term referring to bulky invasive tumors that may

ave varying degrees of breast skin and/or chest wall involve-ent or cases with matted axillary and/or supraclavicularodal disease. More precise definitions have varied over time

n accord with modifications of the breast cancer stagingystem and shifting clinical treatment approaches for breastancer. The classic work of Haagensen during the 1950s,idely referred to as the Columbia Breast Cancer Stagingystem, coined the term “grave signs of LABC,” which in-luded (1) ulceration of the skin, (2) edema of the skin, (3)umor fixation to the chest wall, (4) axillary lymph nodeseasuring at least 2.5 cm, and (5) fixation of axillary nodes to

he skin or deep structures of the axilla. The presence of theserave signs was used as a determinant of inoperability viaalstedian radical mastectomy, which was the surgical stan-ard of that era.1,2

The development of multicenter and population-based tu-or registries led to the adoption of alternative and simplified

taging systems, such as the local-regional-distant schema usedy the surveillance, epidemiology, and end results (SEER) Pro-ram since its inception in 1973. With this categorization ofatients as having breast-only/node-negative (local, L) versusode-positive (regional, R) or metastatic (distant, D) disease, the

dentification of LABC cases is more challenging. LABC casesdentified through the publicly available SEER data are thoseases that have been characterized as regional disease at presen-ation. This clearly results in some overestimation of LABC fre-uency because some patients with small tumors will also beound to have node-positive disease.

The American Joint Committee on Cancer (AJCC) Stagingystem (edition 1 published in 1977) evolved concomitantly

reast Care Center, University of Michigan, Ann Arbor, MI.ddress reprint requests to Lisa A. Newman, MD, MPH, FACS, Breast Care

Center, University of Michigan, 1500 East Medical Center Drive, Ann
dArbor, MI 48109. E-mail: [email protected]
053-4296/09/$-see front matter © 2009 Published by Elsevier Inc.oi:10.1016/j.semradonc.2009.05.003

ith the contemporary era of clinical trials and outcome mea-urements in which it is essential that therapies and survivalates are monitored as a function of well-defined extent ofisease categories. The TNM system refers to primary breastumor size (T), regional nodal status (N), and the presenceersus absence of distant organ metastases (M). Each of thesetrata in turn is comprised of several clearly defined subsetsased on the available clinicopathologic measurements, andhe patient is assigned an overall stage based on the subsetroupings. Even with application of well-defined TNM cate-ories, however, we continue to see variations in the group-ngs that are used to identify LABC cases. This variation is aonsequence of both improved breast cancer outcomes overime and shifts in breast cancer treatment approaches. Forxample, early editions of the AJCC breast cancer stagingystem included supraclavicular nodal disease as distant me-astasis (M1), and these patients were considered unresect-ble and generally incurable in the past. Advances in systemicherapy for breast cancer (particularly with neoadjuvant che-otherapy approaches) have yielded markedly improved

urvival rates for patients with supraclavicular nodal diseases the isolated site of distant disease. The current AJCC stag-ng system no longer considers these patients to have M1isease, and supraclavicular nodal disease is now recognizeds another form of LABC; a high-risk form of breast cancerut a form that benefits greatly from aggressive is multimo-ality therapy.Neoadjuvant systemic therapy protocols have also im-

acted on the way LABC cases are identified. Historically,reoperative chemotherapy was developed as a strategy forontrolling unresectable breast cancer and then becamedopted for improving the ease of resecting bulky disease.herefore, the early neoadjuvant chemotherapy protocols forABC of the 1970s and 1980s defined eligibility as cases of

arge-diameter (T3, at least 5 cm) tumors or those with skinnd/or chest wall involvement. Appreciation for the tumor
ownstaging benefits of neoadjuvant chemotherapy grew
195

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196 L.A. Newman

uring the 1990s, leading to expanded definitions for LABCrotocol eligibility. For example, the classic Bonnadona et al3

rticle of 1990 refers to primary (neoadjuvant) chemother-py to avoid mastectomy in patients with primary tumorseasuring at least 3 cm.The remainder of this article summarizes registry data and

ublished studies of LABC defined as stage III breast cancer;umors measuring at least 5 cm (T3 tumors) with positivexillary lymph node(s); cases of bulky, fixed axillary adenop-thy (N2 disease); cases with breast skin involvement (satel-ite lesions or ulceration; T4b disease); and/or cases withhest wall fixation (T4a disease). The so-called “neglected”ABC may have secondary inflammatory changes, and theseases are more frequently seen among impoverished commu-ities that lack resources for appropriate breast cancercreening and treatment. True de novo inflammatory breastancer (T4d) probably has a distinct biological identity and isxcluded from this discussion.

ncidence: United Statesarge-scale data on the cancer burden of the American pop-lation are available through the National Cancer DataBaseNCDB) and the SEER Program. The NCDB is jointly main-ained by the American College of Surgeons and the Ameri-an Cancer Society, and since 1990 it has collected data fromospital-based tumor registrars on cancer diagnosis andreatment patterns on an estimated 80% of cases in thenited States. Publicly available NCDB statistics on breastancer stage distribution are available as AJCC TNM classifi-

Figure 1 The proportion of breast cancer patients diagnpositive disease (as per SEER5) stratified by race/ethnici

ations. The SEER Program is a population-based registry c

hat has documented the cancer burden of the United Statesince 1973. The SEER program was initially established toollect cancer statistics from 7 sites (5 states, Connecticut,owa, New Mexico, Utah, and Hawaii, and 2 metropolitanreas, Detroit and San Francisco-Oakland) that were consid-red to be representative of the American population. It haseen expanded several times over the past 25 years, specifi-ally with the intent of becoming more appropriate in reflect-ng the diverse American cancer population in terms of race/thnicity, culture, and rural versus urban geography. Theurrent SEER program collects data using the local-regional-istant staging system from 17 registries and is estimated toover approximately 26% of the US population. Web-based,ublicly available statistics on the frequency of advancedtage breast cancer among American women can be retrieveds regional disease from the SEER program and as stage IIIreast cancer from the NCDB.Figure 1 shows the stage distribution of 178,764 cases of

reast cancer accessioned into the NCDB for the year 2006including cases of in situ disease), revealing 9.1% diagnoseds stage III disease.4 If the 33,716 cases of stage 0 (in situ)ancers are excluded from consideration, 11.2% of Americanomen with invasive breast cancer were diagnosed with

tage III disease. SEER data show that 33% of Americanomen were diagnosed with regional stage disease in the year000.5 As noted previously, the frequency of regional stageisease will represent a notable overestimation of the propor-ion of cases presenting as true locally advanced, bulky breastancer. As shown in Figures 1 and 2 the proportion of breast

ith stage III disease (as per NCDB4) or regional/node-
osed w
ancers diagnosed as LABC is higher among younger women

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Epidemiology of locally advanced breast cancer 197

nd among racial-ethnic minorities (especially African Amer-cans).

urvivalEER data reveal 5-year survival rates of 98% for patientsith localized disease, 84% for patients with regional disease,

nd 27% for distant-stage disease at presentation. Outcomeased on size alone yields survival rates of 5-year survivalates of 94%, 80%, and 66% for patients with T1, T2, and T3umors at diagnosis, respectively. Combining size and nodaltatus through the TNM staging system provides the mostefined prognostic estimates: 95%, 85%, 70%, 52%, 48%,nd 18% for patients presenting with stage I, IIA, IIB, IIIA,IIB, and IV disease, respectively.6 Improvements in outcomeor LABC over the past few decades have primarily beenelated to both improvements in systemic treatments andnhanced control of locoregional disease because of multi-odality therapy, including the application of neoadjuvant

ystemic therapy and delivery of postsurgical locoregionaladiation therapy. Prospective randomized trials of neoadju-ant compared with adjuvant/postoperative chemotherapyave consistently revealed overall survival equivalence, butreoperative tumor downsizing clearly improves rates of re-ectability for cases of bulky chest wall disease and this se-uence also increases opportunities to offer successful breast-onserving surgery.7 Therefore, neoadjuvant chemotherapys now widely considered the standard of care for managingABC.Advances in our understanding of breast cancer subtypes,

ith the development of targeted therapy based on individ-al tumor markers is likely to be a more successful strategy inchieving increased overall survival for LABC patients. Themportance of individualized tumor profiling in planningystemic therapy is already apparent in studies of the

Figure 2 The proportion of breast cancer patients withirace/ethnicity from the NCDB.4

ncotypeDx Recurrence Score.8 This reverse transcriptase poly- c

erase chain reaction–based multigene assay stratifies the riskf distant recurrence in tamoxifen-treated patients withode-negative, estrogen receptor–positive breast cancer. It issed to determine the extent of benefit from endocrine ther-py alone versus endocrine therapy plus chemotherapy, andts predictive value is independent of primary tumor size.herefore, it is applicable in cases of T3 disease that previ-usly would have been considered LABC tumors and there-ore automatic candidates for chemotherapy on the basis ofrimary cancer size alone. Also, studies of trastuzumab ther-py to target HER2/neu-positive disease are now showing im-roved outcomes for these biologically aggressive cancers, evenhen they present as bulky LABC tumors.

ealth Care Disparitieshe frequency of LABC is largely dependent on the effective-ess of mammography screening programs. Before the im-lementation of breast cancer awareness and early detectionrograms, breast cancer presentation as LABC was common-lace. Surveillance mammography has resulted in dramatic

ncreases in the number of breast cancers diagnosed as in situisease or nonpalpable T1 or T2 tumors, with a correspond-

ng decrease in the proportion of women presenting withulky, locally advanced tumors. Selected population subsetsill be characterized by less effective breast cancer early de-

ection, such as women younger than age 40 years in whomcreening mammography is not routinely recommended andacial/ethnic minorities in whom socioeconomic disparitiesesult in barriers to accessing the health care system. Exam-les of differences in the stage distribution of breast cancer byge and racial/ethnic background are shown in Figures 1 andand Table 1. Approximately 12% of African American andispanic/Latina breast cancer patients are diagnosed with

tage III disease compared with only 8% of white American

ategories diagnosed with stage III disease stratified by
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ases. For women age 30 to 39 years diagnosed with breast

Table 1 Results of Selected Studies Comparing LABC in Racial/Ethnic Subsets of the United States Population

Study Dataset FeatureWhite

AmericansAfrican

AmericansHispanic

AmericansAm Ind/Alas

Nat Asian/PI

Chlebowski et al,9

2005WHI postmenopausal n 3455 242 103 11 88

Mean tumor size (cm) 1.56 1.60 1.89 1.64 1.95Proportion with T3 tumors 2% 2% 1% 0% 0%ER-negative (%) 13% 29% 17% 11% 13%Proportion with node-positive disease 22% 28% 27% 36% 22%Mortality hazard (95% confidence interval);

adjusted for age, BMI, and stage1.0 (Ref) 1.79 (1.05-3.05) NR NR NR

Hance et al,12

2005SEER, 1988-2000 N (number LABC cases analyzed) 2892 535 NR NR NR

Incidence rate for LABC (age-adjusted, per100,000 woman years)

2.1 3.8 NR NR NR

Breast cancer–specific median survivalfrom LABC

7.5 Years 3.1 Years NR NR NR

Joslyn et al,13

2005NAACCR, 1994-1998 N 363,801

Age-specific incidence rates for regionalstage disease (per 100,000 population)

40-44 41.82 47.65 33.91 NR 35.6945-49 66.67 71.18 51.96 45.15 53.1450-54 80.62 85.91 53.46 46.39 57.7055-59 89.02 93.25 57.50 58.39 69.5660-64 95.54 89.14 66.98 74.80 68.24

Li et al,33 2003 SEER, 1992-1998 N 97,999 10,560 7219 322 8834Proportion with stage III breast cancer 6.8% 11.0% 9.6% 10.9% 6.7%Proportion with T3 tumors 8.0% 15.0% 13.9% 11.5% 10.0%

NAACCR, North American association of central cancer Registries; WHI, Women’s Health Initiative; PI, Pacific Islander.

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ancer, 15% of white Americans are diagnosed with stage IIIisease, and this frequency increases to 18% and 19% forfrican American and Hispanic/Latina patients, respectively.ppropriate and standardized oversight of health care can

ower the frequency of LABC in women of all racial/ethnicackgrounds. This is shown by follow-up studies of thelosely monitored postmenopausal women participating inhe Women’s Health Initiative: of the breast cancers that wereiagnosed in these prospectively followed women; only 1%o 2% were detected as T3 tumors in the white American,frican American, and Hispanic American participants. Someace/ethnicity-associated disparities in breast tumor biologyersisted, however, with African American women still beingore likely to present with node-positive and estrogen recep-

or–negative disease.9

igh-Risk/LABCnd African American Women

ace/ethnicity-associated disparities in breast cancer burdenave been studied most extensively for African Americansompared with white Americans. Poverty rates and lack ofealth care insurance are the 2 metrics most commonly citeds a means of assessing socioeconomic status, and Africanmericans are notably overrepresented among both of theseisadvantaged communities. Twenty-four percent of the Af-ican American population live below the poverty level com-ared with 8% of the white American population; and 19% offrican Americans have no medical insurance compared with1% of white Americans (Fig. 3).10,11 These socioeconomic

nequities will clearly lead to delays in breast cancer diagnosiss well as appropriate and timely treatment.

Hance et al12 evaluated SEER-based trends in detectionnd outcome from inflammatory, locally advanced and non-ABC recently and reported interesting ethnicity/race-relatedatterns. Incidence rates for both inflammatory breast cancernd LABC were higher for African American compared withhite American women (3.1 v 2.2 per 100,000 for inflam-

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Figure 3 Proportions of impoverished and medicallytion.11,14,32 (Color version of figure is available online.)

atory disease and 3.8 v 2.1 per 100,000 for LABC). The r

frican American women with these high-risk breast cancerslso tended to be younger than their white American coun-erparts, and they had poorer survival rates.

African American women have been shown repeatedlyhrough single-institution, population-based, and multi-enter studies to present with more advanced stages of dis-ase. Recently, Joslyn et al13 reported findings from the Northmerican Association of Central Cancer Registries, showing

hat this statistically significant increased risk for more ad-anced stage disease is seen at nearly all age ranges for Africanmerican women. The lower frequency of early-stage disease

s consistent with suboptimal breast cancer screening prac-ices among African American women; however, data fromhe American Cancer Society, based on the National Healthnterview Study14 and others,15 have documented only mod-st magnitude differences in the use of mammographycreening between African American and white Americanomen (averaging at approximately 70% for white Ameri-

ans and 67% for African Americans). Other factors, such asccess to the health care system for diagnostic biopsy andreatment interventions, are probably also contributing tohese stage distribution differences. Gorin et al16 found thatfrican American breast cancer patients were more likely toxperience diagnostic as well as treatment delays when com-ared with all other racial-ethnic subsets of the Americanemale breast cancer population aged 65 and older. Thistudy was based on analysis of SEER and Medicare data.

Table 1 summarizes the results of several studies that haveompared stage distribution, hormone receptor status, andther tumor features among African American versus whitemerican breast cancer patients. The increased prevalence ofigh-grade, hormone receptor–negative disease is shownonsistently by various investigators. Anderson et al17 haveocumented lower population-based incidence rates ofstrogen receptor–positive disease for African Americanomen within all age deciles of life. Hance et al12 analyzedopulation-based incidence rates for estrogen receptor–posi-ive disease after stratifying by stage of disease. Incidence

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frican American women compared with white Americanomen regardless of age and regardless of whether the breast

ancer was diagnosed as early stage, LABC, or inflammatoryreast cancer. Furthermore, several studies have shown thatfrican Americans are also more likely to be diagnosed with

riple-negative breast cancer, tumors that lack expression ofhe estrogen receptor, the progesterone receptor, and theER2/neu marker. These studies are summarized in Table 2.Disentangling the confounding effects of breast cancer

ubtype, stage distribution, and socioeconomic status is crit-cal for investigations of race/ethnicity-related breast cancer

Figure 4 Meta-analysis of breast cancer survival studies isocioeconomic status, age, and stage at diagnosis. Pool(Mortality hazard � relative risk for mortality, Africapatients) from Newman et al.20 *Outcome data in Simon**Outcome data in Albain study stratified by menop

able 2 Frequency of Triple-Negative Breast Cancer in Africa

Study Dataset/Sample Size

arey et al,34 2006 97 Premenopausal AA v 164 premennon-AA women from Carolina BreaCancer Study

orris et al,35 2007 2230 Thomas Jefferson University Hpts and 197,274 SEER patients

und et al,36 2008 Population-based Atlanta, GA cohortAA, 360 WA cases

und et al,37 2008 167 AA and 23 WA cases from GradHospital; urban Atlanta, GA

oran et al,38 2008 99 AA and 968 WA breast conservatfrom Yale University School of Me

A, African American; WA, White American.

pausal.

isparities. Endocrine-resistant and triple-negative tumorsre biologically aggressive and will be more likely to presents LABC. Therefore, racial/ethnic ancestry associated withereditary susceptibility for high-risk breast cancer subtypesould account for the higher frequency of LABC observed infrican American women. By contrast, as noted previously,frican Americans are overrepresented among the impover-

shed in the United States, and socioeconomic deprivation isssociated with an increased risk of LABC because of inade-uate screening and delayed diagnoses. It has also been pos-ulated that poverty might somehow be an independent risk

an American and 2hite American patients adjusted forrtality hazard ratio � 1.27 (95% confidence interval).rican compared with White American breast cancerstratified by age less than 50 versus 50 years and older.tatus. Premen, premenopausal; postmen, postmeno-

rican Women

Frequency of Triple-Negative Breast Cancer

AfricanAmericans (%)

WhiteAmericans (%) P Value

al 39 (basal subtype) 16 (basal subtype) <.001

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actor for the development of estrogen receptor–negative dis-ase.18 However, NCDB data show persistently higher pro-ortions of estrogen receptor–negative tumors among Afri-an American women compared with white Americanomen, even after controlling for age, stage, and income

evel.19 Also, a meta-analysis by Newman et al20 involvingore than 15,000 African American breast cancer patients

nd more than 75,000 white American breast cancer patientshowed that African American race/ethnicity is an indepen-ent, adverse prognostic factor for breast cancer mortalityven after accounting for socioeconomic status (Fig. 4). Fur-hermore, international studies (in which the confoundingffects of African American race/ethnicity and socioeconomictatus are nonexistent) have shown no correlation betweenoverty versus affluence and frequency of estrogen receptor–egative breast cancer.21,22

nternational Patternss shown in Figure 5, countries that are less well developed

eg, many countries in Africa and Asia) tend to have relativelyow incidence and mortality rates for breast cancer. This di-

inished breast cancer burden is a consequence of severalactors including reproductive patterns that lower the life-ime estrogen exposure of mammary tissue (early and morerequent childbearing and prolonged lactation); competing

Figure 5 Age-standardized breast cancer incidence and m

ortality risks, especially from infectious causes; and lack of L

reast cancer documentation because of limited screening asell as biopsy capability. Scanty health care resources pre-

lude support for tumor registries, and so it is more difficulto accurately report the frequencies of LABC in these parts ofhe world. However, the limited breast cancer surveillanceesults in few screen-detected tumors and larger proportionsf advanced-stage disease with correspondingly higher mor-ality rates. Therefore, it is reasonable to resort to the use ofortality-to-incidence ratios as a proxy for estimating the

urden of LABC in countries that lack well-developed tumoregistry data. Figure 5 depicts the incidence and mortalityata estimated by the Globocan 2002 Database23 (which inurn is generated and maintained by the Descriptive Epide-iology Group of the International Agency for Research onancer) as well as the mortality-to-incidence ratios. These

atios are highest in the less developed nations of Africa andsia (where incidence rates are lowest, but the screening and

reatment opportunities are most limited), and they are low-st in westernized, industrialized nations (where breast can-er incidence is highest, but early detection and treatmentptions are most advanced).The limited reported data in the published literature on

reast cancer burden in populations of developing nationsave confirmed the higher proportions of cases presenting aslinically overt, non–screen-detected LABC. In most of thesetudies, the reported range of breast cancers presenting as

ty rates with corresponding mortality:incidence ratios.

ABC is 20% to more than one half of cases. This more

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dvanced breast cancer stage distribution has been docu-ented in underprivileged populations of Singapore,24 Egypt

nd Northern Africa,25,26 India,27 and sub-Saharan Africa.28,29

he Breast Health Global Initiative convened a meeting ofheir Global Initiative Systemic Therapy Focus Group in Oc-ober 2007 in which this extensive burden of LABC in devel-ping nations was discussed extensively. The group stressedhe fact that neoadjuvant chemotherapy is simply not feasibleor most LABC patients in developing countries because ofnancial constraints; proceeding to primary modified radicalastectomy is therefore the only option in these situations.30

he focus group also discussed the need to improve the avail-bility of efficient pathology laboratory resources becauseany facilities in underdeveloped countries are unable toerform basic molecular marker studies such as estrogen re-eptor, progesterone receptor, and HER2/Neu imunohisto-hemistry.

Changes in the breast cancer burden of “transitional” pop-lations within rapidly developing nations have been docu-ented by Fan et al31 based on their study of the population-

ased Shanghai Cancer Registry in China. This registry wasreated in 1963, and it has therefore chronicled the evolutionf breast cancer incidence and mortality among Chineseomen in Shanghai related to industrialization and adoptionf westernized child-bearing/reproductive patterns, imple-entation of breast cancer screening programs, and im-rovements in health care delivery systems. As expected,ge-adjusted breast cancer incidence rates have steadily risenn this population over the past several decades, from 17 per00,000 in 1975 to 40 per 100,000 in 2004. The proportionf cases presenting as LABC/stage III disease has steadilyeclined, from nearly 25% before 1990 to less than 10% in007. Other trends were identified over time in this study

ncluding increasing use of breast-conserving surgery, breasteconstruction, and adjuvant chemotherapy.

It is clear that global incidence rates for breast cancer areikely to increase progressively because the reproductive andietary lifestyles of industrialized societies are more widelydopted worldwide. Therefore, we have an obligation to ag-ressively expand mammography screening/early detectionnd multidisciplinary treatment programs so that breast can-er mortality rates do not rise disproportionately.

onclusionsreast cancer surveillance through screening mammographyrograms has been successful in achieving earlier detection ofisease and decreasing rates of LABC. Nonetheless, approx-

mately 10% of American breast cancer patients are diag-osed with LABC. Younger/premenopausal women and Af-ican Americans are more likely to present with LABCompared with older white American women. Underdevel-ped nations also have higher rates of LABC compared withndustrialized countries. When feasible, neoadjuvant chemo-herapy is the standard of care for managing LABC. Thistrategy improves rates of margin-negative resectability andreast conservation, but this multimodality treatment se-
uence has limited value in underdeveloped countries be-
ause of cost issues. Ongoing research of LABC will focus ontudies to disentangle the potential association between ra-ial-ethnic ancestry and susceptibility for high-risk disease,mprovements in targeted therapy so that the management ofABC can be tailored to match the individual tumor biology,nd international studies to improve screening and treatmentpportunities in populations of developing countries that arexperiencing increases in breast cancer incidence.

eferences1. Haagensen C, Stout A: Carcinoma of the breast II. Criteria of operabil-

ity. Ann Surg 118:859, 19432. Haagensen CD: Diseases of the Breast. Philadelphia, Saunders, 19563. Bonadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to

avoid mastectomy in tumors with diameters of three centimeters ormore. J Natl Cancer Inst 82:1539-1545, 1990

4. Benchmark Reports, V. 9.0. National Cancer Data Base, Commissionon Cancer, American College of Surgeons, 2009. Available at: http://www.facs.org/cancer/publicncdb.html. Accessed May 1, 2009

5. Ries L, Melbert D, Krapcho M, et al: SEER cancer statistics. ReView,1975-2005. Posted to SEER website. Available at: http://seer.cancer.gov/csr/1975_2005. Accessed May 1, 2009

6. American Cancer Society: Breast Cancer Facts and Figures 2007-2008.Atlanta, GA, American Cancer Society, Inc, 2009

7. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy inpatients with operable breast cancer: Nine-year results from nationalsurgical adjuvant breast and bowel project B18. J Natl Cancer InstMonogr 30:96-102, 2001

8. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence oftamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004

9. Chlebowski RT, Chen Z, Anderson GL, et al: Ethnicity and breastcancer: Factors influencing differences in incidence and outcome.J Natl Cancer Inst 97:439-448, 2005

0. Ward E, Jemal A, Cokkinides V, et al: Cancer disparities by race/eth-nicity and socioeconomic status. CA Cancer J Clin 54:78-93, 2004

1. US Census Bureau, Population Division: Population ProjectionsBranch, Maintained by Information and research services. Available at:http://www.census.gov/ipc/www/usinterimproj/. Accessed May 1,2009

2. Hance KW, Anderson WF, Devesa SS, et al: Trends in inflammatorybreast carcinoma incidence and survival: The Surveillance, Epidemiol-ogy and End Results Program at the National Cancer Institute. J NatlCancer Inst 97:966-975, 2005

3. Joslyn SA, Foote ML, Nasseri K, et al: Racial and ethnic disparities inbreast cancer rates by age: NAACCR breast cancer project. Breast Can-cer Res Treat 92:97-105, 2005

4. Ward E, Jemal A, Cokkinides V, et al: Cancer disparities by race/eth-nicity and socioeconomic status. CA Cancer J Clin 54:78-93, 2004

5. Clegg LX, Li FP, Hankey BF, et al: Cancer survival among US whitesand minorities: A SEER (surveillance, epidemiology, and end results)program population-based study. Arch Intern Med 162:1985-1993,2002

6. Gorin SS, Heck JE, Cheng B, et al: Delays in breast cancer diagnosis andtreatment by racial/ethnic group. Arch Intern Med 166:2244-2252,2006

7. Anderson WF, Chatterjee N, Ershler WB, et al: Estrogen receptor breastcancer phenotypes in the surveillance, epidemiology, and end resultsdatabase. Breast Cancer Res Treat 76:27-36, 2002

8. Thomson CS, Hole DJ, Twelves CJ, et al: Prognostic factors in womenwith breast cancer: Distribution by socioeconomic status and effect ondifferences in survival. J Epidemiol Community Health 55:308-315,2001

9. Lee MC, P-PLB, KI, et al: Increased Frequency Estrogen Receptor (ER)Negative and Aneuploid Breast Cancer in African American Women atAll Stages of Disease: First Analysis From the National Cancer Database.
New York, NY, Society of Surgical Oncology, 2007
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0. Newman LA, Griffith KA, Jatoi I, et al: Meta-analysis of survival inAfrican American and white American patients with breast cancer:Ethnicity compared with socioeconomic status. J Clin Oncol 24:1342-1349, 2006

1. Carnon AG, Ssemwogerere A, Lamont DW, et al: Relation betweensocioeconomic deprivation and pathological prognostic factors inwomen with breast cancer. BMJ 309:1054-1057, 1994

2. Halmin M, Bellocco R, Lagerlund M, et al: Long-term inequalities inbreast cancer survival—A ten year follow-up study of patients managedwithin a National Health Care System (Sweden). Acta Oncol 47:216-224, 2008

3. Globocan: International Agency for Research on Cancer. Available at:http://www.isradiology.org/education/globocan%202002%20database/view.htm. Accessed May 1, 2009

4. Tan EY, Wong HB, Ang BK, et al: Locally advanced and metastaticbreast cancer in a tertiary hospital. Ann Acad Med Singapore 34:595-601, 2005

5. Omar S, Khaled H, Gaafar R, et al: Breast cancer in Egypt: A review ofdisease presentation and detection strategies. East Mediterr Health J9:448-463, 2003

6. El Saghir NS, Khalil MK, Eid T, et al: Trends in epidemiology andmanagement of breast cancer in developing Arab countries: A literatureand registry analysis. Int J Surg 5:225-233, 2007

7. Agarwal G, Pradeep PV, Aggarwal V, et al: Spectrum of breast cancer inAsian women. World J Surg 31:1031-1040, 2007

8. Bird PA, Hill AG, Houssami N: Poor hormone receptor expression inEast African breast cancer: Evidence of a biologically different disease?Ann Surg Oncol 15:1983-1988, 2008

9. Fregene A, Newman LA: Breast cancer in sub-Saharan Africa: How does

it relate to breast cancer in African-American women? Cancer103:1540-1550, 2005

0. El Saghir NS, Eniu A, Carlson RW, et al: Locally advanced breast cancer:Treatment guideline implementation with particular attention to low- andmiddle-income countries. Cancer 113:2315-2324, 2008 (suppl)

1. Fan L, Zheng Y, Yu KD, et al: Breast cancer in a transitional society over18 years: Trends and present status in Shanghai, China. Breast CancerRes Treat 2009 [Epub ahead of print]

2. US Census Bureau: Current population survey, 2002-04. Annual Socialand Economic Supplements, Washington, D. C., 2004

3. Li CI, Malone KE, Daling JR: Differences in breast cancer stage, treat-ment, and survival by race and ethnicity. Arch Intern Med 163:49-56,2003

4. Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, andsurvival in the Carolina breast cancer study. J Am Med Assoc 295:2492-2502, 2006

5. Morris GJ, Naidu S, Topham AK, et al: Differences in breast carcinomacharacteristics in newly diagnosed African-American and Caucasianpatients: A single-institution compilation compared with the NationalCancer Institute’s surveillance, epidemiology, and end results database.Cancer 110:876-884, 2007

6. Lund MJ, Trivers KF, Porter PL, et al: Race and triple negative threats tobreast cancer survival: A population-based study in Atlanta, Ga. BreastCancer Res Treat 113:357-370, 2009

7. Lund MJ, Butler EN, Bumpers HL, et al: High prevalence of triple-negative tumors in an urban cancer center. Cancer 113:608-615, 2008

8. Moran MS, Yang Q, Harris LN, et al: Long-term outcomes and clinico-pathologic differences of African-American versus white patientstreated with breast conservation therapy for early-stage breast cancer.
Cancer 113:2565-2574, 2008
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reast Cancer Molecular Subtypes in Patients Withocally Advanced Disease: Impact on Prognosis,atterns of Recurrence, and Response to Therapy

athryn E. Huber, MD, PhD,*,† Lisa A. Carey, MD,‡ and David E. Wazer, MD*,†

Gene expression profiling has led to the discovery of 4 distinct molecular subtypes ofbreast cancer: luminal A, luminal B, basal like, and HER2 enriched. Investigation of thesesubtypes in women with breast cancer has given insight into the heterogeneous biologyand outcomes in patients with locally advanced disease. These subtypes have been foundto be predictors for survival, response to systemic therapy, and locoregional recurrence.This review discusses the biology of locally advanced breast cancer and the available dataon how molecular subtype may provide information regarding response to treatment andprognosis of women with locally advanced breast cancer.Semin Radiat Oncol 19:204-210 © 2009 Elsevier Inc. All rights reserved.

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ocally advanced breast cancer (LABC) is a diverse diseasethat includes a wide range of clinical presentations, in-

luding advanced primary tumors or extensive regionalodal involvement without systemic metastasis. An elderlyoman whose breast cancer has become inoperable afterears of neglect as well as a young woman with rapidly grow-ng, aggressive breast cancer that developed between her an-ual screening mammograms would both be described asaving locally advanced disease. However, even though theyoth represent LABC, these 2 scenarios show divergent bio-

ogical processes. The elderly woman in the first scenario mayave a biologically indolent tumor that is characterized byesponsiveness to hormonal treatment, high estrogen recep-or (ER) expression, low grade, and a low proliferative index.1

n contrast, the young woman who presented with locallydvanced disease within the interval of time between annualcreening is more likely to have an ER-negative, high-gradeumor with a high proliferative index. Despite the fact thathey both present with locally advanced disease, the biologyf their breast cancer will confer strikingly dissimilar prog-

Department of Radiation Oncology, Tufts University School of Medicineand Tufts Medical Center, Boston, MA.

Rhode Island Hospital, Brown University School of Medicine, Providence,RI.

Department of Medicine, Division of Hematology/Oncology, LinebergerComprehensive Cancer Center, University of North Carolina, ChapelHill, NC.

ddress reprint requests to Kathryn E. Huber, MD, PhD, Department ofRadiation Oncology, Tufts Medical Center, 800 Washington Street, Box

s359, Boston, MA 02111. E-mail: [email protected]

04 1053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved.doi:10.1016/j.semradonc.2009.05.004

oses. The elucidation of the mechanisms of these biologicalifferences is the focus of considerable ongoing investigation.Inferior access or use of breast cancer screening can lead topostponement in the detection of a breast tumor until it

ecomes symptomatic, which increases the likelihood that itill be locally advanced at the time of diagnosis. The wide-

pread use of screening mammography resulted in an initialise in breast cancer incidence with a proportional decreasen the amount of LABC diagnosed, although the number ofABC cases remained fairly constant. Recent trends in breastancer in the United States have shown a decline in overallreast cancer incidence starting in the year 2000; however,he rate of patients with larger tumors at the time of diagnosisas not shown the same effect.2,3 These observations mightuggest that there is a biologically distinct subset of tumorshat either have a rapid growth rate allowing them to becomearge tumors in the interval between screening mammogra-hy or have radiographic characteristics that limit earlier de-ection.4-6 In addition, hormone receptor (HR)-negativereast cancer is disproportionately overrepresented in inter-al tumors diagnosed outside of screening, highlighting thatumor biology may limit the impact of screening in someubtypes.7,8

Inflammatory breast cancer (IBC) is an aggressive subset ofABC that is clinically defined by its rapid onset of symptoms

ncluding breast edema, erythema, warmth, and induration.atients with IBC have a worse clinical outcome compared totage-matched noninflammatory LABC.9 Biological charac-eristics of IBC include high nuclear grade, lower ER expres-
ion, and higher expression of markers associated with ag-

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Breast cancer molecular subtypes 205

ressive pathology, such as p53, HER2 epidermal growthactor receptor, and RhoC GTPase.10,11 Although consideredform of LABC, IBC appears to have distinct biology, witharked dysregulation of growth pathways, cellular adhesion,

nd interaction molecules. However, IBCs are still quite het-rogeneous and can be distinguished by the same molecularubtypes that have been defined in non-IBC.12,13 A detailedescription of IBC is comprehensively covered in anothereview in this issue of Seminars in Radiation Oncology.

The advent of genomic technology has allowed for molec-lar analysis of breast cancers, showing that the molecularrofiles of the tumors from the 2 patients discussed previ-usly are likely to be quite different from one another. Theumor’s molecular “fingerprint” may have within it informa-ion regarding prognosis and response to therapy that willelp us better treat LABC. The goal of this review was toiscuss LABC from the standpoint of molecular subtyping,ith regard to its diversity in prognosis and response to ther-

py.

eterogeneity of Breast Cancerreast cancer is a heterogeneous collection of diseases witharious histologically defined subsets, clinical presentations,esponses to treatment, and outcomes. Several clinical andistologic factors have prognostic value, such as the presencend extent of lymph node metastasis, age at diagnosis, tumorrade and histology, and size of the primary tumor. The ear-iest observations of the heterogeneity of breast tumors led to theistopathologic classification of these tumors based on theirorphologic features. Currently, 15 distinct histopathologic

orms of breast cancer are recognized by the American Jointommittee on Cancer.14 A few of these subsets are associatedenerally with favorable (pure tubular or medullary) or un-avorable (metaplastic or undifferentiated) prognoses; how-ver, most of the histologic forms have considerable variationn their behavior. In addition, the development of LABC doesot correlate with a particular histologic subtype and mostABCs, like most non-LABC primary breast cancers, are in-asive ductal and/or lobular cancers. Further characteriza-ion of microscopic cellular heterogeneity in breast cancer,uch as nuclear pleomorphism, tubule formation, and mi-otic index, has led to widely used tumor grading systemshat show a strong correlation with prognosis.15 However,lthough LABC can be associated with high grade, this asso-iation is not consistent. The limitations in the prognosticalue of these clinical and microscopic variables have drivenhe exploration of the molecular diversity of this disease withhe anticipation that it will help identify patients with poorrognosis and lead to the development of novel treatmentshat will target the specific aberrant biology of their cancer.

The first molecular distinction made in breast cancer wasrom the work in the 1960s and 1970s that identified andharacterized estrogen and progesterone receptor expressionn breast cancer cells. This discovery quickly led to the de-elopment of antiestrogen therapies. Responsiveness of theumor to hormonal therapy correlated directly with receptor
xpression and identified an important biological subdivi- s
ion within breast cancer: those that were ER-positive andespond to antiestrogens and those that are ER-negative andre refractory to hormonal manipulation.16 This crucial bio-ogical distinction is mirrored in noninflammatory LABC;eglected disease is more likely to be ER-positive, whereashe more aggressive forms of LABC are more likely to beR-negative. Another biologically distinct subset of breastancer was discovered by novel work investigating the am-lification of the HER2/neu oncogene in breast cancer.17 Thenalysis of 189 primary breast tumors showed that the am-lification of the HER2/neu oncogene occurred in 25% to0% of the specimens and that this genomic alteration pre-icted poor clinical outcome, even after adjustment for otherrognostic variables. Similar to the earlier breakthrough in-estigations of HRs in breast cancer, this finding led to theevelopment of targeted therapy and has had a significant

mpact on the outcome of women with HER2 overexpressingumors.18,19

olecularubtypes of Breast Cancer

ene expression profiling, which examines the relative ex-ression of thousands of genes in a single sample simulta-eously, led to the discovery of distinct molecular subtypesithin breast cancer.20 These molecular subtypes have phe-otypic diversity with regard to multiple clinical outcomes,

ncluding response to treatment, disease-free survival, andverall survival. Multiple datasets have confirmed these mo-ecular breast cancer subtypes, which include (1) at least 2uminal subtypes (luminal A and B) that comprise most ER-ositive breast cancer and are characterized by a high expres-ion of HR-related genes; (2) the basal-like subtype, whichs characterized by a high expression of a unique “basal”ignature that includes genes common to the breast myoepi-helium, high expression of proliferation genes, and low ex-ression of the ER signature and HER2 signatures; and (3) theER2-enriched subtype, which is typified by high expressionf HER2-related and proliferation genes and low expressionf HR-related genes.21-23 Another subtype, the normal breastubtype, has expression patterns similar to nonmalignant tis-ue and may be a sampling artifact.

Survival analysis performed using the data from the 49atients with locally advanced disease determined that thereas a significant difference in overall survival among theolecular subtypes.21 The basal-like and HER2-enriched

ubtypes showed the poorest prognosis with both shorterime to progression and overall survival. Patients belongingo the luminal A subtype had a considerably better prognosisompared with all groups, and the luminal B subtype had anntermediate outcome. The luminal subtypes are the mosteterogeneous with regard to biology and outcomes.20-23 Lu-inal A tumors have variable proliferation gene expression

nd also have highly variable prognostic signatures.24 Lumi-al B tumors, although still expressing the HR-related gene
ignature, do so at a lower level, have variable expression of

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206 K.E. Huber, L.A. Carey, and D.E. Wazer

he HER2 signature, and are generally more proliferative thanhe luminal A subtype. In multiple datasets, patients withuminal B tumors have worse outcome compared with lumi-al A tumors, despite both usually being ER-positive.Because of the technical limitations of performing microar-

ay expression analysis on formalin fixed, paraffin-embeddedissue, the use of the ER, HER2, and cytokeratin immunohis-ochemical (IHC) markers has been used as a surrogate to theolecular subtypes. The marker combinations that bestatched the molecular profiles segregated the tumors into 4

roups: (1) ER� and/or PR�, HER2� for luminal A subtype;2) ER� and/or PR�, HER2� for luminal B subtype (al-hough this is known to misclassify a significant proportion);3) ER�, PR�, HER2�, cytokeratin 5/6�, and/or EGFR�or basal-like subtype; and (4) ER�, PR�, and HER2� forhe HER2-enriched subtype.25,26 Of course, the major limita-ion to this simplification is that the prognostic power of theubtypes is based on a complex gene expression signaturend that these molecular profiles are only associated withhese protein markers and not synonymous. In fact, the mo-ecular profiles have been found to have a more robust pre-ictive value compared with the surrogate markers.27 However,he correlation between the molecular subtypes and thesearker combinations is reasonable, and their proxy use has

llowed for the analysis of large datasets and the discovery ofmportant aspects of the biology of these tumor subtypes. Inhe future, it is likely that RT-PCR–based approaches, such ashe recently developed PAM50 assay, which can measure aet of 50 intrinsic genes from formalin-fixed, paraffin-embed-ed tissue, will permit additional molecular subtyping inrchival specimens.28

A large population-based study using the IHC surrogatearkers for molecular subtype examined the association ofolecular subtype with clinical characteristics and found

hat the luminal A, luminal B, basal-like, and HER2-enrichedubtypes differed significantly by age, race, menopausal sta-us, lymph node involvement, histology group, tumor grade,nd mitotic index.25 The most striking distinction was theverrepresentation of basal-like tumors in premenopausallack women (39% in premenopausal black women v 14% inostmenopausal black women and 16% in nonblack womenf all ages, P � .001). Subsequent studies have confirmedhat basal-like tumors are more frequent in younger patientsnd blacks.29,30 In addition patients with basal-like tumorsended to have aggressive features including high nuclearrade, high mitotic index, and unfavorable histology (meta-lastic, anaplastic, or undifferentiated high-grade carcino-as). Paradoxically, this subtype was not associated withigher regional lymph node involvement. More recent anal-ses have provided supporting evidence for the decreasedrevalence of lymph node metastasis in basal-like tumors andave shown a disconnect between tumor size and positive

ymph nodes in this subtype.31,32 This finding suggests a dif-erence in mechanisms of metastasis between luminal andasal tumors and highlights that these breast cancer molec-
lar subtypes are distinct biological entities. s
ow Biology Mayffect Treatment Outcome

multidisciplinary approach to the treatment of LABC withcombination of systemic therapy, surgery, and radiation hasesulted in improved survival. Before the routine use of che-otherapy, 5-year survival was approximately 25% in pa-

ients with locally advanced disease.33 Combined modalityreatment now yields 5-year rates of survival in operable stageIIA patients and inoperable stage IIIB patients of 80% and5%, respectively.33 However, patients who present withtage III disease with identical clinical predictors of prognosisontinue to have quite variable outcomes such that manyatients develop rapid disease progression despite contem-orary multimodal management. The discovery that there areistinct molecularly defined subtypes of breast cancer hasiven insight into the heterogeneous outcome in patientsith LABC and has prompted continued efforts in identifyingredictors of both response to treatment and survival basedn the tumor’s molecular profile.The frequent use of preoperative chemotherapy as part

f the management of LABC has provided a unique opportu-ity to investigate the molecular mechanisms of tumor re-ponse to therapy. A number of studies have explored theffect of molecular subtype on both response to treatmentnd survival in patients with LABC.12,34-41 Although subtypeas identified by using various methodologies, these inves-

igations have consistently shown that the rate of pathologicomplete response (pCR) differs considerably among the mo-ecular subtypes (Table 1). The luminal A subtype had a veryow rate of pCR in patients treated with a variety of preoper-tive chemotherapy regimens. In contrast, there was a highate of pCR seen with the basal-like and HER2-enriched sub-ypes. The luminal B subtype was associated with an inter-ediate rate of response. Interestingly, 2 studies included theormal breast subtype in their analysis and found that nonef the patients who were in this subset achieved a pCR; how-ver, this finding is limited by the small sample size (collec-ive n � 16).34,35

At first glance, the inferior survival of patients withasal-like and HER2-enriched tumors appears to stand inontrast with the high rate of pCR observed in these patientsecause achieving pCR has been shown to be associated with

mproved overall survival.42,43 However, patients who haveCR have superior survival regardless of their sub-

ype.36,38,44 The unfavorable outcomes observed in the basal-ike and HER2-enriched subtypes were caused by a higherrequency of relapse or death in those who did not achieve aCR with preoperative chemotherapy.36,44 Interestingly,rior work has shown that a lower expression of HR-relatedenes and a higher expression of proliferation-related genes,imilar to those that define the basal-like subtype, are asso-iated with a higher pCR rate.45 Therefore, increased prolif-ration may be a double-edged sword, where rapidly divid-ng cells leads to increased response to chemotherapy butlso may increase their capacity for recurrence and metasta-
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The impact of molecular subtype on the response to post-astectomy radiation was recently investigated using data

rom 1,000 patients enrolled in the large Danish postmastec-omy radiation trials DBCG82 b and c.46 These patients hadlinical features associated with an increased risk of localecurrence and had been randomized to either receive or noteceive postmastectomy radiation. High-risk features in-luded large primary tumors (�5 cm), positive lymph nodes,r invasion of the primary tumor to the adjacent skin orectoral fascia. The IHC surrogate markers were used forolecular subtype classification. In this study, basal-like

HR�/HER2�) and HER2-enriched (HR�/HER2�) sub-ypes showed a lower reduction in local recurrence fromostmastectomy radiation compared with the luminal sub-ypes (Table 2). This finding may suggest radioresistance inhe poor prognosis subtypes in contrast to the relative radio-ensitivity of luminal subtypes. An alternative explanation forhe increased rate of local recurrence could be related tohe intrinsic aggressiveness of the surviving cells from bas-l-like and HER2-enriched tumors. However, this is dis-uted by the finding that the de novo probability for localecurrence among the patients not receiving postmastec-omy radiation was fairly similar among the IHC-basedolecular subtypes (Table 2).46

Evidence supporting the effect of molecular subtype onocal recurrence is seen in the Harvard analysis of 793 womenreated with breast-conservation surgery followed by radia-ion.47 They showed a significant increase in 5-year localecurrence as the first event in the basal-like (HR�/HER2�)nd HER2-enriched (HR�/HER2�) subgroups (7.1% and

able 1 Effect of Breast Cancer Molecular Subtype on Rate o

PreoperativeRegimen N

LuminalA (%)

LuminalB (%)

AC 82 6 NDAC 50 9 NDAC 107 0 15BC, TAC 68 13 25BC, TBC, or TAC 1,731 6 15BC 21 27 ND, A, or TAC 100 3 33AC � Tr 127 5 ND

bbreviations: TBC, taxane-based chemotherapy; ABC, anthracycchemotherapy; T, taxane single therapy; A, anthracycline single

Immunohistochemistry measuring ER, PR, and HER2 expression wData from patients with IBC.

able 2 15-Year Overall Survival and Locoregional Recurrence

15 Years O

RT (%) No RT (%

uminal A (n � 628) 44 33uminal B (n � 96) 38 15asal like (n � 152) 39 32ER2 enriched (n � 120) 17 28

bbreviations: RT, radiotherapy; OS, overall survival; LRR, locoregi
ata from Kyndi et al.46
.4%, respectively) compared with the luminal A (HR�/ER2�) and luminal B (HR�/HER2�) subgroups (0.8%

nd 1.5%, respectively). However, the difference in local re-urrence could in part be caused by differences in systemicreatment in these subgroups. When the patients with HR�umors were given hormonal therapy, none of the HER2�atients in this study received trastuzumab, and there is nourrently targeted treatment available for basal-like tumors.rior reports have not detected an increase in ipsilateral breastecurrence for basal-like, triple receptor-negative breast can-er treated with breast conservation and whole-breast irradi-tion.7,48 However, a few distinctions can be made betweenhese reports and the Harvard study. First, the overall rate ofocal recurrence was much higher in the earlier studies (13%or Dent et al,7 17% for Haffty et al48 v 1.8% Nguyen et al47).econd, the earlier studies used IHC alone for HER2 classifi-ation, whereas the latter study required HER2 gene ampli-cation in tumors with intermediate HER2 expression toualify as HER2�, likely resulting in a reduced rate of mis-lassification. In addition, the earlier studies compared tri-le-negative tumors to all others, opposed to determining theecurrence rate in each of the 4 subtypes. The inclusion ofER2� tumors in the “other” subset could have diminished

he difference between the molecular subtypes. Despite theifferences in the findings on local recurrence among theseeports, all showed an increase in the rate of distant metasta-is and decreased overall survival of the patients with basal-ike tumors.

Interestingly, the patterns of metastatic disease seem toary among the molecular subtypes.49-52 The luminal A pa-

to Preoperative Chemotherapy

Basalike (%)

HER2Enriched (%) P References

45 45 .026 3410 46 .024 3527 36 .01 3657 62 <.0001 37*22 29 <.0001 38*80 20 .08 12†39 36 <.01 39*58 40 <.001 40*

ased chemotherapy; TAC, taxane and anthracycline combinationy; Tr, trastuzamab; ND, not determined.ed as surrogates for molecular subtype classification.

Function of Breast Cancer Molecular Subtype and Radiation

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ients who develop metastatic disease have a significantlyigher portion of bone relapse in contrast to those with theasal-like subtype who have a predominance of visceral sitesf metastases. These findings again support that these sub-ypes are distinct biological variants of breast cancer thatredispose these patients to a particular outcome. HER2-verexpressing tumors have been found to have a predilec-ion for metastasis to the brain52 as have basal-like (or triple-egative) tumors.50 The comparison of HER2-overexpressingreast cancer patients to HER2-negative patients showed a.5-fold increase in the incidence of developing brain metas-asis (P � .0001). It is possible that this effect is caused by theack of penetration of trastuzumab through the blood–brainarrier. Alternatively, this pattern of recurrence may be causedy a biological distinct phenotype that leads to homing andenetration of the central nervous system, as is suggested byhe studies noting other site-specific tropisms. Interestingly,his study also showed a protective effect of ER-positive tu-ors for brain metastasis, suggesting that the ER-positive

ubset of tumors lack the biological property that promoteshis process. These observations merit further investigationor the monitoring of central nervous system metastasis inatients with the HER2-enriched or basal-like subtypes anderhaps the development of treatments that can cross thelood–brain barrier.

ow Biology Mayffect Locoregionalreatment Decisions

ata from the Danish Breast Cancer Cooperative Group show-ng that patients with basal-like and HER2-enriched subtypeumors had an appreciably lower benefit from postmastec-omy radiation suggests that information regarding molecu-ar subtype may one day assist in the assessment as tohether a patient should receive postmastectomy radia-

ion.46 The survival benefit from postmastectomy radiationbserved in this randomized study was limited to the luminalsubtype (HR � .78, P � .009). The patients with luminal B

ubtype had a trend toward improved survival associatedith radiation, but this did not reach statistical significance

HR � .65, P � .07). The basal-like subtype displayed annferior local control benefit compared with the luminal sub-ypes, and there was no detectable survival benefit from ra-iation (HR � .85, P � .4). Of note, there was a trend towardsurvival deficit with radiation therapy in the HER2-en-

iched subgroup (HR � 1.35, P � .14). Definitive conclu-ions as to the relative effect of radiation therapy in this con-ext are limited by the retrospective nature of the study. Inddition, because of the natural distribution of the molecularubtypes, there were fewer patients with luminal B, basal-ike, and HER2-enriched tumors for analysis (luminal A 63%,uminal B-10%, basal-like 15%, and HER2 enriched 12%),

aking it less likely that a survival difference would haveeen detected in the less common subtypes. However, theseata call into question whether standard delivery of PMRT is
ufficient for locoregional control in LABC patients with d
asal-like or HER2-enriched tumors and argues for the in-estigation of strategies for improved local control in theseatients (eg, dose escalation or radiosensitization).The finding that HR-negative/HER2� tumors may have a

iminished benefit from postmastectomy radiation may in-icate a relative radioresistance of this subtype. Preclinicalata support the hypothesis of HER2 overexpression relatingo radioresistance; however, clinical data to support this ob-ervation are limited.53,54 A retrospective analysis of 108 pa-ients treated with neoadjuvant chemotherapy, mastectomy,nd postmastectomy radiation did not reveal an excess ofocal failure in patients with HER2� disease.55 In addition, inhe molecular subtype analysis of the Danish postmastec-omy radiation trials, HER2 status alone did not predict forither local recurrence probability or the relative benefit ofadiation.46 It was the combination of HR negativity andER2 overexpression that was associated with a lack of ben-

fit from radiation in this study. The probability of localecurrence after postmastectomy radiation in patients withhe HER2-enriched molecular subtype merits further inves-igation. In addition, HER2-targeted therapy with trastu-umab, which has become a standard therapy for HER2�atients, may alter the sensitivity of this molecular subtype toadiation resulting in improved local control.

The frequent use of neoadjuvant chemotherapy has led ton increase in the number of women with locally advancedisease who are candidates for breast conservation. There-ore, the effect of molecular subtype on local recurrence inatients who choose to have breast conservation may be ofarticular importance in this high-risk subgroup. The find-

ngs by Nguyen et al47 showed that the basal-like and HER-nriched subtypes are associated with significantly higherates of local recurrence in the intact breast after partial mas-ectomy and whole-breast irradiation. Patients with locallydvanced disease made up a very small proportion of theohort (approximately 6%) in this study. Likewise, the ratesf local recurrence were quite low, with the high-risk basalnd HER2 subtype local recurrence rates under 10% at 5ears. However, the incidence of local recurrence in patientsith the basal-like and HER2-enriched subtype with LABCho have breast conservation and whether molecular sub-

ype alters the rate of in-breast recurrence in these patientsre yet to be determined.

uture Directionsdvances in the use of cytotoxic chemotherapy have played aubstantive role in the improved outcome seen in patientsith LABC. In addition, hormonal therapy and HER2-tar-eted agents have become key components to adjuvant ther-py in patients with tumors expressing these markers. How-ver, the lack of targeted therapy for the basal-like subtypeas clearly defined the need for the development of novelgents directed against the aberrant biology of this subtype.hese tumors have a robust response to anthracycline- and

axane-based chemotherapies but are subsequently associ-ted with an unacceptable rate of relapse, high incidence of
istant metastasis, and poor overall survival. Gene analysis

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as identified several abnormal processes within basal-likeumors that may serve as therapeutic targets including abnor-al DNA repair, increased proliferation, loss of PTEN, and

GFR and c-KIT overexpression. The clinical data for theffectiveness of these target-specific therapies are still limited,ut advances in the understanding of the heterogeneous bi-logy of breast cancer are giving clear direction for futureesearch.

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7. Sørlie T: Molecular portraits of breast cancer: Tumor subtypes as dis-tinct disease entities. Eur J Cancer 40:2667-2675, 2004

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1. Crabb SJ, Cheang MC, Leung S, et al: Basal breast cancer molecularsubtype predicts for lower incidence of axillary lymph node metastasesin primary breast cancer. Clin Breast Cancer 8:249-256, 2008

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4. Rouzier R, Perou CM, Symmans WF, et al: Breast cancer molecularsubtypes respond differently to preoperative chemotherapy. Clin Can-cer Res 11:5678-5685, 2005

5. Rody A, Karn T, Solbach C, et al: The erbB2� cluster of the intrinsicgene set predicts tumor response of breast cancer patients receivingneoadjuvant chemotherapy with docetaxel, doxorubicin and cyclo-phosphamide within the GEPARTRIO trial. Breast 16:235-240, 2007

6. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Pri-mary tumor chemosensitivity of breast cancer subtypes. Clin CancerRes 13:2329-2334, 2007

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0. Sânchez-Muñoz A, García-Tapiador AM, Martínez-Ortega E, et al: Tu-mour molecular subtyping according to hormone receptors and HER2status defines different pathological complete response to neoadjuvantchemotherapy in patients with locally advanced breast cancer. ClinTrans Oncol 10:646-653, 2008

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4. Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapyand long-term survival in patients with triple-negative breast cancer.J Clin Oncol 26:1275-1281, 2008

5. Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in par-affin-embedded core biopsy tissue predict response to chemotherapy inwomen with locally advanced breast cancer. J Clin Oncol 23:7265-7277, 2005

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7. Nguyen PL, Taghian AG, Katz MS, et al: Breast cancer subtype approx-imated by estrogen receptor, progesterone receptor, and Her-2 is asso-ciated with local and distant recurrence after breast-conserving ther-apy. J Clin Oncol 26:2373-2378, 2008

8. Haffty BG, Yang Q, Reiss M, et al: Locoregional relapse and distantmetastasis in conservatively managed triple negative early-stage breast
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1. Smid M, Wang Y, Zhang Y, et al: Subtypes of breast cancer showpreferential site of relapse. Cancer Res 68:3108-3114, 2008

2. Gabos Z, Sinha R, Hanson J, et al: Prognostic significance of humanepidermal growth factor receptor positivity for the development ofbrain metastasis after newly diagnosed breast cancer. J Clin Oncol24:5658-5663, 2006

3. Liang K, Lu Y, Jin W, et al: Sensitization of breast cancer cells toradiation by trastuzumab. Mol Cancer Ther 2:1113-1120, 2003

4. Pietras RJ, Poen JC, Gallardo D, et al: Monoclonal antibody to Her-2/neureceptor modulates repair of radiation-induced DNA damage andenhances radiosensitivity of human breast cancer cells overexpressingthis oncogene. Cancer Res 59:1347-1355, 1999

5. Buchholz TA, Huang EH, Berry D, et al: HER2/neu-positive diseasedoes not increase risk of locoregional recurrence for patients trea-ted with neoadjuvant doxorubicin-based chemotherapy, mastec-tomy, and radiotherapy. Int J Radiat Oncol Biol Phys 59:1337-
1342, 2004

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orkup and Staging ofocally Advanced Breast Cancerary J. Whitman, MD,* and Eric A. Strom, MD†

This article reviews current approaches for workup and staging in patients with locallyadvanced breast cancer (LABC). Careful clinical examination and detailed imaging arediscussed to accurately classify the extent of local, regional, and distant disease. Mostpatients with LABC receive neoadjuvant chemotherapy as initial treatment, and, in suchpatients, it is critical to accurately delineate the initial extent of disease because the initialclinical stage affects subsequent local-regional treatment decisions. Emphasis is placed onsonography, which is used extensively at the University of Texas M. D. Anderson CancerCenter for regional lymph node staging. Other modalities discussed in this article includemammography, magnetic resonance imaging, positron emission tomography (PET), andPET/computed tomography (CT). Conventional imaging (chest radiography, bone scan, andabdominal CT scans) techniques used in the evaluation of possible metastatic disease arediscussed. In addition, the role of sentinel lymph node mapping in LABC patients isreviewed.Semin Radiat Oncol 19:211-221 © 2009 Elsevier Inc. All rights reserved.

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espite recent advances in screening mammography, lo-cally advanced breast cancer (LABC) remains a chal-

enging clinical problem. LABC, which includes all patientsith stage III disease, constitutes approximately 20% ofewly diagnosed breast cancers. LABC encompasses ad-anced primary tumors (T3 and T4); advanced lymph nodeisease, including fixed axillary lymph nodes and/or involve-ent of the ipsilateral supraclavicular, infraclavicular, or in-

ernal mammary lymph nodes (N2 and N3); and the un-ommon inflammatory breast carcinoma (IBC) variant.1,2

omen with LABC require careful, comprehensive workupnd staging evaluations to accurately depict the extent ofisease. Furthermore, workup and staging should be per-ormed in a detailed manner before the initiation of multimo-al treatment. Most patients with LABC are treated with neo-djuvant chemotherapy, which changes the pathologicxtent of disease in most patients. For such patients, thenitial extent of disease, defined by clinical examination andmaging studies, is a critical determinant of subsequent local-egional therapeutic decisions. Therefore, it is imperative that

Division of Diagnostic Imaging, The University of Texas M. D. AndersonCancer Center, Houston, TX.

Division of Radiation Oncology, The University of Texas M. D. AndersonCancer Center, Houston, TX.

ddress reprint requests to Gary J. Whitman, MD, Division of DiagnosticImaging, The University of Texas M. D. Anderson Cancer Center,Unit 1350, PO Box 301439, Houston, TX 77230-1439. E-mail:

[email protected]

053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.semradonc.2009.05.006

ll patients with LABC undergo appropriate staging studiesnd have an assignment of a clinical TNM stage before thetart of treatment. In addition, prognosis depends on tumorize, lymph node involvement, and the presence or absencef an inflammatory component at the time of initial presen-ation.

In this article, initial staging recommendations are re-iewed for evaluation of the breast, the regional lymph nodes,nd distant sites, including the roles of mammography,onography, magnetic resonance imaging (MRI), positronmission tomography (PET), and PET/computed tomogra-hy (CT). Accurate clinical staging is reviewed along withultidisciplinary assessment and treatment planning. In ad-ition, placement of marker clips in the tumor bed before

nitiating systemic therapy is discussed.

linical Examinationhe prognoses for women with LABC depend on tumor size,

he extent of regional lymph node involvement, and the pres-nce or absence of inflammatory signs.1 Clinical examinationy experienced practitioners can be helpful in estimatingumor size and confirming or excluding inflammatory fea-ures such as diffuse erythema, peau d’orange, warmth, ten-erness, breast enlargement, and diffuse induration.3,4 Also,linical examination can identify markedly enlarged axillarynd supraclavicular lymph nodes. Smaller lymph nodes and
ymph nodes in the infraclavicular and the internal mammary
211


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212 G.J. Whitman and E.A. Strom

egions are usually identified with imaging, especially ononography.

A multidisciplinary approach is suggested in women withABC because optimal therapy involves multiple modalities.5

ABC patients are usually treated with neoadjuvant chemo-herapy followed by surgery and radiation therapy.6 Multi-isciplinary involvement may be helpful in selecting certainubsets of LABC patients. For example, several clinicians in aultidisciplinary setting may select women with large tu-ors or with limited skin involvement who may be eligible

or breast conservation therapy after initial chemotherapy.7

linical experience and limited outcome data suggest thatven with a good response to neoadjuvant chemotherapy,reast conservation is contraindicated in patients with IBC.6

ammographyammography is usually the first imaging test performed

fter clinical examination. Mammography is used to estimateumor size, and mammography is more accurate in womenith fatty mammary parenchyma compared with those withense breast tissue.8 Mammography is the best test for iden-ifying microcalcifications, which may be within or adjacento the known malignancy. Adjacent suspicious microcalcifi-ations may represent associated ductal carcinoma in situDCIS). In addition, mammography can identify multifocalnd multicentric disease.

Careful mammographic evaluation of known or suspectedalignancies is important, especially when characterizing

alcifications and evaluating mass margins. Attention shoulde paid to the entire breast, including the axillary regionwhere enlarged lymph nodes may be identified) and theeriareolar region (as tumors may spread through the ductetwork to the region of the nipple). Magnification viewshould be performed for evaluating calcifications and theargins of masses. Spot compression views are used when

he breast imager is trying to determine if a finding is a realass or caused by superimposition of normal structures.Although mammography images most of the breast tissue,

he posterior breast tissue (adjacent to the chest wall) may note included, depending on the patient’s body habitus and theammography technologist’s skills. Also, in general, mam-ography covers only a portion of the inferior axillary re-

ion. The other local nodal basins (the infraclavicular, theupraclavicular, and the internal mammary basins) are notncluded on mammography. Thus, to accurately stage pa-ients with known or suspected LABC, additional imaging iseeded. At the University of Texas M. D. Anderson Cancerenter (UTMDACC), all LABC patients are evaluated with

onography. MRI and PET/CT can also play important rolesn staging LABC patients.

ltrasoundltrasound is commonly used throughout the United States

or further assessment of breast abnormalities identified onammography. At UTMDACC, ultrasound also serves as the
ajor locoregional staging examination in patients with t
ABC. When ultrasound is combined with ultrasound-uided fine-needle aspiration (FNA), sonography is highlypecific.9 Sonography can identify additional lesions in thepsilateral breast and the contralateral breast and identifybnormal lymph nodes in the axillary, infraclavicular, supra-lavicular, and internal mammary regions.

Nearly all LABC patients at UTMDACC undergo sonogra-hy before initial treatment to provide a full staging evalua-ion. If supplemental staging evaluation with sonography or

RI was not performed before excision, then a staging eval-ation should be performed after initial excision and before

nitiating radiation therapy. Although patients with multifo-al malignancy often qualify for breast conservation therapy,n general, documented multicentric disease is usually a con-raindication for breast conservation. Berg and Gilbreath10

howed that whole breast ultrasound complements mam-ography in the preoperative evaluation of women with

reast cancer. Their study used sonography to evaluate thepsilateral breast of 40 women with known malignancy or aigh suspicion for cancer. Ultrasound identified 45 (94%) of8 invasive tumor foci and 16 foci of DCIS. Mammography

dentified 39 (81%) of 48 invasive tumor foci and 14 foci ofCIS. Nine (14%) of 64 malignant foci were seen only onltrasound.10

Moon et al11 evaluated the ipsilateral and the contralateralreasts in 201 women with recently diagnosed breast cancerr with a suspicion of breast cancer. In the ipsilateral breasts,ltrasound showed 194 (97%) of 201 invasive cancer focind 52 (75%) of 69 DCIS foci. Mammography and clinicalxamination showed 173 (86%) invasive cancer foci and 5681%) DCIS foci. In the contralateral breasts, ultrasoundhowed 11 (92%) of 12 invasive cancer foci and 4 (57%) of 7CIS foci compared with 6 (50%) invasive cancer foci and 5

71%) DCIS foci identified by mammography and clinicalxamination. Ultrasound showed mammographically andlinically occult multifocal or multicentric cancers in 28 pa-ients (14%) and contralateral cancers in 8 patients (4%). Inhe study, sonography resulted in a change in therapy in 32atients (16%).11

Ultrasound also plays an important role in evaluating theegional (axillary, infraclavicular, supraclavicular, and inter-al mammary) lymph nodes and in guiding percutaneous

ymph node biopsies. The likelihood of axillary metastases iselated to the primary breast tumor size, and the relationships almost linear. A breast tumor measuring less than 2 cm haspproximately a 30% risk of axillary metastasis, and a tumoreasuring 5 cm has a 70% risk.12

Although ultrasound evaluation of the axillary lymphodes (Fig. 1) is being performed more commonly, carefulonographic evaluation of the infraclavicular (Fig. 2), supra-lavicular, and internal mammary lymph nodes is very im-ortant in accurate staging of women with LABC.13-15 Sono-raphic staging of the regional lymph node basins should beerformed before the initiation of neoadjuvant chemother-py. Klauber-Demore et al16 showed that postchemotherapyonography was poor at identifying axillary lymph node me-
astases. On postchemotherapy axillary lymph node ultra-

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Locally advanced breast cancer 213

ound, the positive predictive value was 83%, and the nega-ive predictive value was 52% in a series of 53 patients.16

Current ultrasound technology used in daily clinical prac-ice is not capable of identifying micrometastatic disease.

acrometastatic disease may be identified on ultrasound asortical thickening, hilar displacement, hilar compression,nd loss of the normal echogenic hilum.14 Metastatic lymphodes tend to be rounder than benign lymph nodes.17 Yang etl18 evaluated 145 axillary lymph nodes in 135 women withreast cancer and found that the mean longitudinal-trans-erse axis ratio was significantly lower in malignant (1.8)han in benign (2.6) lymph nodes. Also, indistinct marginsre suggestive of metastatic involvement.19 In general, onltrasound, more superficially located lymph nodes are iden-ified more often and characterized more accurately than

Figure 1 A 42-year-old woman presented to her doctorbreast. Clinical examination revealed a suspicious, largewas noted in the right axillary region. (A) Right breast lalobular mass (long arrow) with associated skin thickearrow). (B) The right breast lateromedial mammogram shnodes (short arrow). (C) The right breast longitudinal exmass (large arrow) extending to the skin (small arrow).poorly differentiated invasive ductal carcinoma (estrogenneu overexpression negative). (D) Longitudinal right axnode (arrow). Ultrasound-guided FNA showed metasta

eeper lymph nodes. g

Ultrasound allows the capability for guidance of biopsies.t UTMDACC, nearly all lymph node biopsies are performedith FNA. Once the aspirate is obtained, cytology technolo-ists prepare the slides in the ultrasound procedure room,nd cytologists assess the adequacy of the aspirate and renderreliminary interpretations before the patient is dischargedrom the breast imaging suite.20

Krishnamurthy et al21 evaluated 103 women with breastancer and compared the findings on axillary lymph nodeNA with the histologic findings in the entire axilla after axillary

ymph node dissection. Ultrasound-guided FNA identified allhe cases with 3 or more metastatic lymph nodes and 93% of theases with a metastatic deposit measuring more than 0.5 mm.he sensitivity of ultrasound-guided FNA was 86.4%, and thepecificity was 100%. The diagnostic accuracy of ultrasound-

oting a palpable abnormality in the upper outer rightbreast mass involving the skin. A palpable lymph nodeexaggerated craniocaudal mammogram shows a large,rrowhead) and enlarged axillary lymph nodes (shorte large mass (long arrow) and suspicious axillary lymph-field-of-view sonogram shows the suspicious, lobular

trasound-guided core biopsy was performed, revealingtor negative, progesterone receptor negative, and HER2ltrasound shows an enlarged, oval, hypoechoic lymphase.

after nrightterally

ning (aows thtendedAn ulrecep

illary u

uided FNA was 79%, the positive predictive value was 100%,

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nd the negative predictive value was 67%. In most of the casesith false-negative results (8 of 12 cases, 66%), the size of theetastatic deposits ranged from 0.1 to 0.5 cm.21

If expert cytology support is not available, then ultra-ound-guided core biopsy of suspicious lymph nodes is via-

le. Short-throw (1-cm) core biopsy needles are helpful es-ecially when the lymph nodes are situated close to vessels,erves, implants, and chest wall structures. Topal and col-

eagues performed ultrasound-guided core needle biopsiesn suspicious axillary lymph nodes in 39 women with breast

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ancer. In the study by Topal et al,22 ultrasound-guided ax-llary lymph node core biopsy resulted in a sensitivity of 90%,specificity of 100%, and an accuracy of 92%.Sonography plays a crucial role for treatment planning.

ecause the breast cancer staging system is based on thessessment of the tumor (T), the regional lymph nodes (N),nd metastatic (M) disease, nodal assessment must be per-ormed before assigning an accurate T, N, M stage. Theseonsiderations are particularly critical when considering pre-perative chemotherapy for patients with LABC in whomrechemotherapy surgical data will not be obtained.23

Regarding accurate T, N, M staging, clinical examination isotoriously inaccurate. On most mammograms, only a por-ion of the inferior axilla is included routinely. The infracla-icular, supraclavicular, and internal mammary regions areot included on mammography. Most breast MRI protocols

nclude only the inferior axillary region, and coverage of thenfraclavicular region is variable. Although the internal mam-

ary region is covered with routine breast MRI, additionalmaging would be needed to cover the entire axillary andnfraclavicular regions and the supraclavicular region. CTnd PET of the chest usually cover the axillary, infraclavicu-ar, supraclavicular, and internal mammary basins. However,dentification of abnormal lymph nodes tends to be based onize (�1 cm being abnormal) on a CT scan24 and standardptake values on PET.25,26 Sonography, by contrast, may

dentify subclinical disease involving the regional lymphodes. On ultrasound, morphology suspicious for metastaticisease (cortical expansion or displacement of the echogenicilum) may be identified before lymph node enlargement.etastatic disease may then be confirmed with ultrasound-

uided biopsy. Thus, the extent of nodal disease may beapped with sonography before the initiation of treatment.When chemotherapy is the first therapeutic step in the

reatment of a patient with LABC, pretreatment imaging isandatory, including sonographic evaluation of the regional

ymph node basins. Preoperative chemotherapy is designedo shrink the primary tumor and possibly facilitate breastonservation therapy, to treat subclinical distant micrometas-ases, and to provide a platform for in vivo assessment ofystemic therapies.6 After the initiation of chemotherapy, pe-iodic follow-up imaging, usually with ultrasound, is helpfuln showing that the chemotherapy is efficacious and in deter-

Figure 2 A 75-year-old woman presented for routine, anwhich showed a benign sclerosing lesion with focal atypsuspicious findings in either breast or in the right or theof the right breast shows an irregular mass (arrow). (B)shows a hypoechoic, taller-than-wide mass (arrow) corsound-guided core biopsy (white arrow) was performedrevealed high-grade, poorly differentiated invasive ductanegative, and HER2 neu overexpression negative) witbiopsy, a clip marker was placed in the known malignbreast mammogram obtained after the marker placemen(E) Transverse sonography of the medial right infraclavicAn ultrasound-guided FNA (long arrow) of the hypoech
performed, revealing evidence of metastatic disease.
ining the operability of the primary breast tumor.4 Re-ponse to treatment in the lymph nodes is thought to haverognostic significance.27 Shanta et al28 studied 1,117 con-ecutively treated LABC patients and showed that the bestrognosis was in the women who were tumor- and node-egative postoperatively. In that study, nodal downstagingalved the risk of disease recurrence and death, irrespectivef the status of the tumor bed. Patients with no response orrogression on therapy in the primary tumor or in the re-ional lymph nodes may be switched to an alternative che-otherapy regimen or offered investigational therapy.29

Local treatment planning is enhanced by the detailed re-ional nodal information provided by sonographic assess-ent. For example, when patients present with disease in the

onographic infraclavicular region or the anatomic level II toII axillary region and the interpectoral space, radiation ther-py can address these findings.30 Most surgeons do not per-orm full, level I to III axillary dissections, and the interpec-oral space is rarely entered. The information regarding nodalisease sites can be used by the radiation oncologist for tar-eting specific sites for boosting. Likewise, disease identifiedn the internal mammary and/or the supraclavicular regions,hich is rarely resected, can be addressed by appropriate

adiation therapy planning.Altinyollar et al30 used sonography to examine the axillary

nd the infraclavicular regions in 100 consecutive breast can-er patients. They identified axillary lymph nodes in 77 pa-ients, and, in 52 of these patients, metastatic-appearingymph nodes were seen on ultrasound. In 49 of these 52atients, the presence of lymph node metastases was estab-

ished by histopathology. In 13 cases, sonography showed novidence of axillary lymph node metastases, but histopatho-ogic examination showed metastatic deposits. Thirty-fiveatients had negative sonographic evaluations of the axillaryegion, and no metastatic deposits were seen on histopatho-ogic examination. In the evaluation of the axillary region forhe presence of metastatic disease, sonography had a speci-city of 92.1%, a sensitivity of 79%, a positive predictivealue of 94.2%, a negative predictive value of 72.9%, and anverall accuracy of 84%.In the study by Altinyollar et al,30 sonography showed

ndings suspicious for infraclavicular lymph node metasta-es in 20 patients. In 19 of these patients, infraclavicular

ammography after left breast excision 10 years earlier,ctal hyperplasia. The clinical examination revealed noional nodal basins. (A) The lateromedial mammogram

udinal ultrasound in the right breast 10 o’clock regionding to the mammographic abnormality. (C) An ultra-e right breast 10 o’clock mass (black arrow). Pathologyoma (estrogen receptor negative, progesterone receptorssociated lymphoplasmacytic infiltrate. After the coreith sonographic guidance. (D) The lateromedial rightthe clip marker within the known malignancy (arrow).

gion reveals a hypoechoic, oval lymph node (arrow). (F)dial right infraclavicular lymph node (short arrow) was

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ymph node metastases were verified on histopathologic ex-mination. Sonography showed no suspicious infraclavicularymph nodes in 21 patients, but all 21 of these patients hadnfraclavicular lymph node metastases on histopathologicxamination. In 59 patients, infraclavicular sonographyhowed no suspicious lymph nodes, and histopathologyhowed no evidence of metastatic disease. Regarding sono-raphic evaluation of the infraclavicular region for the pres-nce of metastases, the specificity was 98.3%, the sensitivity

Figure 3 A 45-year-old woman presented to her doctor wlower left breast. The clinical examination revealed a 9-cmnipple inversion, and raised erythematous plaques in ththe left axillary region. (A) The left craniocaudal mammnipple inversion. (B) The left lateromedial mammogramlymph nodes (small arrow) and nipple inversion. (C) Thelarge mass along with chest wall invasion (large arrow), nThe longitudinal extended-field-of-view ultrasound shoarrow), and skin involvement (small arrow). Ultrasoundcarcinoma (estrogen receptor positive, progesterone reLongitudinal left axillary sonography shows an enlargedsound-guided left axillary FNA (long arrow) was perforevidence of metastatic carcinoma. (G) An ultrasound-guileft infraclavicular lymph node (thin arrow), showing ev

as 47.5%, the positive predictive value was 95%, the nega- (

ive predictive value was 73.7%, and the overall accuracy was8%.30

Iyengar et al31 performed a retrospective analysis on 1,200tage III patients treated with radiation therapy at UTMDACCrom 1996 to 2006. Of the 1,200 patients, 865 patients hadndergone sonography, which included assessment of theegional nodal basins, at the time of their initial evaluation. Inhis study, 325 out of 865 (37%) women had initial diseaseeyond the breast and the low axillary region. Ninety percent

breast thickening and redness involving the skin of thein the left breast, fixed to the chest wall, with associated’clock position. A mobile lymph node was palpated inreveals a large, central mass (arrow), with associateds the mass (large arrow) along with enlarged axillary

al dynamic contrast-enhanced left breast MRI shows theinversion (star), and skin involvement (arrowhead). (D)

large hypoechoic mass, chest wall involvement (larged core biopsy demonstrated low-grade invasive lobularpositive, and HER2 neu overexpression negative). (E)h node (arrow) with a prominent cortex. (F) An ultra-n the hypoechoic lymph node (short arrow), revealingA (thick arrow) was performed on a hypoechoic medialof metastatic carcinoma.

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ymph nodes after ultrasound-guided biopsy. Comparedith clinical examination, mammography, and targetedreast ultrasound, sonography of the regional lymph nodesevealed previously undocumented infraclavicular disease in2% of patients (275/865), supraclavicular disease in 16% ofatients (140/865), and internal mammary disease in 11% ofatients (98/865). Seventy-two percent of the patients withxtra-axillary regional lymph node involvement had T3 (94/25) or T4 (141/325) primary malignancies, and 28% ofhese patients had T1 or T2 primary tumors (90/325).31

In the study by Iyengar et al,31 in the most common sce-ario, sonographic staging changed the N stage from N1 to3. In patients initially presenting with T1 or T2 tumors,

here was a shift from N1 disease to N3 disease in 22% ofatients and a shift from N2 to N3 disease in 22% of patients.or patients presenting with T3 tumors, sonography resulted

n a shift in 13% of the patients from N1 to N3 disease, and% of patients converted from N2 disease to N3 disease. Inatients initially presenting with T4 tumors, 13% of patientsere converted by sonography from N1 to N3 disease (Fig.), and 11% were converted by sonography from N2 to N3isease. In this study, all the LABC patients with N3 disease37%) would have been understaged if sonography of theegional lymph node basins was not performed. All the pa-ients with extra-axillary regional lymph node involvementeceived a radiation boost to the involved areas. Therefore, ateast 37% of the LABC patients had their radiation therapylans altered by the information provided by sonography in

Figure 3

he study by Iyengar et al.31 n

Sonography has also been used before the initiation ofadiation therapy to localize and measure the depth of theumpectomy cavity and the internal mammary lymph nodesnd to measure the chest wall thickness. Helyer et al32 usedonography to determine the depth of the tumor bed in aeries of 53 early-stage postoperative breast cancer patients.n 60% of the patients, sonography resulted in a change in thelectron energy compared with the clinically assessed mea-urements. After sonography, the energy was as likely to bencreased as decreased in the study by Helyer et al.32

Rabinovitch et al33 showed that ultrasound underesti-ated the dimensions of the lumpectomy cavity and con-

luded that sonography should not be used to guide theesign of boost fields. In general, CT-based treatment plan-ing has superseded sonographic assessment of the chestall thickness and sonographic assessment of the excision

ite and the internal mammary lymph node basins. A recenttudy by Coles et al34 showed that 3-dimensional ultrasoundas superior to standard 2-dimensional sonography. In ad-ition, the 3-dimensional ultrasound data could be coregis-ered with the planning CT data to help design appropriateadiation fields.34

Clip markers may be placed in the primary tumor withonographic guidance.35 In some patients with LABC whoespond to neoadjuvant chemotherapy, the placement of cliparkers in the tumor bed may facilitate breast conservation

urgery rather than mastectomy. In some patients, the re-ponse to neoadjuvant chemotherapy is so good that there is

inued)

o evidence of residual tumor on clinical examination or on

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maging studies.36 The placement of clip markers should beonsidered at the time of the initial ultrasound-guided breastiopsy. If clip markers were not placed at the time of the

nitial biopsy, then clip markers should be placed in theumor if it shows significant shrinkage (a decrease in diame-er of 50% or greater), becomes 1 cm or less in greatestength, or is no longer palpable. Oh et al37 retrospectivelytudied 410 patients who received doxorubicin-based neo-djuvant chemotherapy and underwent breast conservationherapy and showed that the placement of clip markers wasssociated with better local control independent of stage andther clinicopathologic findings. Oh et al concluded that thelacement of clip markers should be an integral part of theultidisciplinary approach in patients undergoing neoadju-

ant chemotherapy.Sonography may be performed in the breast imaging area

r in the operating room at the time of breast conservationurgery to aid in localization of the primary tumor mass orreviously placed clip markers.38,39 A localizing needle maye placed with sonographic guidance. Alternatively, sonog-aphy may be used to guide skin marking directly over thebnormality. These techniques may obviate the need forammographically-guided needle localization.40 In addi-

ion, sonography can be used in the breast imaging area or inhe operating room to localize lymph nodes before excision.

RIompared with mammography and sonography, MRI has

he highest sensitivity for detecting invasive breast cancer,ith sensitivities reported between 94% and 99%.8 MRI haseen able to show additional ipsilateral disease in the breast

n 7% to 37% of cases.8 Also, MRI is particularly useful forhowing chest wall involvement.41 Berg et al42 analyzed theammography, sonography, and MRI results in 111 consec-tive patients with known or suspected breast cancer. Com-ined clinical examination, mammography, and MRI wereore sensitive than any 1 individual test or combination of

ests.42 After combined clinical examination, mammography,nd ultrasound, MRI showed additional tumor foci in 12 of6 (12%) breasts and led to the overestimation of disease in 66%) breasts.42 Contralateral breast cancer was shown byammography in 6 of 111 (5%) women and with sonogra-hy and MRI in an additional 3 (3%) women.42 In the studyy Berg et al, 1 contralateral breast cancer was shown only onlinical examination.

Lehman et al43 evaluated the contralateral breast in 969omen with recently diagnosed breast cancer in the Ameri-

an College of Radiology Imaging Network 6667 Trial. In all69 women, no abnormalities were noted in the contralateralreast on clinical examination or mammography. MRI iden-ified clinically and mammographically occult breast cancern the contralateral breast in 30 of 969 (3.1%) women. Of the0 tumors identified with MRI, 18 were invasive malignan-ies and 12 were DCIS. The sensitivity of MRI in evaluatinghe contralateral breast was 91%, the specificity was 88%,
nd the negative predictive value was 99%.43 fi
MRI has been shown to be an accurate modality for assess-ng the extent of residual disease after preoperative chemo-herapy. Kim et al44 used MRI to evaluate breast tumor size in0 women before and after neoadjuvant chemotherapy withoxorubicin and docetaxel. Kim et al found that the measure-ents on MRI agreed with the pathologically determined

umor size in 36 patients (72%) and disagreed in 14 patients28%), overestimating the tumor size in 13 patients (26%)nd underestimating the tumor size in 1 woman (2%).44

ulius et al45 studied 34 LABC patients and noted that MRIas able to accurately identify those patients suitable forreast conservation therapy after neoadjuvant chemother-py.

To be useful as a regional nodal staging examination, MRIhould cover the entire nodal basins. Most clinical breast MRIrotocols include the internal mammary and the infraclavic-lar regions, cover a portion of the axillary region, and ex-lude the supraclavicular region. Thus, the development ofrotocols to adequately image all the regional nodal regionsnd the breasts in a short scan time should be encouraged. Inddition, no firmly established criteria for metastatic lymphode morphology on MRI have been established. MRI withltra-small superparamagnetic iron oxide agents has shownreat promise with a sensitivity ranging between 82% and00% and a specificity ranging between 80% and 100% inhe assessment of axillary lymph node metastases.46-48

entinel Lymph Node Evaluationhe role of sentinel lymph node evaluation in LABC patientseing treated with neoadjuvant chemotherapy is evolving.urrent data suggest that sentinel lymph node evaluation isot accurate for IBC patients, and these patients should un-ergo axillary lymph node dissection. At many centers, sen-inel lymph node evaluation is performed in LABC patientsefore the initiation of neoadjuvant chemotherapy. This ap-roach is based on the hypothesis that all involved axillary

ymph nodes may not respond to chemotherapy in an iden-ical manner.12 Thus, an axillary lymph node with a meta-tatic deposit at the time of the original breast cancer diagno-is may be treated with chemotherapy and renderedathologically free of disease. If that same axillary lymphode was designated as the sentinel lymph node, the sentinel

ymph node biopsy would show no evidence of tumor. How-ver that sentinel lymph node may not be representative ofhe entire axillary region because higher echelon axillaryymph nodes may not have responded to neoadjuvant che-

otherapy as well as the sentinel lymph node and still con-ain metastatic desposits.12 The false-negative rate for sentinelymph node biopsy performed after treatment with neoadju-ant chemotherapy has been reported to range between 0%nd 33%.49 The higher false-negative rates were noted ineries with larger (greater than 3.5 cm) tumors.49

If a sentinel lymph node biopsy is performed before thetart of neoadjuvant chemotherapy and the sentinel lymphode biopsy shows metastatic disease, completion axillary

ymph node dissection will be performed at the time of de-
nitive breast surgery. If the sentinel lymph node biopsy

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hows no pathologic evidence of metastatic disease, thenompletion axillary lymph node dissection is not required.49

ystemic Stagingn women presenting with LABC, systemic staging is per-ormed to rule out distant metastatic disease.6 Staging is usu-lly performed with chest radiography, a bone scan, and anbdominal CTscan.50 An abnormality in one of the first-linexaminations will usually lead to a second tier study. Forxample, an abnormality on a chest radiograph would beurther evaluated with a chest CT scan. Al-Husaini et al51

erformed initial staging evaluations on 144 patients withABC and identified 15 patients (10.4%) with overt meta-tatic disease. Additional imaging investigations revealed an-ther 4 patients with metastatic disease, resulting in preva-ent metastases in 13.2% of the patients.51

Al-Husaini et al51 noted that because of the high rate ofystemic relapse in LABC patients, current conventionalaseline staging evaluations likely underestimate the extentf disease. Thus, an unremarkable conventional baselinetaging evaluation may be falsely reassuring. Accurate stagingn LABC patients is crucial, and further research is needed toefine the role and the sequence of newer imaging tech-iques, such as MRI and PET.51

ET8F-fluorodeoxyglucose (FDG) PET has been evaluated as aool for assessing the axillary lymph nodes in breast canceratients with mixed results. An added value for PET is that itan show disease in the supraclavicular and the internalammary nodal basins. In addition, PET allows for staging of

he entire body with high sensitivity. PET can be used tovaluate the visceral organs (such as the liver and the lung)nd the bones. PET tends to detect more osteolytic boneesions than bone scans, whereas bone scans are sometimes

ore sensitive than PET for identifying osteoblastic lesions.50

Mahner et al52 used PET to stage 69 patients with recentlyiagnosed breast cancer and 50 patients with a previous his-ory of breast cancer. PET was superior to conventional im-ging (chest radiography, sonography of the abdomen andhe axilla, bone scintigraphy as well as skeletal radiography,nd contrast-enhanced CT scans as clinically indicated) forhe detection of distant metastases. PET detected distant met-static disease with a sensitivity of 87% and a specificity of3%. Combined conventional imaging yielded a sensitivity of3% and a specificity of 98%, and contrast-enhanced CTcans revealed a sensitivity of 83% and a specificity of 85%.52

Van der Hoeven et al53 evaluated 48 LABC patients withhole body PET after conventional imaging (chest radiogra-hy, bone scan, and liver ultrasound or CT) failed to showistant metastases. Fourteen of the 48 patients showed ab-ormal FDG uptake, and metastases were suspected in 12ases. Further workup revealed 4 sites consistent with meta-tatic disease. The authors concluded that PET can be helpfuln distinguishing stage III disease from stage IV disease. In
ddition, the authors emphasized that abnormal PET find- n
ngs require confirmatory imaging and/or biopsy becausehere were 8 cases with false-positive FDG uptake on PET.53

Mahner et al52 used PET to evaluate the axillary region withsensitivity of 86% and a specificity of 97% (52). Wahl et al54

nalyzed the PET scans of 360 women with recently diag-osed breast cancer. In that study, the PET scans were inter-reted by 3 experienced readers in a blinded fashion. Wahl etl concluded that PET may fail to detect axillary lymph nodeetastases if there is a small number of lymph nodes and/or

f the lymph nodes are small (less than 3-5 mm).54 By con-rast, PET is highly predictive for nodal involvement whenultiple intense regions of uptake are present.52

Bellon et al55 retrospectively reviewed the PET scans of 28onsecutive patients before neoadjuvant chemotherapy foruspected LABC. Clearly, abnormal FDG uptake was notedn the internal mammary lymph nodes in 7 patients (25%).rospective conventional imaging failed to identify metasta-es involving the internal mammary lymph nodes in anyatient. FDG uptake in the internal mammary lymph nodesas associated with a large primary tumor size and with

nflammatory disease. FDG uptake in the internal mammaryymph nodes predicted treatment failure by a pattern consis-ent with spread from internal mammary lymph node metas-ases.55

Baslaim et al56 used PET to evaluate 7 patients with IBC.ET showed axillary lymph node involvement in 6 of 7 pa-ients (85%) and skeletal metastatic disease in 1 patient14%). These findings were not identified on conventionalmaging. By contrast, PET may fail to detect small (less than 1m) masses, and, in 2 out of 7 patients with proven IBC, thereere false-negative PET studies.56

Recently, integrated PET/CT scanners have been devel-ped, allowing PET and CT images to be obtained in closeemporal proximity without the need to reposition the pa-ient. PET/CT studies offer whole body, dual-modality imag-ng in a single examination. Tatsumi et al57 evaluated 75atients with known breast cancer and determined thatET/CT increased the readers’ diagnostic confidence com-ared with PET alone in 60% of cases with increased FDGptake. In addition, in the study, PET/CT scans showed sig-ificantly better accuracy than CT alone. Therefore, Tatsumit al recommended PET/CT scans rather than PET alone orT scan alone in the evaluation of patients with known breastancer.

Carkaci et al58 used PET/CT scans in the initial stagingvaluation of 41 women with IBC. PET/CT scans showedypermetabolic uptake in the skin in all 41 patients, in theffected breast in 40 patients (98%), in the ipsilateral axillaryymph nodes in 37 patients (90%), and in the ipsilateralubpectoral lymph nodes in 18 patients (44%). PET/CT scanshowed distant metastases in 20 patients (49%). In 7 (35%)f the 20 patients with metastatic disease, the metastasesere not identified on conventional imaging before theET/CT examination. PET/CT scans identified metastatic dis-ase involving the bone; the liver; the contralateral axilla; theung; the chest wall; the pelvis; and lymph nodes in theubpectoral, supraclavicular, internal mammary, mediasti-
al, and abdominal regions.58

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PET and PET/CT scans are useful in assessing the responsef the primary breast tumor, the regional lymph nodes, andistant metastases to neoadjuvant chemotherapy.59 PET andET/CT scans can be used to differentiate responders fromonreponders early in the course of therapy.56 A decline inrimary tumor FDG uptake by 50% or more is predictive ofgood response to neoadjuvant chemotherapy, whereas aore modest decline in FDG uptake is characteristic of a lack

f response to treatment.59 Schelling et al60 showed that theistopathologic response of breast cancer to chemotherapyould be predicted by PET after the first and the secondourses of chemotherapy with an accuracy of 88% and 91%,espectively.

onclusionsn patients with LABC, accurate workup and staging evalua-ions are extremely important in facilitating appropriate mul-idisciplinary treatment. Careful clinical evaluation should beollowed with mammography. Thereafter, sonography is par-icularly helpful in showing multifocal and/or multicentricisease and regional lymph node involvement. Ultrasound-uided biopsy can be performed to document the presence ofdditional tumor foci in the breast and regional lymph nodeetastases. MRI plays a role in some cases, and it is especiallyseful in showing multifocal and multicentric disease andhest wall involvement in the ipsilateral breast as well asisease in the contralateral breast.Conventional imaging used to evaluate for distant meta-

tatic disease includes chest radiography, bone scan, and ab-ominal CT. PET and PET/CT scans have been shown to beseful in identifying distant metastatic disease not identifiedn conventional imaging. In the future, with developments inadiopharmaceuticals and imaging detectors, it is likely thatET/CT will play a greater role in regional lymph node stag-

ng. At the current time, because PET and PET/CT scans arenable to identify microscopic metastatic deposits, PET andET/CT scans should not be used instead of axillary lymphode biopsy or sentinel lymph node biopsy in patients withABC. If sentinel lymph node biopsy is being considered in aABC patient, it is suggested that sentinel lymph node biopsye performed before the initiation of neoadjuvant chemo-herapy.

cknowledgmentse thank Barbara Almarez Mahinda for assistance in manu-

cript preparation.

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8. Gittleman MA: Single-step ultrasound localization of breast lesions andlumpectomy procedure. Am J Surg 186:386-390, 2003

9. Bennett IC, Greenslade J, Chiam H: Intraoperative ultrasound-guidedexcision of nonpalpable breast lesions. World J Surg 29:369-374, 2005

0. Paramo JC, Landeros M, McPhee MD, et al: Intraoperative ultrasound-guided excision of nonpalpable breast lesions. Breast J 5:389-394, 1999

1. Morris EA: Breast cancer staging with MRI. Radiol Clin North Am40:443-466, 2002

2. Berg WA, Gutierrez L, NessAiver MS, et al: Diagnostic accuracy ofmammography, clinical examination, US, and MR imaging in preoper-ative assessment of breast cancer. Radiology 233:830-849, 2004

3. Lehman CD, Gatsonis C, Kuhl CK, et al: MRI evaluation of the con-tralateral breast in women with recently diagnosed breast cancer.N Engl J Med 356:1295-1303, 2007

4. Kim HJ, Im YH, Han BK, et al: Accuracy of MRI for estimating residual
tumor size after neoadjuvant chemotherapy in locally advanced breast
cancer: Relation to response patterns on MRI. Acta Oncol 46:996-1003, 2007

5. Julius T, Kemp SE, Kneeshaw PJ, et al: MRI and conservative treatmentof locally advanced breast cancer. Eur J Surg Oncol 31:1129-1134,2005

6. Michel SC, Keller TM, Frohlich JM, et al: Preoperative breast cancerstaging: MR imaging of the axilla with ultrasmall superparamagneticiron oxide enhancement. Radiology 225:527-536, 2002

7. Stadnik TW, Everaert H, Makkat S, et al: Breast imaging. Preoperativebreast cancer staging: Comparison of USPIO-enhanced MR imagingand 18F-fluorodeoxyglucose (FDC) positron emission tomography(PET) imaging for axillary lymph node staging—Initial findings. EurRadiol 16:2153-2160, 2006

8. Memarsadeghi M, Riedl CC, Kaneider A, et al: Axillary lymph nodemetastases in patients with breast carcinomas: Assessment with nonen-hanced versus USPIO-enhanced MR imaging. Radiology 241:367-377,2006

9. Cox CE, Cox JM, White LB, et al: Sentinel node biopsy before neoad-juvant chemotherapy for determining axillary status and treatmentprognosis in locally advanced breast cancer. Ann Surg Oncol 13:483-490, 2006

0. Bombardieri E, Gianni L: The choice of the correct imaging modality inbreast cancer management. Eur J Nucl Med Mol Imaging 31:S179-S186, 2004 (suppl 1)

1. Al-Husaini H, Amir E, Fitzgerald B, et al: Prevalence of overt metastasesin locally advanced breast cancer. Clin Oncol (R Coll Radiol) 20:340-344, 2008

2. Mahner S, Schirrmacher S, Brenner W, et al: Comparison betweenpositron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-D-glucose, conventional imaging and computed tomography for stagingof breast cancer. Ann Oncol 19:1249-1254, 2008

3. van der Hoeven JJM, Krak NC, Hoekstra OS, et al: 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography in staging of locallyadvanced breast cancer. J Clin Oncol 22:1253-1259, 2004

4. Wahl RL, Siegel BA, Coleman RE, et al: Prospective multicenter study ofaxillary nodal staging by positron emission tomography in breast can-cer: A report of the staging Breast Cancer with PET Study Group. J ClinOncol 22:277-285, 2004

5. Bellon JR, Livingston RB, Eubank WB, et al: Evaluation of the internalmammary lymph nodes by FDG-PET in locally advanced breast cancer(LABC). Am J Clin Oncol 27:407-410, 2004

6. Baslaim MM, Bakheet SM, Bakheet R, et al: 18-Fluorodeoxyglucose-positron emission tomography in inflammatory breast cancer. WorldJ Surg 27:1099-1104, 2003

7. Tatsumi M, Cohade C, Mourtzikos KA, et al: Initial experience withFDG-PET/CT in the evaluation of breast cancer. Eur J Nucl Med MolImaging 33:254-262, 2006

8. Carkaci S, Macapinlac HA, Cristofanilli M, et al: Retrospective study of18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: Pre-liminary data. J Nucl Med 50:231-238, 2009

9. Rosen EL, Eubank WB, Mankoff DA: FDG PET, PET/CT and breastcancer imaging. Radiographics 27:S215-S229, 2007 (suppl 1)

0. Schelling M, Avril N, Nahrig J, et al: Positron emission tomographyusing [18F]fluorodeoxyglucose for monitoring primary chemotherapy
in breast cancer. J Clin Oncol 18:1689-1695, 2000

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eoadjuvant Chemotherapy forocally Advanced Breast Cancer

ennifer Specht, MD, and Julie R. Gralow, MD

Preoperative systemic therapy is the standard of care in locally advanced breast cancer.In this setting, the intent of preoperative systemic therapy is to expand surgical optionsand to improve survival. Locally advanced and inflammatory breast cancer have differ-ent biological features, but they share the use of preoperative (primary, neoadjuvant)systemic therapy as the initial treatment of choice. The management of these patientsnecessitates involvement of a multidisciplinary team from the onset and during therapy.The eradication of invasive cancer from the breast and axillary lymph nodes, pathologiccomplete response, is a predictor of outcome associated with improved disease-freeand overall survival. However, conventional chemotherapy regimens result in patho-logic complete response in only a minority of patients. The management of patients withresidual invasive disease after preoperative therapy is a common clinical problem forwhich additional research is necessary. The differential expression of genes andpathways in locally advanced and inflammatory breast cancer allows for the exploitationof targeted therapy, and early trials have shown exciting target and tumor effects. Muchwork remains, and future trials combining targeted and conventional therapies based onmolecular subtypes and/or specific targets are needed if we hope to improve survivalfor patients with locally advanced breast cancer.Semin Radiat Oncol 19:222-228 © 2009 Published by Elsevier Inc.

KEYWORDS breast cancer, locally advanced, inflammatory breast cancer, preoperative ther-apy, neoadjuvant therapy

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ocally advanced breast cancers (LABCs) have historicallybeen defined as those that are inoperable on presenta-

ion, usually with the involvement of regional lymph nodesnd possibly the skin and/or chest wall and having a poorurvival with locoregional therapies alone.1-3 In these can-ers, the use of preoperative systemic therapy has beenhown to induce tumor response and improve the local con-rol rates after subsequent surgery and radiation therapy. Theoals of preoperative systemic therapy in LABCs include earlyradication of subclinical distant micrometastases, downstag-ng of the primary tumor to allow for operability (includingreast-conserving surgery in some cases), in vivo assessment ofesponse to specific systemic therapies, and ultimately prolong-ng survival and improving quality of life. The magnitude of

epartment of Medicine, Medical Oncology, University of WashingtonSchool of Medicine, Seattle, WA.

r Specht was supported by Pfizer grant IIR #GA9000S1 (CC IRB #6488)and NCCN grant (CC IRB #6489).

ddress reprint requests to Julie R. Gralow, MD, Seattle Cancer CareAlliance, 825 Eastlake Avenue East, G3-630, Seattle, WA 98109.

2E-mail: [email protected]

22 1053-4296/09/$-see front matter © 2009 Published by Elsevier Inc.doi:10.1016/j.semradonc.2009.05.001

urvival benefit of preoperative systemic therapy is unclear,owever, because of relatively few comparative clinical trialspecifically in LABC patients. Randomized trials in stage IIIreast cancer that first used local therapy followed by adju-ant systemic therapy v not have shown a survival advantageor combined modality therapy.4-6 In primary operable breastancer, a series of randomized trials of neoadjuvant v adju-ant chemotherapy showed equivalent outcomes.7-9 Givenhat there appear to be no major disadvantages in givingreoperative systemic therapy in operable breast cancer andecause there are multiple possible advantages to giving neo-djuvant therapy in more advanced stages as outlined earlier,reoperative systemic therapy is the initial treatment ofhoice for patients presenting with LABC.

ptimalhemotherapy Regimens

n early studies of chemotherapy in LABC, anthracycline-ased regimens resulted in improved survival rates (up to
5% at 10 years) compared with historical experience with

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Neoadjuvant chemotherapy 223

ocal therapy alone.10-15 More recent trials have focused onhe addition of newer agents (particularly taxanes) and alter-ative schedules, such as dose-dense chemotherapy. A phaseII trial involving large (�3 cm) primary and LABCs showeduperiority for the sequential addition of 4 cycles of docetaxelfter 4 cycles of a neoadjuvant anthracycline-based regimencyclophosphamide, vincristine, doxorubicin, and pred-isone [CVAP]) when compared with 8 cycles of the anthra-ycline regimen alone in the preoperative setting.16 Otherrials have looked at combinations of anthracycline and tax-nes given concurrently and in sequence.17,18 In a trial ofreoperative chemotherapy specifically in LABC/inflamma-ory breast cancer (IBC), dose intensification of an anthracy-line regimen was not superior to a standard anthracyclineegimen, although interpretation of these results is difficultecause in addition to the chemotherapy interval timinghere were many other dissimilarities in drug administrationetween the 2 arms.19

A newer approach to chemotherapy sequencing that hashown promise in LABC is metronomic or continuous dosecheduling. Strickly speaking, metronomic chemotherapyefers to subtherapeutic, low doses of chemotherapy given onfrequent or continuous schedule without dose interruption.

n vitro, metronomic dosing appears to exert antiangiogenicffects. In breast cancer clinical therapy, metronomic orontinuous chemotherapy refers to the administration ofigher, cytotoxic doses of chemotherapy at shorter treat-ent intervals, often weekly for intravenous drugs, such

s doxorubicin, and daily for oral cyclophosphamide.ost recently, the preliminary results of a large trial of

ABC/IBC patients randomized to conventional anthracy-line and cyclophosphamide (doxorubicin, 60 mg/m2, andyclophosphamide, 600 mg/m2 both every 3 weeks) v met-onomic dosing doxorubicin, 24 mg/m2 weekly, and cy-lophosphamide, 60 mg/m2 daily) with growth factor sup-ort (both arms followed by standard weekly paclitaxel)howed an improved pathologic complete response (pCR)ate (19% v 31%, respectively; OR � 2.11, P � .020) withhe metronomic schedule.20 The pCR improvement wasost pronounced in the IBC cohort (12% v 32%). Mature

esults of the trial are awaited. Further studies with otheronventional chemotherapeutic combinations or sched-les are ongoing, but future significant gains will likely bechieved with targeted agents in combination with con-entional chemotherapeutic agents as preoperative ther-py.

It is highly unlikely that a single preoperative chemother-py regimen will be optimal for all types of patients andancers. Identifying which tumors are most likely to respondo specific agents and regimens could significantly improvereoperative treatment outcomes. In general, patients receiv-

ng preoperative chemotherapy should receive treatment reg-mens that reflect state-of-the-art adjuvant chemotherapyegimens. Outside of a clinical trial, there is no current ratio-ale for using different chemotherapy approaches in the pre-perative setting than would be used in the postoperative
etting. d
nitial Chemotherapyesponse As A Guide

o Subsequent Treatmentunique aspect of preoperative therapy is the opportunity

o monitor tumor response and potentially to tailor treat-ent based on response. Changes on physical examina-

ion and breast imaging have shown a moderate correla-ion with the ultimate pathologic assessment of residualisease. Although it is clear that early clinical response isssociated with higher rates of pCR and better long-termutcome, trials have not shown a consistent improvementn outcome with a midcourse chemotherapy switch basedn presence or lack of response. In the GeparTrio trial,21,22

atients received 2 cycles of preoperative docetaxel, doxo-ubicin, and cyclophosphamide (TAC). Patients with clin-cally nonresponding disease (defined as a failure to de-rease in size by at least 50% by ultrasound), representingbout 30% of patients on the study, were randomized toeceive 4 more cycles of TAC v 4 cycles of vinorelbine andapecitabine before surgery. The pCR rate in the nonre-ponders was low (5.3% and 6% for TAC and vinorelbinend capecitabine, respectively) and was not improved bywitching to the non– cross-resistant chemotherapy regi-en. In another trial, investigators in Aberdeen used an

arly assessment of clinical response to ask if prolonginghe duration of the initial treatment would be beneficial inhose patients whose tumors were responding to this ther-py.23 All patients received 4 cycles of preoperative CVAP.ased on the assessment of clinical response, patients withtable or progressive disease after 4 cycles were switchedo docetaxel for 4 cycles. pCR in this group was 2%, suggest-ng that tumors not responding to one chemotherapy regimenre unlikely to show dramatic response to another regimen.atients who had a complete or partial clinical response in thistudy to the first 4 cycles of CVAP were randomized to 4 moreycles of CVAP v a switch to 4 cycles of docetaxel. The pCR waswice as high in the group that switched to docetaxel (31% v6%). Both disease-free (DFS) and overall survival (OS) wereignificantly superior for responders randomized to the CVAP/ocetaxel arm compared with those who continued with CVAP.Although both the GeparTrio and Aberdeen studies in-

olved a randomization to continue treatment or switch tonew regimen, they differ in terms of the randomized

atient populations (sensitive v resistant disease) and withegard to the timing of randomization (4 v 2 cycles). Nev-rtheless, both studies suggest that a treatment planhould be devised at the outset and should not be alteredased on early response, unless there is clear evidence ofisease progression. Deviating from the planned course ofherapy in clinical nonresponders has not been shown toncrease either clinical or pCR rates or improve survival.atients with outright disease progression during preop-rative systemic treatment should be switched to an alter-ate regimen, offered local therapy, or considered candi-ates for investigational approaches, particularly if their
isease is unresectable. To date, we have been unable to

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224 J. Specht and J.R. Gralow

xploit the potential for improved outcome based onhanging chemotherapy based on the response to specificrugs given in the preoperative setting.

he Role of Additionalhemotherapy in Patientsith Residual Disease athe Time of Definitive Surgery

fter preoperative chemotherapy, patients should receive de-nitive breast surgery and, when indicated, radiation ther-py. In addition, patients should receive appropriate endo-rine therapy and human epidermal growth factor receptor-2HER-2)–targeted therapy, according to the biological fea-ures of their tumor. To date, no trial has shown that addi-ional chemotherapy given to patients with residual diseasefter a “modern” preoperative chemotherapy (generally an-hracycline and taxane based) improves outcome. In an M. D.nderson trial of adjuvant chemotherapy after preoperativenthracycline-based chemotherapy, 106 patients with �1m of residual disease were randomized to continue the reg-men they received preoperatively (CVAP) or received vin-lastine, methotrexate with calcium leukovorin rescue, and-fluorouracil postoperatively.24 Although there was no sta-istical difference between the arms, there was a trend favor-ng the vinblastine, methotrexate with calcium leukovorinescue, and 5-fluorouracil arm with respect to DFS (P � .16).iven the limited size of the trial, no definitive conclusionsan be drawn from this experience. Moreover, the trial wasonducted before the time when taxanes were generally in-luded in the treatment plan. Although there is no evidencehat more chemotherapy will be of value, it is also fully rec-gnized that this clinical situation is one that arises frequentlyn clinical practice because most patients treated with preop-rative therapy do not achieve a pCR. Outside of a clinicalrial, the use of additional chemotherapy after a standardourse of treatment should be discouraged. Within the con-ext of a clinical trial, a variety of approaches could be tested,ncluding the use of non–cross-resistant chemotherapy, an-iogenesis inhibitors, high-dose bisphosphonates, vaccines,nd a variety of other biological therapies.

Phase III trials proposed to address the management ofatients with residual disease after neoadjuvant chemother-py include National Surgical Adjuvant Breast and Bowelroject B45, which will randomize patients with residual in-asive disease to receive sunitinib (an oral multitargeted re-eptor tyrosine kinase inhibitor of vascular endothelialrowth factor (VEGF)-1, -2, -3; platelet-derived growth fac-or receptor, kit, and FMS-like tyrosine kinase 3) v placebo.he use of additional chemotherapy is not specified in this

rial. In the Southwest Oncology Group (SWOG), a phase IIIrial is planned for breast cancer patients with residual HER-–negative invasive disease to be randomized to receive ad-itional non–cross-resistant chemotherapy and/or a biologi-al agent or no further therapy postoperatively. Results ofhese studies will provide much-needed data on how to im-
rove outcomes in both locally advanced and early-stage pa- M
ients who do not achieve a complete response to preopera-ive therapy.

reoperative Endocrine Therapyhere is a smaller body of evidence regarding preoperativendocrine approaches. Although not widely used in thenited States, preoperative endocrine therapy is a treatmentption for women with endocrine-sensitive tumors, usuallyefined as expressing the estrogen receptor (ER) and/or pro-esterone receptor. Studies have established the safety of thistrategy for limited durations, typically not exceeding 6onths, before definitive local therapy. When endocrine

herapy is given preoperatively, clinical responses are fre-uently observed and the proportion of patients who canndergo breast conservation can be increased.25-28 Despitehe clinical activity of preoperative endocrine therapy, pCR isare, occurring in less than 5% of cases. Trials of 3 to 4onths of preoperative tamoxifen v aromatase inhibitors

howed statistically significant improvements in breast-con-ervation rates in the aromatase inhibitor arms.25-27 Either aecline in the Ki-67 percent after exposure to preoperativendocrine therapy or the absolute Ki-67 percent after 2eeks of therapy appear to be predictors of long-term out-

ome.29 In a trial of preoperative letrozole v tamoxifen, pa-ients with high ER expression had similar favorable re-ponses to the 2 endocrine agents, whereas patients withntermediate ER expression had a higher response rate toetrozole.30 Patients with low ER expression had minimaln-breast response to either agent. At this time, the optimaluration of preoperative endocrine therapy is uncertain andill depend on the goals of the treatment for the individualatient. A longer duration of preoperative endocrine therapyppears to be associated with higher response rates. In 63atients treated with extended durations of preoperative

etrozole, tumor volume continued to decrease for up to 12 to4 months.31 Outside of a clinical trial, preoperative endo-rine therapy appears to be a reasonable approach for post-enopausal patients who are not thought to be candidates

or preoperative chemotherapy either because of comorbidityr tumor biology.In general, preoperative endocrine therapy should not be

iewed as a substitute for surgery. A study in operable breastancer patients over the age of 70 comparing tamoxifen alonesurgery plus tamoxifen showed a significantly higher lo-

oregional relapse rate with tamoxifen alone (23% v 8%) andworse overall and breast cancer mortality (HR � 1.68) for

he tamoxifen-alone group.32,33

argeted Biologicalherapies for HER-2–verexpressing Breast Cancer

n tumors with overexpressed or amplified HER-2, numer-us phase II studies have shown that adding trastuzumab toreoperative chemotherapy achieves high pCR rates. The
. D. Anderson group conducted a small, randomized phase

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I preoperative trial of paclitaxel and fluorouracil, epirubicin,nd cyclophosphamide chemotherapy with or without tras-uzumab in HER-2–overexpressing breast cancer.34 The pCRate was 25% in the chemotherapy-only arm v 67% in thehemotherapy-trastuzumab arm. This magnitude of increasen pCR in the trastuzumab arm was similar to the magnitudef improvement in DFS seen in the adjuvant trastuzumabrials. Similar results have been reported by Gianni et al in arial that randomized patients with locally advanced, HER-–positive breast cancer to chemotherapy alone or chemo-herapy plus trastuzumab.35 The primary endpoint of thishase III trial was event-free survival. At a median follow-upf 3 years, the hazard ratio for event-free survival was 0.56P � .006) for patients with HER-2–positive disease receiv-ng chemotherapy plus trastuzumab. In patients with HER-–positive disease receiving trastuzumab, pCR was observed

n 43% v 23% in those treated with chemotherapy only. Inhis study, as in the M. D. Anderson trial, trastuzumab wasdministered concurrently with an anthracycline-basedhemotherapy regimen. Caution must be advised regard-ng the concomitant use of trastuzumab with anthracy-lines. If used, protocol evaluated doses and scheduleshould be given. The safety of concurrent v sequentialdministration of trastuzumab with epirubicin is undervaluation in the American College of Surgeons Uncologyroup Z1041 trial.A number of other HER-2–targeted agents are in devel-

pment. Lapatinib, an oral tyrosine kinase inhibitor ofpidermal growth factor receptor and HER-2, receivedood and Drug Administration approval based on resultsf a randomized phase III trial comparing capecitabinelone with capecitabine with lapatinib in patients withdvanced HER-2–positive breast cancer who had pro-ressed on an anthracycline, a taxane, and trastuzumab.36

lso, in the advanced-disease setting, a phase II trial ofapatinib in refractory/relapsed IBC (of which most pa-ients had previously received trastuzumab) reported alinical response rate of 50% on skin lesions and a 28%esponse rate by response evaluation criteria in solid tu-ors criteria was observed.37 In the neoadjuvant setting,

apatinib monotherapy followed by lapatinib and weeklyaclitaxel in patients with newly diagnosed IBC resulted inclinical response rate of 77% (including a 30% response

ate to only 2 weeks of lapatinib monotherapy) and a pCRf 17% in patients with HER-2–positive IBC.38 The opti-al preoperative therapy strategy for HER-2– overex-ressing tumors is under evaluation in a number of ongo-

ng trials. Trastuzmab v lapatinib or the combination withhemotherapy is being evaluated in the neo-adjuvant lapat-nib and/or trastuzumab treatment optimization Grupo Españole Investigación del cáncer de Mama 2006-14, and Cancer andeukemia Group B 40601 trials. The role of new agents withctivity against HER-2–overexpressing tumors, such as nera-inib (HKI-272) and trastuzumab-DM1 (HER-2 antibody-rug conjugate), are eagerly awaited as the armamentarium
gainst this tumor type expands. z
ntiangiogenicherapy in LABC

ecause of the overexpression of particular genes and pro-eins, the aggressive nature of LABC, and the ability to mea-ure treatment response in vivo, clinical trials of neoadju-ant-targeted agents either alone or in combination withhemotherapeutic agents are particularly attractive. Bevaci-umab is a humanized monoclonal antibody to VEGF-A thatarnered Food and Drug Administration approval for thereatment of advanced breast cancer in combination withaclitaxel based on a significant improvement in DFS from.9 to 11.8 months (HR � 0.60, P � .001).39 The experienceith bevacizumab in the neoadjuvant setting is fairly limited

o date.A small, phase II pilot trial of bevacizumab in combination

ith doxorubicin and docetaxel as preoperative therapy inABC/IBC yielded a clinical response rate of 67% (with a 5%CR rate).40 Importantly, this trial showed a marked decrease

n tumor VEGF receptor activation and an increase in tumorell apoptosis after treatment with the bevacizumab alone.hese correlative studies suggest that by blocking VEGF, be-acizumab inhibits the activation of VEGFR2 and inducesumor apoptosis. Greil et al41 have reported on the combina-ion of bevacizumab, docetaxel, and capecitabine as preop-rative therapy in HER-2–negative breast cancer.41 In thishase II trial, pCR was observed in 22% of patients, with allhe pCRs occurring in patients with hormone receptor–nega-ive disease. There were no surgical complications, conges-ive heart failure, hypertension, or wound-healing disordersbserved with the preoperative use of bevacizumab. Theafety and efficacy of neoadjuvant bevacizumab or placeboollowed by TAC in patients with stage II and III breast canceras reported by Hurvitz et al.42 In this trial, patients were

andomized to 1 of 4 arms with low-dose bevacizumab, 7.5g/kg; a standard dose of bevacizumab, 15 mg/kg; or pla-

ebo all given as an initial run-in followed by bevacizumab orlacebo with TAC chemotherapy for 6 cycles and then fol-

owed by bevacizumab or placebo in the adjuvant setting.reliminary data on the first 50 evaluable patients included aCR rate of 20%, which was not significantly different acrosshe treatment arms with and without bevacizumab. Wound-ealing complications were observed more often in patientseceiving neoadjuvant bevacizumab (21% v 12%, P � .699).

Based on the pilot experiences described earlier, the effi-acy of antiangiogenic therapy in the metastatic setting, andhe substantial unmet need for more efficacious systemicherapy options, bevacizumab and other targeted agents areeing evaluated in neoadjuvant clinical trials for women withABC and high-risk operable breast cancer. In an ambitious,andomized, phase III trial, National Surgical Adjuvantreast and Bowel Project B40 will evaluate 3 neoadjuvanthemotherapy regimens each with or without bevacizumabor patients with operable, HER-2–negative breast cancer.he primary endpoint of this trial is pCR with secondaryndpoints to evaluate efficacy of the addition of bevaci-
umab, safety, and evaluation of DFS.

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In the North American Breast Cancer InterGroup, an alter-ative strategy combining sunitinib with nabpaclitaxel fol-

owed by doxorubicin and cyclophosphamide chemotherapyill be led by the SWOG for patients presenting with LABC

nd IBC (SWOG S0800). Sunitinib is one of several, oral,mall-molecule tyrosine inhibitors with promising antitumornd antiangiogenic activities through the inhibition of plate-et-derived growth factor receptor, VEGF receptors (VEGF-1,2, and -3), kit, and FMS-like tyrosine kinase 3. Investigatorst the University of Washington and Arizona Cancer Centerre evaluating the safety and efficacy of sunitinib in combi-ation with weekly paclitaxel followed by metronomiceekly doxorubicin and daily oral cyclophosphamide as pre-perative therapy for patients with LABC and IBC in a phaseI pilot trial that is ongoing.

redictive Factors foresponse and Prognosisf Attaining A pCR

here is a clear correlation between tumor response in thereast and lymph nodes and both DFS and OS. pCR andther pathologic measures may be useful as surrogate end-oints in evaluating and understanding new therapies. pCRas emerged as the most commonly used surrogate endpointor gauging the efficacy of preoperative therapy for severaleasons. First, the attainment of pCR is associated with aavorable prognosis; such patients have a far lower risk ofubsequent recurrence than do patients with residual inva-ive tumor at the time of surgery and also appear to havemproved OS.8,10,43-49 Second, although there are variationsn the criteria and reporting for pathologic response, the mea-urement of pCR has been more uniform and less subject toifficulties in interpretations. Nonetheless, the definition ofCR has varied across clinical trials and throughout the liter-ture.50

There is a general agreement that the preferred definitionf pCR is the absence of residual invasive cancer within bothhe breast and axillary lymph nodes. The presence or absencef residual ductal carcinoma in situ after preoperative ther-py does not impact long-term DFS or OS.51 The presence ofny amount of nodal disease after preoperative therapy pre-icts for a poorer prognosis and should be included as resid-al disease in defining pCR.52-56

Not all patients who achieve a pCR remain free of recur-ence, and not all patients who do not achieve a pCR developecurrent disease. pCR after chemotherapy is probably mostredictive with respect to relapse and death for ER-negative,ER-2–negative tumors.57,58 Even in this setting, however,athologic response cannot be used as an endpoint to defineew standards of care. It is widely believed that pCR is not aufficiently robust endpoint, and other surrogate endpointsnd pathologic grading systems are under evaluation.59,60

Ultimately, the most significant benefit of systemic therapyests in its impact on OS. In the adjuvant setting, DFS is oftensed as a surrogate for OS because systemic recurrences fre-
uently lead to breast cancer deaths, and there is a high a
orrelation between DFS and OS. In the preoperative setting,CR has emerged as an important prognostic factor. Patientschieving a pCR have a significantly lower risk of recurrencehan patients with residual invasive tumor. Factors associatedith a higher likelihood of pCR include tumor size, histology

ductal � lobular), tumor intrinsic subtype (basal-like orER-2 enriched � luminal), hormone receptor status (ERegative � ER positive), and grade (high � low). Of these

actors, negative hormone receptor status appears to be theost predictive for response to preoperative therapy andCR.49,61-65

More recently, gene expression profiling by microarray hasevealed greater complexity in breast tumors and definedintrinsic” subtypes of breast cancer incuding luminal A, lu-inal B, HER-2 enriched, basal like, and normal like.66,67

ultiple studies have shown important interactions betweenntrinsic subtype and prognosis.66,68 These intrinsic subtypeseveal the limitations of classic histologic prognostic factors,uch as tumor grade, ER, and HER-2 by immunohistochem-stry in that all the intrinsic subtypes are present in cohorts ofatients with ER-positive or ER-negative tumors.69 A recentublication by Parker et al69 reports on the development ofisk of relapse predictor based on a 50-gene set (PAM50ssay) that classifies breast tumors by intrinsic subtypes. ThisAM50 assay was used to develop a risk of relapse model thatenerates a score that was also highly predictive of responseo neoadjuvant anthracycline and taxane chemotherapy. Theevelopment of this and other molecular profiling models70

epresent exciting advances that may allow one to furtherpersonalize” preoperative systemic therapy for specific tu-or types in the future.

onclusionsn LABC, the use of preoperative systemic therapy has beenhown to induce tumor response, to improve surgical op-ions because of the tumor response to therapy, to facilitateocal control through subsequent surgery and radiation ther-py, and to improve survival. Preoperative systemic therapys established as the standard of care for patients with LABC.

Preoperative therapy should be administered as part of aultimodality treatment program. When patients are givenreoperative systemic therapy, the preferred therapeutic reg-

mens are the same as those established as safe and active inhe adjuvant setting. A variety of clinical, imaging, and patho-ogic measurements are available to gauge tumor response toreatment. At present, there are no data to suggest that sys-emic treatment should be tailored in one direction or an-ther based on the initial tumor response or the lack thereofexcept in the setting of frank disease progression while onreatment) or the extent of residual disease.

The preoperative setting provides a unique opportunity totudy the impact of systemic therapies on breast cancer biol-gy. Using pCR and other pathologic measures as surrogatendpoints, it is hoped that promising therapies can undergoreliminary evaluation and then be definitely studied in

arger, adjuvant trials. The preoperative setting can thus serve
s a testing ground, and preoperative trials are likely to be-

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ome more prevalent over the next decade. Research in thereoperative setting has the potential to facilitate drug devel-pment and lead to more rapid improvements in the care ofomen with breast cancer.

eferences1. Davila E, Vogel CL: Management of locally advanced breast cancer

(stage III): A review. Int Adv Surg Oncol 7:297-327, 19842. Zucali R, Uslenghi C, Kenda R, et al: Natural history and survival of

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5. Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment ofpostmenopausal breast cancer patients with letrozole: A randomizeddouble-blind multicenter study. Ann Oncol 12:1527-1532, 2001

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7. Cataliotti L, Buzdar AU, Noguchi S, et al: Comparison of anastrozoleversus tamoxifen as preoperative therapy in postmenopausal womenwith hormone receptor-positive breast cancer: The pre-operative“Arimidex” compared to tamoxifen (PROACT) trial. Cancer 106:2095-2103, 2006

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2. Bates T, Riley DL, Houghton J, et al: Breast cancer in elderly women: Acancer research campaign trial comparing treatment with tamoxifenand optimal surgery with tamoxifen alone. The Elderly Breast CancerWorking Party. Br J Surg 78:591-594, 1991

3. Fennessy M, Bates T, MacRae K, et al: Late follow-up of a randomizedtrial of surgery plus tamoxifen versus tamoxifen alone in women agedover 70 years with operable breast cancer. Br J Surg 91:699-704, 2004

4. Buzdar AU, Valero V, Ibrahim NK, et al: Neoadjuvant therapy withpaclitaxel followed by 5-fluorouracil, epirubicin, and cyclophospha-mide chemotherapy and concurrent trastuzumab in human epidermalgrowth factor receptor 2-positive operable breast cancer: An update ofthe initial randomized study population and data of additional patientstreated with the same regimen. Clin Cancer Res 13:228-233, 2007

5. Gianni L, Eiermann W, Semiglazov V, et al: Neoadjuvant trastuzmab inpatients with Her-2 positive locally advanced breast cancer: Primaryefficacy analysis of the NOAH trial. Presented at the 31st Annual SanAntonio Breast Cancer Symposium. San Antonio, TX, December 10-14,2008

6. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for

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7. Spector NL, Blackwell K, Hurley J, et al: EGF103009, a phase II trial oflapatinib monotherapy in patients with relapsed/refractory inflamma-tory breast cancer (IBC): Clinical activity and biologic predictors ofresponse: Presented at the ASCO Annual Meeting, Atlanta, GA, June2-6 2006. J Clin Oncol 24:502, 2006 (suppl)

8. Cristofanilli M, Boussen H, Ben Ayed F: A phase II combination studyof lapatinib (TYKERB) and paclitaxel as neoadjuvant therapy in patientswith newly diagnosed inflammatory breast cancer. IBC. Presented at29th Annual San Antonio Breast Cancer Symposium. San Antonio, TX,December 14-17, 2006

9. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versuspaclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666-2676, 2007

0. Wedam SB, Low JA, Yang SX, et al: Antiangiogenic and antitumoreffects of bevacizumab in patients with inflammatory and locally ad-vanced breast cancer. J Clin Oncol 24:769-777, 2006

1. Greil R, Moik M, Reitsamer R, et al: Neoadjuvant bevacizumab, do-cetaxel and capecitabine combination therapy for HER2/neu-negativeinvasive breast cancer: Efficacy and safety in a phase II pilot study. EurJ Surg Oncol 2009 July 13; [epub ahead of press]

2. Hurvitz SA, Bosserman LD, Leland-Jones B, et al: A multicenter, dou-ble-blind randomized phase II trial of neoadjuvant treatment with sin-gle-agent bevacizumab or placebo, followed by docetaxel, doxorubicin,and cyclophosphamide (TAC), with or without bevacizumab, in pa-tients with stage II or stage III breast cancer: Presented at ASCO AnnualMeeting. Chicago, IL, May 30-June 3, 2008

3. Feldman LD, Hortobagyi GN, Buzdar AU, et al: Pathological assess-ment of response to induction chemotherapy in breast cancer. CancerRes 46:2578-2581, 1986

4. Sataloff DM, Mason BA, Prestipino AJ, et al: Pathologic response toinduction chemotherapy in locally advanced carcinoma of the breast: Adetermination of outcome. J Am Coll Surg 180:297-304, 1995

5. Honkoop AH, Pinedo HM, de Jong JS, et al: Effects of chemotherapy onpathologic and biologic characteristics of locally advanced breast can-cer. Am J Clin Pathol 107:211-218, 1997

6. Honkoop AH, van Diest PJ, de Jong JS, et al: Prognostic role of clinical,pathological and biological characteristics in patients with locally ad-vanced breast cancer. Br J Cancer 77:621-626, 1998

7. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemother-apy on outcome of women with operable breast cancer. J Clin Oncol16:93-100, 1998

8. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breastcancer patients with complete pathologic primary tumor and axillarylymph node response to doxorubicin-based neoadjuvant chemother-apy. J Clin Oncol 17:460-469, 1999

9. Guarneri V, Broglio K, Kau S, et al: Prognostic value of pathologiccomplete response after primary chemotherapy in relation to hormonereceptor status and other factors. J Clin Oncol 24:1037-1044, 2006

0. Buzdar AU: Preoperative chemotherapy treatment of breast cancer: Areview. Cancer 110:2394-2407, 2007

1. Mazouni C, Peintinger F, Wan-Kau S, et al: Residual ductal carcinomain situ in patients with complete eradication of invasive breast cancerafter neoadjuvant chemotherapy does not adversely affect patient out-come. J Clin Oncol 25:2650-2655, 2007

2. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillary
nodes following neoadjuvant chemotherapy predict disease-free sur-
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3. Machiavelli MR, Romero AO, Pérez JE, et al: Prognostic significance ofpathological response of primary tumor and metastatic axillary lymphnodes after neoadjuvant chemotherapy for locally advanced breast car-cinoma. Cancer J Sci 4:125-131, 1998

4. Gajdos C, Tartter PI, Estabrook A, et al: Relationship of clinical andpathologic response to neoadjuvant chemotherapy and outcome oflocally advanced breast cancer. J Surg Oncol 80:4-11, 2002

5. McCready DR, Hortobagyi GN, Kau SW, et al: The prognostic signifi-cance of lymph node metastasis after preoperative chemotherapy foradvanced breast cancer. Arch Surg 124:21-25, 1989

6. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy inoperable breast cancer: Eight-year experience at the Milan Cancer In-stitute. J Clin Oncol 16:93-100, 1998

7. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Pri-mary tumor chemosensitivity of breast cancer subtypes. Clin CancerRes 13:2329-2334, 2007

8. Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapyand long-term survival in patients with triple negative breast cancer.J Clin Oncol 26:1275-1281, 2008

9. Ogston KN, Miller ID, Payne S, et al: A new histological grading systemto assess response of breast cancers to primary chemotherapy: Prognos-tic significance and survival. Breast 12:320-327, 2003

0. Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residualbreast cancer burden to predict survival after neoadjuvant chemother-apy. J Clin Oncol 28:4414-4422, 2007

1. Bear HD, Anderson S, Smith RE, et al: Sequential preoperative or post-operative docetaxel added to preoperative doxorubicin plus cyclophos-phamide for operable breast cancer: National surgical adjuvant breastand bowel project protocols B–27. J Clin Oncol 24:2019-2027, 2006

2. Colleoni M, Viale G, Zahrieh D, et al: Chemotherapy is more effective inpatients with breast cancer not expressing steroid hormone receptors: Astudy of preoperative treatment. Clin Cancer Res 10:6622-6628, 2004

3. Fisher ER, Wang J, Bryant J, et al: Pathobiology of preoperative chemo-therapy findings from the national surgical adjuvant breast and bowelproject (NSABP) protocols B–18. Cancer 95:681-695, 2002

4. Faneyte IF, Schrama JG, Peterse JL, et al: Breast cancer response toneoadjuvant chemotherapy: Predictive markers and relation to out-come. Br J Cancer 88:406-412, 2003

5. Mittendorf EA, Tucker SL, Meric-Bernstam A: Relationship betweenextent of estrogen receptor (ER) expression and pathologic completeresponse and pathologic complete response rates after administrationof neoadjuvant chemotherapy: Presented at the ASCO Breast CancerSymposium. Washington, DC, September 5-7, 2008

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7. Sørlie T, Perou CM, Tibshirani R, et al: Gene expression patterns ofbreast carcinomas distinguish tumor subclasses with clinical implica-tions. Proc Natl Acad Sci U S A 98:10869-10874, 2001

8. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breasttumor subtypes in independent gene expression sets. Proc Natl AcadSci U S A 100:8418-8423, 2003

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0. Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in par-affin-embedded core biopsy tissue predict response to chemotherapy inwomen with locally advanced breast cancer. J Clin Oncol 23:7265-
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reast Conservation Therapy foratients With Locally Advanced Breast Cancerohamed A. Alm El-Din, MD,*,† and Alphonse G. Taghian, MD, PhD*

Neoadjuvant chemotherapy achieves high response rates in patients with breast cancerand has been used to reduce tumor size and allow for breast conservation in individualswho initially required mastectomy. The goals of this approach are to achieve optimallocoregional control together with acceptable cosmesis. In the setting of locally advanceddisease, breast preservation appears to be feasible for appropriately selected patientswhose tumors show adequate downstaging in response to induction chemotherapy. Nev-ertheless, further prospective randomized trials are warranted to better evaluate the resultsof this approach as compared with mastectomy.Semin Radiat Oncol 19:229-235 © 2009 Elsevier Inc. All rights reserved.

KEYWORDS breast cancer, locally advanced, breast conservation

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astectomy followed by postmastectomy radiation hasbeen the standard of treatment for patients with locally

dvanced breast cancer (LABC) in that a breast-conservingpproach for patients with larger primary tumors may notave been technically feasible, may not have been as effective,nd may have resulted in significant cosmetic deformity.owever, since the introduction of neoadjuvant chemother-

py (NACT), a large number of patients with locally ad-anced primary disease have enjoyed a conservative ap-roach. This review addresses some of the issues andoncerns related to the use of this approach.

uccessates of Breastonservation After NACT

number of studies and clinical trials have shown that breastonservation after NACT is possible for selected patients whotherwise would require mastectomy. A study from M. D.nderson Cancer Center was one of the early reports that

nvestigated the feasibility of breast conservation after induc-ion chemotherapy in patients with locally advanced dis-

Department of Radiation Oncology, Massachusetts General Hospital, Har-vard Medical School, Boston, MA.

Department of Radiation Oncology, Tanta University Hospitals, Tanta Fac-ulty of Medicine, Tanta, Egypt.

ddress reprint requests to Alphonse G. Taghian, MD, PhD, Department ofRadiation Oncology, Massachusetts General Hospital, 100 Blossom Street

sCox Building 302, Boston, MA 02114. E-mail: [email protected].

053-4296/09/$-see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.semradonc.2009.05.005

ase.1 Mastectomy specimens from 143 patients with stageIB and III breast cancer (77% stage IIIA or IIIB) were retro-pectively analyzed after NACT. A complete response wasbserved in 16%, whereas 86% were considered as partialesponders. The authors were able to define strict selectionriteria for breast conservation on the basis of the pathologicssessment of mastectomy specimens. These criteria in-luded complete resolution of skin edema, residual tumorize of less than 5 cm, no evidence of multicentric lesions,nd the absence of extensive intramammary lymphatic inva-ion or extensive microcalcifications. The authors found that3% of this study cohort would have been eligible for con-ervative surgery rather than modified radical mastectomy onhe basis of these criteria.

Two randomized prospective trials, the National Surgicaldjuvant Breast and Bowel Project (NSABP) B18 trial anduropean organization of research and treatment of cancerEORTC) 10902 trial, which compared preoperative versusostoperative chemotherapy, have showed that a higher per-entage of patients among preoperative chemotherapy armsnderwent breast-conserving surgery.2-4 Among the B18rial, there was an overall increase in lumpectomies by 12% inhe preoperative chemotherapy group. The improvement inumpectomy rate was more pronounced, with 7-fold in-rease, in patients with tumors �5 cm. In the 10902 trial, 57atients (23%), among the preoperative chemotherapyroup, underwent breast-conserving surgery and not thelanned mastectomy.Other smaller studies have also indicated that breast con-

ervation is feasible after NACT. In a study involving 97

229


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230 M.A. Alm El-Din and A.G. Taghian

atients with LABC, the addition of docetaxel to CVAP (cy-lophosphamide, vincristine, doxorubicin, and prednisone)s opposed to further CVAP as induction chemotherapy re-ulted in higher complete clinical and pathologic response,nd this translated into a higher breast conservation rate67% v 48%).5 In another study on a small cohort of patientsith LABC (n � 29) who received NACT, Lebowitz et al6

ound that 59% underwent breast conservation, whereasnly 13% were considered eligible for this type of surgery atresentation. In the NSABP B27 trial, 2,411 patients withperable breast cancer were randomized to anthracyclinesith or without taxanes.7 Although the pathologic complete

esponse was doubled (26.1% v 13.7%), there was no signif-cant improvement with regard to the rate of the breast con-ervation rate (61.6% v 63.7%) or the overall survival.

Several studies have documented acceptable rates of localecurrence in patients with breast cancer undergoing breastonservation after NACT (Table 1).4,8-12 However, when in-erpreting such data, it is important to consider that some ofhese studies included both patients with early stage andhose with locally advanced disease. In the NSABP B18, thereas no significant difference in the rates of ipsilateral breast

umor recurrence (IBTR) between women treated withumpectomy in the setting of preoperative versus postopera-ive chemotherapy. However, the rate of IBTR among pa-ients who underwent breast conservation after their tumorsad been downstaged by NACT was significantly higherompared with that encountered among those who were ini-ially candidates for breast conservation (15.9% v 9.9%, P �04).4 It is important to note that the selection of type ofurgery was not randomized in the B18 study, which mightffect the accuracy of the results. Asoglu et al13 reportedlightly higher locoregional recurrence (LRR) rate in a groupf patients with LABC who were treated by induction che-otherapy followed by surgery. Most of this study cohort

75%) was stage III (Table 1). Mauriac et al14 also reported aigher rate of isolated local recurrence among breast canceratients with operable tumors larger than 3 cm who werereated by initial chemotherapy (Table 1).

Buchholz et al15 suggested that higher rates of local recur-

able 1 Local Recurrence Rate for Breast-Conserving Surger

Study Population Stage

cIntoch, et al10 173* T2 > 4 cm, T3, T4 or N2hen, et al12 340 I-IIIhen, et al11 33 IIIB and IIIClark, et al8 34 T3/T4, N0-2unt, et al9 93 IIA-IV†

SABP B184 1531 T1-3, N0-1soglu, et al13 28 IIB-IIIBauriac, et al14 272 T2 > 3 cm/T3, N0-1

bbreviations: BCS, breast-conserving surgery; LRR, locoregionalProject.

Data available for 166.Supraclavicular metastases only.The number of lumpectomies among patients who had preoperativThe rate of ipsilateral breast tumor recurrence.

ence among patients undergoing breast conservation after f

ACT could be explained by the small volume of resectionhat might not be appropriate for a large tumor that hasesponded to induction chemotherapy. Several prospec-ive clinical trials have addressed the issue of survival inatients with early stage or LABC receiving preoperativehemotherapy versus those receiving postoperative che-otherapy.2,4,14,16-20 These trials have confirmed overall

urvival equivalence for the two approaches further empha-izing the safety of the NACT. Based on these results togetherith the advantage of improving tumor resectability, induc-

ion chemotherapy followed by surgery and radiation hasecome the preferred approach for patients with bulky, lo-ally advanced disease at the time of diagnosis. Furthermore,uerer et al21 and Schwartz et al17 reported better disease-freend overall survival in patients with LABC undergoing breastonservation after NAC. However, when the responders weretratified with regard to age, there was no difference in sur-ival between the mastectomy arm and the breast conversa-ion arm. In addition, the studies with better survival in pa-ients with LABC undergoing breast conservation afternduction chemotherapy as compared with those undergoingastectomy might represent selection bias because the breast

onservation group likely includes patients who achieve a goodesponse to chemotherapy.

oncerns Over Thispproach/Volume of Resection

s shown in several pathologic studies, the pattern of re-ponse to induction chemotherapy is not uniform but rathereterogeneous, with some cases leaving clusters of viableumor cells at a distance from the central residual tumorite.3,22 This might explain the discrepancy between the clin-cal and the pathologic response to induction chemotherapyhat was reported in several studies.3,21,23-25

In a retrospective study by Clouth et al,26 101 patientsith LABC underwent NACT. Twenty-five patients (25%)

chieved a complete clinical and radiologic response andere subjected to multiple core biopsies centrally and at all

r NACT

umber of BCS LRR (%) Median Follow-up (mo)

44 2 62340 5§ 6033 6§ 6015 6.6 3086 9.7 55

503‡ 10.7 11428 14 6040 22.5§ 124

ence rate; NSABP, National Surgical Adjuvant Breast and Bowel

otherapy.

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Breast conservation therapy 231

omplete response in 16 patients, and they received adjuvantadiotherapy with no further surgery. Most of the patients8/9) who had residual disease underwent mastectomy indi-ating the existence of tumor in more than one quadrantespite achieving complete clinical and radiologic responsefter NACT. In another study of 226 patients with tumors �3m (87% had tumors between 3 and 5 cm) receiving NACTollowed by surgery, the histopathology showed multifocal-ty in the primary tumor in 37 patients (16.3%) and completeathologic response was seen in only 8 patients (3.5%).22

herefore, the assessment of tumor response to inductionhemotherapy with the elimination of patients with multifo-al disease is crucial when offering breast conservation inatients with LABC undergoing NACT.

ppropriate Selection Criteriaeveral institutions have reported their experience regardinghe role of breast conservation following induction chemo-herapy for LABC, nevertheless the fraction of patients of-ered breast conservation varies tremendously due to vari-bility of methods utilized as well as the inconsistence ofelection criteria.

The eligibility criteria for breast conservation after induc-ion chemotherapy in LABC are similar to those applied inarly-stage breast cancer. Presence of multicentric disease,xtensive micro-calcification, extensive skin changes, andymphatic permeation are generally considered as contrain-ications for breast conservation in those patients.27 Mathewt al28 suggested that breast conservation should be per-ormed for selected group of patients with LABC particularlyhose who achieve pathological complete response afterACT. Nevertheless, patients who respond partially with a

ignificant downstaging of the tumor size, as long as lumpec-omy is technically feasible, could also be candidates for con-ervative surgery after NACT.

In the study from M. D. Anderson Cancer Center, 110 of43 patients were not considered as good candidates forreast conservation after induction chemotherapy.1 Amonghose patients, 55 (50%) had tumor in other quadrants. Theactors most commonly associated with multiple quadrantnvolvement were persistent skin edema, residual tumor sizearger than 4 cm, extensive intramammary lymphatic inva-ion and mammographic evidence of multicentric disease.he patient desire for breast preservation is an important

ssue and should be also considered.Magnetic resonance imaging (MRI) may also play an im-

ortant role in better identification of patients who would beood candidates for breast conservation following NACT.ultiple studies have addressed the benefit of MRI in patientsith known breast cancer reporting that approximately 9%ill be found to have multicentric disease that was not de-

ected by conventional imaging.29-33 Evaluation of diseaseesponse to chemotherapy is another potential role of breastRI in the setting of preoperative chemotherapy. Several

tudies have suggested a greater agreement between MRI andxtent of residual disease as compared to that achieved with
hysical examination or conventional imaging.34-38 Yet, the t
ole of breast MRI to evaluate the feasibility of breast conser-ation after NACT has to be defined. Concerns regarding theensitivity, the availability and the cost of MRI should be alsoonsidered. Positron emission tomography scans, as predic-ors of pathological response, have been also tried but theata remain immature and require further validation.39

mportance ofrechemotherapy Clip Placement

ocalization of the tumor within the breast following NACTppears to be challenging particularly in the subset of pa-ients who achieve a complete clinical or radiological re-ponse. In a study by Edeiken et al,40 implantation of metallicarkers guided by ultrasound has shown to be optimal in

ocalization of the tumor bed in case complete response oc-urs following NACT. In 23 patients (47%), the metallicarkers were the only remaining marker for the tumor bed

ollowing NACT. The authors added that the metallic mark-rs showed no evidence of migration as comparisons wereade on mammograms after implantation and shortly before

urgery. The position of the markers was also confirmed onistopathological examination by proximity to fibrosis orcar tissue related to post-chemotherapy changes.

In a recent study from M. D. Anderson Cancer Center, themission of radio-opaque clip placement in patients under-oing preoperative chemotherapy was associated with in-reased incidence of local recurrence.41 The 5-year rate ofocal control was 98.6% in patients who had radio-opaquelips placed versus 91.7% in patients who did not have tumorarker clips placed (P � .02). The authors recommendedlacement of radio-opaque clips in the tumor bed before oruring NACT to facilitate accurate tumor bed localizationnd to reduce the risk of breast tumor recurrence. However,lip placement may not be required for lesions associatedith microcalcifications as they have an inherent target for

ubsequent localization. Skin tattooing has been shown to beffective in identification of the tumor bed as suggested byeronesi et al.22 Nevertheless, localization by metallic mark-rs has been more popular among surgeons particularly withhe advent of recent imaging modalities.

adiotherapy Afterreast Conservation in LABC

s in early breast cancer, postoperative radiotherapy is anntegral part in the management of patients with LABC un-ergoing breast conservation. The technique of irradiation isenerally the same; however, existing data are limited regard-ng whether comprehensive irradiation is absolutely neces-ary to achieve optimal locoregional control in patientshose tumors achieve substantial degree of downstaging in

esponse to chemotherapy.The results of surgical pathology have been traditionally

sed to estimate the odds of locoregional recurrence follow-ng surgery in breast cancer patients and hence identifying
hose who would benefit from nodal irradiation. However,

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his could not be applied for patients undergoing preopera-ive chemotherapy with an expected response rate up to 80%.he investigators at M. D. Anderson Cancer Center suggest

hat, in the preoperative chemotherapy setting, both the ini-ial clinical stage and the final pathologic extent of the diseasendependently predict the risk of a locoregional recurrence.42

After NACT and mastectomy, comprehensive radiationas found to benefit both local control and survival for pa-

ients presenting with clinical T3 tumors or stage lll-IV (ipsi-ateral supraclavicular nodal) disease and for patients withour or more positive nodes.43 The 5-year locoregional recur-ence rate in 12 patients with stage III disease who achievedpathologic complete remission, remained high when radi-

tion was not used (33.3% � 15.7%).44 Therefore, for se-ected patients undergoing breast conservation after NACT,rradiation of the supraclavicular and may be the upper in-ernal mammary nodes might be considered in conjunctionith breast radiotherapy regardless the response to systemic

reatment. Mauriac et al14 highlighted the role of surgery forxillary control as they reported higher nodal relapse in pa-ients undergoing preoperative chemotherapy who werereated exclusively by nodal irradiation as compared to thoseho had axillary dissection (10 v 1, respectively).The data from NSABP B-18 & B-27 and M. D. Anderson

ancer Center suggest that patients with clinical stage II dis-ase who have negative lymph nodes after induction chemo-herapy have an 8-year risk of LRR after mastectomy that isess than 10%.45,46 Given that local or regional radiotherapyas not given in the above mentioned studies, the rate of LRRoes not appear to justify nodal irradiation in this subset ofatients. The power of such conclusions is limited and needsurther confirmation in prospective randomized trials espe-ially all patients from the above mentioned studies under-ent axillary dissections (with or without sentinel lymphode surgery).Another challenge in the setting of postoperative radio-

herapy in patients with LABC undergoing NACT is the boostolume. The question is whether or not the pre-chemother-py volume should be irradiated particularly in patientshose tumors show significant or complete response to in-uction chemotherapy. Although the issue of irradiating there- or post-chemotherapy is still controversial, the majorityf institutions consider the pre-chemotherapy size. However,he cosmetic results of irradiating such large volume, in someases, need to be addressed because a large portion of thereast will be included in the treatment portals.

redictors ofocoregional Failure

he investigators at M. D. Anderson Cancer Center reportedhe results of NACT and breast conversation in 340 women,f whom 130 (38%) were stage III.12 At a median follow-uperiod of 60 months, the 5-year actuarial rates of IBTR-freend LRR-free survival were 95% and 91%, respectively. Ratesf IBTR and LRR were correlated with clinical N2 or N3
isease, pathologic residual tumor larger than 2 cm, a multi- p
ocal pattern of residual disease, and lymphovascular inva-ion. The presence of any one of these factors was associatedith 5-year actuarial IBTR-free and LRR-free survival rates of7% to 91% and 77% to 84%, respectively. Nevertheless, theuthors concluded that breast conservation is an acceptableodality of treatment after induction chemotherapy for pa-

ients with stage III disease.The previously mentioned four parameters were incorpo-

ated into a classification system that can be used in clinicalecision-making and to counsel patients treated with thisultimodality approach.47 The M. D. Anderson Prognostic

ndex (MDAPI) was developed by assigning scores of 0 (fa-orable) or 1 (unfavorable) for each of these four variablesnd using the total to give an overall MDAPI score of 0-4.sing the MDAPI score, patients who undergo breast conser-ation after NACT can be stratified into a low, intermediate,r high-risk group for IBTR and LRR. Patients with a score ofto 4, LRR was �60% after breast conservation and was0% with mastectomy.48 The authors suggested that accord-

ng to MDAPI score, patients at higher risk of recurrence mayenefit from alternative locoregional treatment strategies.soglu et al13 suggested that negative surgical margins fol-

owing breast conservation in patients undergoing NACTould be more important than clinical and histological pa-ameters in terms of prediction of local recurrence rate.

redictors ofisease-Free and Overall Survival

he NSABP B-18 trial confirmed the association between theategory of clinical response to induction chemotherapy andurvival in operable breast cancer.4 Of the 682 patients, 24736%) had complete clinical response and 88 (13%) hadomplete pathological response. At 9 years of follow-up, theates of disease-free survival was 64% in patients with com-lete clinical response compared to 46% in non-respondersstable disease and progressive disease; P � 0.0008). Theverall survival was similarly better (75% v 65%, P � 0.005).n this study, histological response was found to be betterredictor of outcome. At 9 years, the disease-free survival inatients who achieved complete pathological response was5% compared to 58% for incomplete responders (P �.0005). For overall survival the rates were 85% and 73%P � .00008).

In a randomized controlled trial including patients withABC, Heys et al5 reported significant increase in disease-freeurvival at 3 years in those with better clinical and patholog-cal response (90% v 77%, P � 0.03). Another study of 200atients with LABC, 17.6% had complete clinical responsend 12.2% had complete pathological response.49 Patientsith complete clinical response had better recurrence-free

nd overall survival as compared to those with partial re-ponse (79% and 85%, v 40% and 52%, respectively; P �.0001). The recurrence-free and overall survival were alsoignificantly better for patients with complete pathologicalesponse (85% for both) as compared to those with incom-
lete response (52% and 59%, respectively; P � 0.0001). In

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he prospective study by Kuerer et al21 that included 372atients with LABC receiving NACT, the 5-year disease-freend overall survival of the patients who achieved completeathological response (87% and 89%, respectively) wasignificantly better than that of patients who did not re-pond completely to chemotherapy (58% and 64%, re-pectively; P � 0.01).

The residual disease in the axilla following NACT has beeneported to be a poor prognostic factor for the out-ome.22,50,51 Rouzier et al50 reported an interesting finding onultivariate analysis of the data of 152 patients with T1 to T3

umors with cytologically proven metastasis in the axilla. Theuthors found that conversion of positive to negative nodesoccurred in 23%) was a strong predictor of survival (P �.01) where complete pathological response in the breast wasmarker of pathological axillary conversion following che-otherapy rather than a predictor of survival by itself.

s Breast Surgery Necessary?he choice of local treatment modality after NACT has beenlways an area of major controversy particularly in patientsith complete clinical response. After NACT, surgery and

adiotherapy have been tried solely or in combination in theontext of multidisciplinary approach. Touboul et al52

reated 147 patients with tumors more than 3 cm with fourycles of chemotherapy. Ninety-five patients were eligible forreast conservation (48; complete response and 47; residualisease). Patients with complete response received only ra-iotherapy boost where those with residual disease under-ent wide excision and received two more cycles of chemo-

herapy followed by radiotherapy. The 5-year overall survivaln the patients who underwent wide excision and radiother-py was 81% as compared to 65% in the radiotherapy aloneroup. For those who underwent mastectomy, the 5-yearurvival was 76%. Another French study reported extremelyigh rate of locoregional recurrence (34%) in a group ofreast cancer patients who were treated by initial chemother-py followed by breast and nodal irradiation with no sur-ery.14

The results of two meta-analyses stressed on the potentialole of surgery in breast cancer patients receiving NACT. Therst meta-analysis evaluated the results of nine randomizedtudies, including a total of 3946 patients with breast can-er.53 Among the included studies, the tumor size rangedrom T0 to T4b where the nodal status ranged from N0 to N2.rimary outcomes were death, disease progression, distantisease failure, and locoregional disease recurrence. The au-hors reported no statistically or clinically significant differ-nce between neoadjuvant therapy and adjuvant therapyrms associated with death (risk ratio [RR] � 1.00; 95%onfidence interval [CI], 0.90 to 1.12), disease progressionRR � 0.99; 95% CI, 0.91 to 1.07), or distant disease failureRR � 0.94; 95% CI, 0.83 to 1.06). However, the risk ofocoregional disease recurrences (RR � 1.22; 95% CI, 1.04 to.43) was significantly higher in neoadjuvant therapy com-ared with adjuvant therapy, particularly in trials where
ore patients in the neoadjuvant arm received radiation
herapy without surgery (RR � 1.53; 95% CI, 1.11 to 2.10).he authors recommended avoiding the use of radiotherapyithout any surgical treatment, even in the presence of an

pparently good clinical response to NACT.More recently, the rates of breast conservation as well as

he rates of local recurrence were examined in those receivingACT compared to those receiving adjuvant chemotherapy

n meta-analysis of 11 studies including over 5000 patientsith operable breast cancer.54 Despite the significantly de-

reased rates of mastectomy among the neoadjuvant group,he local recurrence rates were significantly higher among theame group. In the three studies, which account for morehan one third of the patients, radiotherapy was the onlyodality of local treatment as surgery was not done after

omplete response. After exclusion of the results of thesetudies, there was no significant difference between the tworoups with regard to local recurrence (Hazard Ratio 1.12;5% CI, 0.92-1.37).Resection is also essential for documenting chemotherapy

esponse and achieving locoregional control.55 Surgery,herefore, remains the mainstay in management of patientsith LABC receiving NACT as clinical assessment could beeceiving.

eview of Datan summary, breast conservation after NACT appears to beeasible in patients with LABC because it offers an acceptableate of disease control. The proper selection of patients whore candidates for this modality is crucial because it will affecthe treatment outcome in terms of locoregional control rate,isease-free survival, and overall survival. Pre-chemotherapylip placement is an integral part if breast conservation is toe considered after NACT, especially for those patients whoight achieve complete clinical and radiologic responses.rozen section and histopathological examination at the timef breast-conserving surgery could be important because thendings from the pathology might reveal a high probabilityf multicentricity, which would preclude the use of a conser-ative approach.

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3. van der Hage JA, van de Velde CJ, Julien JP, et al: Preoperative chemo-therapy in primary operable breast cancer: results from the EuropeanOrganization for Research and Treatment of Cancer trial 10902. J ClinOncol 19:4224-4237, 2001

4. Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy inpatients with operable breast cancer: Nine-year results from NationalSurgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer InstMonogr 30:96-102, 2001

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1. Shen J, Valero V, Buchholz TA, et al: Effective local control and long-term survival in patients with T4 locally advanced breast cancer treatedwith breast conservation therapy. Ann Surg Oncol 11:854-860, 2004

2. Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation afterneoadjuvant chemotherapy: the MD Anderson cancer center experi-ence. J Clin Oncol 22:2303-2312, 2004

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6. Mauriac L, Durand M, Avril A, et al: Effects of primary chemotherapy inconservative treatment of breast cancer patients with operable tumorslarger than 3 cm. Results of a randomized trial in a single centre. AnnOncol 2:347-354, 1991

7. Schwartz GF, Birchansky CA, Komarnicky LT, et al: Induction chemo-therapy followed by breast conservation for locally advanced carci-noma of the breast. Cancer 73:362-369, 1994

8. Schwartz GF, Lange AK, Topham AK: Breast conservation followinginduction chemotherapy for locally advanced carcinoma of the breast(stages IIB and III). A surgical perspective. Surg Oncol Clin N Am4:657-669, 1995

9. Powles TJ, Hickish TF, Makris A, et al: Randomized trial of chemoen-docrine therapy started before or after surgery for treatment of primarybreast cancer. J Clin Oncol 13:547-552, 1995

0. Makris A, Powles TJ, Ashley SE, et al: A reduction in the requirementsfor mastectomy in a randomized trial of neoadjuvant chemoendocrinetherapy in primary breast cancer. Ann Oncol 9:1179-1184, 1998

1. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breastcancer patients with complete pathologic primary tumor and axillarylymph node response to doxorubicin-based neoadjuvant chemother-apy. J Clin Oncol 17:460-469, 1999

2. Veronesi U, Bonadonna G, Zurrida S, et al: Conservation surgery afterprimary chemotherapy in large carcinomas of the breast. Ann Surg222:612-618, 1995

3. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy inoperable breast cancer: eight-year experience at the Milan Cancer In-stitute. J Clin Oncol 16:93-100, 1998

4. Gardin G, Rosso R, Campora E, et al: Locally advanced non-metastaticbreast cancer: analysis of prognostic factors in 125 patients homoge-neously treated with a combined modality approach. Eur J Cancer31A:1428-1433, 1995

5. von Minckwitz G, Costa SD, Eiermann W, et al: Maximized reductionof primary breast tumor size using preoperative chemotherapy withdoxorubicin and docetaxel. J Clin Oncol 17:1999-2005, 1999

6. Clouth B, Chandrasekharan S, Inwang R, et al: The surgical manage-
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8. Mathew J, Asgeirsson KS, Cheung KL, et al: Neoadjuvant chemother-apy for locally advanced breast cancer: a review of the literature andfuture directions. Eur J Surg Oncol 35:113-122, 2009

9. Harms SE, Flamig DP, Hesley KL, et al: MR imaging of the breast withrotating delivery of excitation off resonance: clinical experience withpathologic correlation. Radiology 187:493-501, 1993

0. Fischer U, Kopka L, Grabbe E: Breast carcinoma: effect of preoperativecontrast-enhanced MR imaging on the therapeutic approach. Radiol-ogy 213:881-888, 1999

1. Mumtaz H, Hall-Craggs MA, Davidson T: Staging of symptomatic pri-mary breast cancer with MR imaging. AJR Am J Roentgenol 169:417-424, 1997

2. Liberman L, Morris EA, Dershaw DD, et al: MR imaging of the ipsilat-eral breast in women with percutaneously proven breast cancer. AJRAm J Roentgenol 180:901-910, 2003

3. Schelfout K, Van Goethem M, Kersschot E, et al: Contrast-enhancedMR imaging of breast lesions and effect on treatment. Eur J Surg Oncol30:501-507, 2004

4. Balu-Maestro C, Chapellier C, Bleuse A, et al: Imaging in evaluation ofresponse to neoadjuvant breast cancer treatment benefits of MRI. BreastCancer Res Treat 72:145-152, 2002

5. Rosen EL, Blackwell KL, Baker JA, et al: Accuracy of MRI in the detec-tion of residual breast cancer after neoadjuvant chemotherapy. AJRAm J Roentgenol 181:1275-1282, 2003

6. Weatherall PT, Evans GF, Metzger GJ, et al: MRI vs. histologic mea-surement of breast cancer following chemotherapy: comparison withx-ray mammography and palpation. J Magn Reson Imaging 13:868-75,2001

7. Yeh E, Slanetz P, Kopans DB, et al: Prospective comparison of mam-mography, sonography, and MRI in patients undergoing neoadjuvantchemotherapy for palpable breast cancer. AJR Am J Roentgenol 184:868-877, 2005

8. Partridge SC, Gibbs JE, Lu Y, et al: Accuracy of MR imaging for reveal-ing residual breast cancer in patients who have undergone neoadjuvantchemotherapy. AJR Am J Roentgenol 179:1193-1199, 2002

9. Kim SJ, Kim SK, Lee ES, et al: Predictive value of [18F]FDG PET forpathological response of breast cancer to neo-adjuvant chemotherapy.Ann Oncol 15:1352-1357, 2004

0. Edeiken BS, Fornage BD, Bedi DG, et al: US-guided implantation ofmetallic markers for permanent localization of the tumor bed in pa-tients with breast cancer who undergo preoperative chemotherapy.Radiology 213:895-900, 1999

1. Oh JL, Nguyen G, Whitman GJ, et al: Placement of radiopaque clips fortumor localization in patients undergoing neoadjuvant chemotherapyand breast conservation therapy. Cancer 110:2420-2427, 2007

2. Buchholz TA, Tucker SL, Masullo L, et al: Predictors of local-regionalrecurrence after neoadjuvant chemotherapy and mastectomy withoutradiation. J Clin Oncol 20:17-23, 2002

3. Huang EH, Tucker SL, Strom EA, et al: Postmastectomy radiation im-proves local-regional control and survival for selected patients withlocally advanced breast cancer treated with neoadjuvant chemotherapyand mastectomy. J Clin Oncol 22:4691-4699, 2004

4. McGuire SE, Gonzalez-Angulo AM, Huang EH, et al: Postmastectomyradiation improves the outcome of patients with locally advancedbreast cancer who achieve a pathologic complete response to neoadju-vant chemotherapy. Int J Radiat Oncol Biol Phys 68:1004-1009, 2007

5. Garg AK, Strom EA, McNeese MD, et al: T3 disease at presentation orpathologic involvement of four or more lymph nodes predict for lo-coregional recurrence in stage II breast cancer treated with neoadjuvantchemotherapy and mastectomy without radiotherapy. Int J Radiat On-col Biol Phys 59:138-145, 2004

6. Mamounas T: Sentinel node biopsy after neoadjuvant chemotherapy:
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7. Chen AM, Meric-Bernstam F, Hunt KK, et al: Breast conservation afterneoadjuvant chemotherapy. Cancer 103:689-695, 2005

8. Huang EH, Strom EA, Perkins GH, et al: Comparison of risk of local-regional recurrence after mastectomy or breast conservation therapy forpatients treated with neoadjuvant chemotherapy and radiation strati-fied according to a prognostic index score. Int J Radiat Oncol Biol Phys66:352-357, 2006

9. Thomas E, Holmes FA, Smith TL, et al: The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response toa neoadjuvant doxorubicin-based regimen in women with operablebreast cancer: long-term results from a prospective randomized trial.J Clin Oncol 22:2294-2302, 2004

0. Rouzier R, Extra JM, Klijanienko J, et al: Incidence and prognostic signifi-cance of complete axillary downstaging after primary chemotherapy inbreast cancer patients with T1 to T3 tumors and cytologically proven
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1. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillarylymph nodes following neoadjuvant chemotherapy predict disease-freesurvival in patients with locally advanced breast cancer. Am J Surg176:502-509, 1998

2. Touboul E, Lefranc JP, Blondon J, et al: Primary chemotherapy andpreoperative irradiation for patients with stage II larger than 3 cm orlocally advanced non-inflammatory breast cancer. Radiother Oncol 42:219-229, 1997

3. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant sys-temic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst97:188-194, 2005

4. Mieog JS, van der Hage JA, van de Velde CJ: Preoperative chemothe-rapy for women with operable breast cancer. Cochrane Database SystRev CD005002, 2007

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ation therapy. Cancer 62:2507-2516, 1988

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ostmastectomy Radiation Therapy foratients With Locally Advanced Breast Cancer

eshma Jagsi, MD, DPhil, and Lori Pierce, MD

Radiation therapy is an integral component of the multimodal treatment of locally advancedbreast cancer. Even after mastectomy and systemic therapy, occult residual disease in thechest wall and/or regional lymph nodes may serve as the source of morbid locoregionalrecurrence as well as the source of distant seeding or reseeding of metastases. Thus,postmastectomy radiation therapy offers substantial benefits in appropriately selectedpatients. This review article summarizes the data from randomized trials revealing asignificant benefit from postmastectomy radiation therapy in patients with locally advanceddisease as well as results from other relevant studies. It concludes with a summary ofconsensus guideline recommendations in this important area.Semin Radiat Oncol 19:236-243 © 2009 Elsevier Inc. All rights reserved.

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or patients with pathologic stage III breast cancer eitherhistorically defined1 or as defined in the current 6th edi-

ion of the American Joint Committee on Cancer’s Cancertaging Manual,2 radiation therapy is an integral componentf multimodal treatment. Even after mastectomy and sys-emic therapy, occult disease may remain in the chest wallnd/or regional lymph nodes. This residual disease may serveot only as a source of potentially morbid locoregional recur-ence but also as an important reservoir from which distantetastases may be seeded or reseeded after the initial elimi-ation of distant disease by sophisticated modern systemicherapies. Interest in postmastectomy radiation therapyPMRT) stems from the concept that when an isolated locore-ional reservoir of tumor cells remains after surgery and sys-emic therapy, if radiation therapy is able to eliminate thiseservoir, PMRT may contribute both to the improvement ofocal control and also to the reduction of breast cancer-re-ated mortality.

In 2005, the Oxford Early Breast Cancer Trialists’ Collab-rative Group published a landmark update of their compre-ensive meta-analysis, considering data from 8,505 womenith lymph node-positive disease treated with mastectomy

nd axillary clearance and enrolled on randomized trials ofMRT. In this update, which included patients enrolled onrials initiated through 1995, the 5-year local recurrence riskas reduced with radiotherapy from 22.8% to 5.8%, with5-year breast cancer mortality risks of 54.7% v 60.1% (re-

epartment of Radiation Oncology, University of Michigan, Ann Arbor, MI.ddress reprint requests to Reshma Jagsi, MD, DPhil, Department of Radi-

ation Oncology, UHB2C490, SPC 5010, 1500 East Medical Center
PDrive, Ann Arbor, MI 48109-5010. E-mail: [email protected]

uction 5.4%, 2P � .0002) and an overall mortality reduc-ion of 4.4% (64.2% v 59.8%, 2P � .0009).3 Figure 1 showshese findings. Thus, there has now been documented notnly substantial improvement in local control but also a clearverall survival (OS) advantage because of the use of PMRT inode-positive patients.These findings provide a strong rationale for the use of

adiation therapy in the management of patients with locallydvanced breast cancer. In this article, we first review thevidence gathered from the randomized trials of PMRT re-arding the relative reduction in risk of locoregional recur-ence afforded by radiotherapy and associated effects onurvival, including a detailed discussion of the issues of ap-ropriate patient selection that continue to generate debate inhe field. We then turn to the particular complexities intro-uced into the decision-making process when neoadjuvanthemotherapy has been used. Finally, we conclude by pre-enting a summary of the consensus statements issued byarious professional societies and organizations to guideractice in this area.

vidence Fromandomized Trials

MRT has been a subject of considerable study over the pasteveral decades. Multiple randomized trials have consistentlyevealed a substantial reduction in the risk of locoregionalecurrence of breast cancer with the use of PMRT.4-6

However, most early studies failed to show an improve-ent in OS, and meta-analyses suggested that the benefits of

MRT in cancer control were offset by treatment-related tox-


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Postmastectomy radiation therapy 237

city, especially cardiotoxicity.7 Outdated radiation tech-iques, such as anterior “hockey stick” photon fields, led

arge volumes of the heart to receive high doses of radiation inany older studies. Therefore, the salutary effect of PMRTpon OS was not convincingly established until large studiestilizing modern techniques of radiotherapy matured.The Eastern Cooperative Oncology Group conducted a

rial from 1982 to 1987 focusing exclusively on patients withperable locally advanced disease as defined by 1978 Amer-can Joint Committee on Cancer staging treated with both

astectomy and systemic therapy.8 It included patients withathologic T4 lesions excluding T4d disease, T3 lesions withositive nodes, N2 disease (defined as metastases to ipsilat-ral lymph nodes fixed to one another or to other structures),r earlier stage lesions fixed to underlying muscle. Patientsnderwent modified or standard radical mastectomy withrossly tumor-free margins and had examination of at leastaxillary nodes. Patients went on to receive 6 courses of

yclophosphamide, doxorubicin, fluorouracil, tamoxifen,nd fluoxymesterone (CAFTH) systemic therapy and werehen randomized to PMRT or observation. By focusing on aroup at high risk of locoregional recurrence, all of whomeceived systemic therapy in the hopes of addressing anyistant micrometastatic disease that existed on presentation,nd by using relatively modern techniques and doses of ra-iotherapy, this study attempted to address many of the con-erns of critics of the previous trials. Unfortunately, highates of noncompliance with treatment assignment and insuf-cient numbers of patients analyzed with relatively short fol-

ow-up to allow detection of a modest survival differenceltimately limited the impact of the study.9 The analysis ofutcomes in the 312 randomized patients, after a medianollow-up of 9 years, revealed a significant and substantialeduction in locoregional recurrence as a component of ini-ial failure in patients who were assigned to radiotherapy

Figure 1 Early Breast Cancer Trialists’ Collaboratve Gropositive patients. (Reprinted with permission.3)

MRT (15% v 24%). However, PMRT had no detectable im- f

act on overall time to relapse or survival in this series ofocally advanced breast cancer patients.

In contrast, randomized trials from Denmark and Britisholumbia, initially published in 1997, did finally show a

ignificant survival benefit from PMRT. The British Columbiarial randomized 318 premenopausal patients with patholog-cally positive lymph nodes, status post modified radical mas-ectomy with axillary lymph node dissection, to CMF chemo-herapy alone or chemotherapy and PMRT to the chest wallnd regional lymph nodes.10 In this study, PMRT both re-uced locoregional failure (from 28% to 10%) and improvedS (20-year OS improved from 37% to 47%, P � .03). Theanish 82b trial randomized 1,708 premenopausal womenith high-risk breast cancer (defined as involvement of the

xillary nodes, tumor size �5 cm, or invasion of the skin orectoral fascia), status post total mastectomy and axillaryissection, to CMF chemotherapy and PMRT to the chestall and regional lymph nodes v CMF chemotherapy alone.11

n this study, PMRT also led to both a reduction in locore-ional failure (from 32% to 9%) and an improvement in OS10-year OS improved from 45% to 54%, P � .001). The Dan-sh 82c trial randomized 1,375 postmenopausal high-risk breastancer patients younger than 70 years of age, status post totalastectomy and axillary dissection, to radiation therapy plus

amoxifen v tamoxifen alone.12 Again, PMRT reduced locore-ional recurrence (from 35% to 8%) and improved OS (10-yearS improved from 36% to 45%, P � .03). Of note, in each of

hese 3 trials, PMRT benefited not only patients with 4 or morexillary nodes involved but also those with 1 to 3 nodes positive.ogether, these studies have been extremely influential in shift-

ng opinion in favor of PMRT, at least for patients at high risk ofocoregional recurrence, such as those presenting with locallydvanced disease by current staging.

These studies met with certain criticisms, however. Thesencluded concerns about the adequacy of the surgery per-

ta-analysis results regarding effects of PMRT in node-
up me
ormed. The median number of lymph nodes removed in the

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238 R. Jagsi and L. Pierce

anish study was only 7, lower than that expected from atandard level I/II axillary dissection, prompting the concernhat inadequate regional surgery may have led to the under-stimation of the true extent of axillary disease in these pa-ients and possibly also contributed to an increased incidencef locoregional failures. Because locoregional recurrenceates after mastectomy (and without PMRT) in retrospectivemerican series of patients with 1 to 3 positive lymph nodesave been lower (13% in large series from Eastern Coopera-ive Oncology Group13 and the National Surgical Adjuvantreast and Bowel Project (NSABP)14) than those observed inhe Danish and British Columbia studies, some have ques-ioned the role of PMRT for American patients with only 1 tolymph nodes involved. Indeed, consensus panels convened

n this country around the turn of the millennium concludedhat the evidence to support PMRT was only strong enough toustain a recommendation for patients with 4 or more lymphodes involved as well as a suggestion for treatment for pa-ients with T3, node-positive disease.15 For patients with 1 to

lymph nodes involved, these panels concluded there wasnsufficient evidence to make suggestions or recommenda-ions for the routine use of PMRT, and practice in the United

Figure 2 Findings from the subset analysis of the Danish po

tates became divided between radiation oncologists whooutinely treat and those who routinely observe this sub-roup of patients.16 Unfortunately, the Intergroup’s random-zed study designed to assess the role of PMRT in Americanatients with 1 to 3 positive lymph nodes failed to accrue andlosed in 2003.

More recently, however, increasing evidence has accumu-ated in support of a role for PMRT even among patients with

to 3 lymph nodes involved. The Danish studies wereooled and reanalyzed to include only the 1152 node-posi-ive patients with 8 or more lymph nodes removed. A survivalenefit of the same absolute magnitude (9%) was observed inatients with 1 to 3 lymph nodes involved as among patientsith 4 or more lymph nodes involved, even though the lo-

oregional recurrence rates were lower among the formerroup (Fig. 2).17 This led the authors to note that the survivalenefit of PMRT is likely related to the ability of systemicherapy to eliminate any existing metastatic deposits at theime of diagnosis; therefore, PMRT may be particularly im-ortant in the subgroup of patients with less extensive nodal

nvolvement in whom the burden of distant disease at diag-osis is likely to be less substantial (and potentially more

stmastectomy trials. (Reprinted with permission.17)

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menable to elimination by systemic therapies) or absent.urther compelling findings have emerged from the Oxfordarly Breast Cancer Trialists’ Collaborative Group’s meta-nalysis, as discussed earlier.

Although the participants in the Danish and Canadian tri-ls were primarily patients with node-positive disease, pa-ients with large or advanced primaries and node-negativeisease were included in the Danish trials and may also ben-fit from PMRT. Patients with node-negative disease whoave large or otherwise locally advanced primary tumors,lthough uncommon, have traditionally been considered atigh risk for locoregional recurrence after mastectomy in thebsence of radiation therapy.18,19 Moreover, in the Danishrials, not only the node-positive patients but also patientsith node-negative high risk disease (ie, tumor size greater

han 5 cm and/or invasion to skin or pectoral fascia) appearedo benefit from radiotherapy. More specifically, among the35 node-negative patients in the 82b randomized trial, lo-oregional recurrence was 3% among patients treated withhemotherapy and radiation and 17% in those treated withhemotherapy alone; 10-year disease-free survival was 74%n patients treated with radiation and chemotherapy and2% in those treated with chemotherapy alone, and 10-yearSs were 82% and 70%, respectively.11 In the 82c random-

zed trial, among the 132 node-negative patients included,ocal recurrence as first recurrence occurred in 6% of theatients treated with radiation and tamoxifen and 23% inhose treated with tamoxifen alone; 10-year disease-free sur-ival was 43% in patients treated with radiation and tamox-fen and 40% in those treated with tamoxifen alone, and0-year OS was 56% and 55%, respectively.12 Given thesendings, we continue to advocate the routine use of PMRT inomen with large or locally advanced primary tumors andode-negative disease.We should note, however, that the use of radiotherapy in

atients with small, node-negative T3 lesions warrants dis-ussion. Recent studies have suggested that rates of locore-ional recurrence may be lower than expected among pa-ients with node-negative, borderline T3 (stage II) disease. Aecent retrospective study of 70 patients treated at 3 institu-ions by mastectomy and systemic therapy (but no PMRT) for2-3, N0 disease (with mean tumor size of 6 cm) revealed a-year locoregional recurrence rate of only 7.6%.20 Anotherecent study examined the long-term outcomes of 313 stageI node-negative patients with tumors greater than or equal tocm (with a median tumor size of 5.5 cm) who underwentastectomy but not PMRT in 5 NSABP trials.21 The investi-

ators found that the overall 10-year cumulative incidence ofsolated locoregional failure was 7.1%, and the incidence ofocoregional failure with or without distant failure in thisopulation was 10.0%. They were unable to identify anytatistically significant prognostic factors for locoregionalailure. With such low incidences of locoregional failure overn extended follow-up period, the authors recommendedhat patients with T2-3 primaries and negative axillae notndergo PMRT. It is important to note, however, that theseere small, retrospective series, and the median size of the

umors in these studies was on the smaller end of the spec- a

rum for T3 tumors so that relatively fewer tumors of ex-remely large size were included. Patients with T3N0 tumorstill warrant consultation with a radiation oncologist whoay discuss these data with the patient as well as the pro-

pective data showing benefit after the use of PMRT in pa-ients with large or advanced primary tumors and node-neg-tive disease. Furthermore, in light of evidence from severalther retrospective studies of node-negative patients that in-luded patients with smaller primary tumors,22-24 it may berudent to consider a number of other potential prognosticeatures, including patient age, tumor size, margin status,resence of lymphovascular invasion, use of systemic ther-py, and nuclear grade, when determining whether to useMRT in patients with node-negative disease without clearlydvanced primary tumors for whom the risk of locoregionalailure appears to be less substantial. Further prospectivetudies are ongoing and necessary to quantify the potentialenefits of PMRT in this group.25

Ultimately, all patients with locally advanced breast cancererit consultation with radiation oncology because there is

trong consensus regarding the need for treatment in patientsith stage III disease. Patients with stage II disease should be

ounseled regarding their estimated risks of locoregional re-urrence in the absence of radiotherapy, the estimated ben-fit in terms of locoregional control expected from radiother-py, and the estimated impact on OS associated with thisreatment so that they may determine whether they wish toeceive treatment.

atients Treated Witheoadjuvant Chemotherapy

ecause none of the patients enrolled on the randomizedrials of PMRT just discussed were treated with neoadjuvantystemic therapy, appropriate patient selection for PMRT af-er neoadjuvant therapy is more complicated than whenathologic staging has been unaffected by disease response toystemic agents. In the absence of prospective trials, deci-ions regarding the role of PMRT in patients treated witheoadjuvant chemotherapy have largely been guided by ret-ospective analyses.

Investigators at the M. D. Anderson Cancer Center haveonducted a series of retrospective studies seeking to illumi-ate these issues. Their data suggest that both the initiallinical stage and final pathologic extent of disease are inde-endently predictive of the risk of locoregional failure in theetting of neoadjuvant chemotherapy and that radiation ther-py is effective at reducing this risk. For example, in onenalysis, they compared the outcomes of 542 patients treatedith neoadjuvant chemotherapy, mastectomy, and PMRTith the outcomes of a control group of 134 patients not

reated with PMRT. At 10 years, local-regional recurrenceates were significantly lower for irradiated patients at 11%ompared with 22%.26 The small subset of patients who pre-ented with clinical stage III disease who subsequentlychieved a complete pathologic response to systemic therapy
lso had a significantly reduced locoregional recurrence rate

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ompared with patients not treated with PMRT. At 10 years,hese patients had a 3% rate of locoregional recurrence (1vent among 35 patients) v 33% (3 events among 11 patients)n nonirradiated patients. Postmastectomy radiation also im-roved cause-specific survival in patients with stage IIIB dis-ase, clinical T4 tumors, and greater than 4 positive lymphodes. The authors suggested that PMRT should be consid-red for patients in all of these subsets, regardless of theiresponse to preoperative systemic chemotherapy.

A follow-up retrospective review of the same series of 542atients was published in 2005 examining the risk factorsssociated with locoregional recurrence after PMRT.27 Theuthors remarked on the importance of disease staging bothefore and after neoadjuvant chemotherapy because severalisk factors were associated with either the pretreatment orosttreatment extent of disease. For the patients who werereated with PMRT after neoadjuvant chemotherapy andastectomy, supraclavicular nodal involvement on presenta-

ion was associated with a higher risk of locoregional recur-ence after treatment. On postneoadjuvant chemotherapy as-essment, evidence of skin or nipple involvement andxtracapsular invasion were also strongly correlated withRR. The lack of tamoxifen use postoperatively was also as-ociated with increased LRR, but, because of the preponder-nce of patients with ER-negative disease with increased LRR,t was believed to be of little clinical significance. Of note,R-receptor negative disease was the strongest predictor ofRR in this group. Patients with 1 or none of these factors had4% 10-year LRR rate, but this rate jumped to 28% with theresence of 3 or more risk factors.The NSABP trials of neoadjuvant chemotherapy, in which

MRT was not administered, also offer an opportunity toetermine which patients face substantial risks of locore-ional failure in the absence of PMRT. In the B18 study,mong patients undergoing mastectomy, multivariate analy-is of risk factors for locoregional recurrence were similar inoth the pre- and postoperative chemotherapy arms withespect to age less than 50 years (related to the use of tamox-fen only in women �50 years of age) and pathologicallyositive axillary nodes. Breast tumor response was also sig-ificantly associated with local control in patients receivingeoadjuvant chemotherapy.28 A pooled analysis of the B18nd B27 trials, conducted by Mamounas,29 reveals an 8-yearisk of locoregional recurrence of 15% for 447 patients withesidual positive lymph nodes on pathologic evaluation aftereoadjuvant chemotherapy (Fig. 3).In 2008, a multidisciplinary expert panel organized by the

ational Cancer Institute published a statement of the sci-nce concerning locoregional treatments after preoperativehemotherapy for breast cancer.30 That statement concludeshat PMRT should be considered for patients presenting withlinical stage III disease or with histologically positive lymphodes after preoperative chemotherapy. It further concludeshat there is a need for prospective trials to evaluate the ben-fits of PMRT in patients with clinical stage II disease whoave negative lymph nodes after preoperative chemotherapy.n any case, given the complexities of assessing risks based on
rechemotherapy clinical data and postchemotherapy pa- I
hology in patients treated with neoadjuvant chemotherapy,reatment in a multidisciplinary context with radiation on-ology consultation before any treatment commences woulde especially prudent in these cases.

onsensus Guidelineshe complexities of the data described earlier motivated sev-ral professional societies to develop practice guidelines re-arding the use of PMRT. The American Society of Clinicalncology (ASCO) Health Services Research Committee com-issioned a multidisciplinary panel of breast cancer experts

or an in-depth review of worldwide data on locoregionalailure from breast cancer and the ability of PMRT to reduceisk of locoregional as well as distant relapse.31 When evi-ence-based data were inadequate, the expert panel washarged with using their expert opinion to assess the utility ofMRT. The panel’s systematic, graded review of all publishedvidence regarding PMRT was assembled into a clinical prac-ice guideline as summarized in Table 1.

Of note, the language used to express the guidelines hasery specific implications. “Recommendation” refers touidelines based on level I or level II data. Level I data areerived from meta-analyses of multiple well-designed, con-rolled studies or from highly powered, randomized trials.evel II data are based on at least 1 well-designed experimen-al trial and low-powered randomized trials. “Suggestion”efers to guidelines based on data from levels III, IV, or V.ata in these levels are weaker so these guidelines are based

n some part on consensus from the ASCO panel. “Insuffi-ient evidence” denotes a lack of either evidence or panelonsensus regarding the population in question.

The ASCO PMRT practice guideline includes recommen-ations for the routine use of PMRT in cases of highest-riskreast cancer, as defined by disease with at least 4 metastatic

ymph nodes. PMRT was suggested for cases of operable stage

igure 3 Eight-year cumulative incidence of locoregional failuremong patients treated with mastectomy and without radiotherapyn NSABP neoadjuvant chemotherapy studies B18 and B27 (E.amounas, unpublished data).

II disease. The panel concluded that data regarding net ben-

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fits of PMRT in cases of T1 to 2 tumors and 1 to 3 metastaticodes were insufficient to make suggestions or recommen-ations for its routine use. Similarly, the panel assessed thevailable evidence on using patient factors (such as age orenopausal status) and primary tumor features (such as lym-hovascular invasion) and concluded that there was insuffi-ient evidence to make recommendations or suggestions forodifying the guidelines based on these factors. Most of theanel favored the routine use of PMRT in breast cancer caseseceiving neoadjuvant chemotherapy because patients withelatively more advanced clinical stages of disease constitutehe population most likely to be referred for this treatmentequence. However, the panel acknowledged the paucity of

able 1 2001 ASCO Practice Guidelines for the Use of PMRT

1. Patients with 4 or more positiveaxillary nodes

PMRT is recommnodes.

2. Patients with 1 to 3 positive axillarynodes

There is insufficT1/T2 tumors

3. Patients with T3N1 or Stage IIItumors

PMRT is suggespatients with o

4. Patients undergoing preoperativesystemic therapy

There is insufficinitially treatedafter surgery.

5. Modification of these guidelines forspecial patient subgroups

There is insuffictumor-related,

6. Chest wall irradiation In patients givenwall is manda

7. Details of chest wall irradiation There is insufficirradiation, su

8. Axillary nodal irradiation The panel suggepatients underinsufficient evfrom axillary ir

9. Supraclavicular nodal irradiation forpatients with 4 or more positiveaxillary nodes

The incidence owith four or msupraclavicula

0. Supraclavicular irradiation for patientswith 1-3 positive axillary nodes

There is insufficor should not

1. Internal mammary nodal irradiation There is insufficinternal mammpatient subgro

2. Sequencing of PMRT and systemictherapy

There is insufficchemotherapyavailable evideconcurrently w

3. Integration of PMRT andreconstructive surgery

There is insufficintegration of

4. Long-term toxicities The potential lonradiation pneusecond neoplain general, thetechniques) iswhen otherwisradiotherapy tcardiac toxicit

5. Toxicity consideration for specialpatient subgroups

There is insufficbe used for so(such as radia

linical trial data to address this issue and concluded that no A

efinitive recommendation could be offered for this patientopulation. Furthermore, neoadjuvant chemotherapy is used

ncreasingly for patients with T2 tumors as a strategy for im-roving lumpectomy eligibility, and this treatment sequence

s no longer restricted to cases of locally advanced disease.dditional evidence from retrospective analyses conductedfter the time of the ASCO panel was considered by theational Cancer Institute’s consensus panel on neoadjuvant

herapy, as described earlier, and its recommendationshould be considered in addition to those of the ASCO panelor this subset of patients.

Similar guidelines have been developed by the Americanociety for Therapeutic Radiology and Oncology,32 the

d for patients with 4 or more positive axillary lymph

vidence to make recommendations regarding patients withto 3 positive axillary nodes.r patients with T3 tumors with positive axillary nodes andle stage III tumors.

vidence to make recommendations whether patientspreoperative systemic therapy should be given PMRT

vidence for modifying the above guidelines based on othernt-related, or treatment-related factors.T, the panel suggests that adequately treating the chest

vidence for the panel to recommend aspects of chest walltotal dose, fraction size, bolus use, and scar boosts.at full axillary radiotherapy not be given routinely tocomplete or level I/level II axillary dissection. There isto suggest whether some patient subgroups may benefit

ion.al supraclavicular failure is sufficiently great in patientssitive axillary nodes that the panel suggestsradiation in all such patients.idence to state whether supraclavicular radiation shouldd in patients with one to three positive axillary nodes.idence to make recommendations on whether deliberate

odal irradiation should or should not be used in any

idence to recommend the optimal sequencing ofxifen, and PMRT. The panel does suggest, given theegarding toxicities, that doxorubicin not be administered

RT.idence to make recommendations with regard to theand reconstructive surgery.risks of PMRT include lymphedema, brachial plexopathy,

is, rib fractures, cardiac toxicity, and radiation-inducedThere is sufficient evidence for the panel to suggest that,f serious toxicity of PMRT (when performed using modernnough that such considerations should not limit its usecated. However, follow-up in patients treated with currentues is insufficient to rule out the possibility of very late

idence to make recommendations that PMRT should notbgroups of patients because of increased rates of toxicity

arcinogenesis) compared with the rest of the population.

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ee on Clinical Practice Guidelines for the Care and Treat-ent of Breast Cancer.34 Of note, all expert panels recom-ended the use of PMRT in patients with 4 or more positive

xillary nodes. They also all acknowledged the lesser clarityurrounding patients with 1 to 3 positive axillary nodes. Ofote, the ASTRO experts stated, “The data regarding patientelection for survival advantage are less clear, but the mostecent evidence suggests that the greatest survival benefit iseen in node-positive patients with low tumor burdens (i.e.,ewer positive nodes or smaller tumors). Radiation therapy inhese patients for survival benefit is worthy of consideration,ending more definitive data . . . . Consultation with a radi-tion oncologist should occur in node-positive patientsreated with mastectomy to help patients assess the risks andenefits of PMRT.” The ACR recommendations echo thistatement. Since the time of these reports, additional pub-ished analyses have shown benefit from PMRT in patientsith 1 to 3 positive nodes. Thus, discussion of the pros and

ons of PMRT is warranted in these patients.As clinical studies continue to mature, the oncology com-unity continues to debate the potential value of PMRT for

ategories of “intermediate-risk” breast cancer in which dataere insufficient to warrant definitive recommendations by

xpert panels. However, there is a strong consensus regard-ng the role of PMRT in patients with truly locally advancedisease. Indeed, a survey of radiation oncologists found thathe vast majority (�98%) reported that they would offeradiation to at least the chest wall in patients with 4 or morenvolved lymph nodes, although there was less consensus inhe cases of T3N0 disease (in which 88.3% would offer PMRTo the chest wall) and even less so for cases in which 1 to 3ymph nodes were involved (with 85.2% offering PMRT to ateast the chest wall if extracapsular extension was noted and1.7% offering it if it were absent).16 Thus, all patients with

ocally advanced breast cancer merit referral to radiation on-ology, and PMRT is considered an integral component ofheir multimodal management.

eferences1. American Joint Committee on Cancer: AJCC: Cancer staging Manuals

(eds 1-5). Chicago, IL, AJCC2. American Joint Committee on Cancer: AJCC: Cancer Staging Manual

and Handbook (ed 6). Chicago, IL, AJCC, 20023. Clarke M, Collins R, Darby S, et al: Early Breast Cancer Trialists’ Col-

laborative Group: Effects of radiotherapy and of differences in the ex-tent of surgery for early breast cancer on local recurrence and 15-yearsurvival: An overview of the randomised trials. Lancet 366:2087-2106,2005

4. McArdle CS, Crawford D, Dykes EH, et al: Adjuvant radiotherapy andchemotherapy in breast cancer. Br J Surg 73:264-266, 1986

5. Griem KL, Henderson IC, Gelman R, et al: The 5-year results of arandomized trial of adjuvant radiation therapy after chemotherapy inbreast cancer patients treated with mastectomy. J Clin Oncol 5:1546-1555, 1987

6. Velez-Garcia E, Carpenter JT, Moore M, et al: Postsurgical adjuvantchemotherapy with or without radiotherapy in women with breastcancer and positive axillary nodes: A South-Eastern Cancer StudyGroup (SEG) trial. Eur J Cancer 28A:1833-1837, 1992

7. Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiother-
apy. J Clin Oncol 12:447-453, 1994
8. Olson JE, Neuberg D, Pandya KJ, et al: The role of radiotherapy in themanagement of operable locally advanced breast carcinoma: Results ofa randomized trial by the Eastern Cooperative Oncology Group. Cancer79:1138-1149, 1997

9. Fowble B: Postmastectomy radiation: A modest benefit prevails for highrisk patients. Cancer 79:1061-1066, 1997

0. Ragaz J, Olivotto IA, Spinelli JJ, et al: Locoregional radiation therapy inpatients with high-risk breast cancer receiving adjuvant chemotherapy:20-year results of the British Columbia randomized trial. J Natl CancerInst 97:116-126, 2005

1. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiother-apy in high-risk premenopausal women with breast cancer who receiveadjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82bTrial. N Engl J Med 337:949-955, 1997

2. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapyin high-risk postmenopausal breast-cancer patients given adjuvant ta-moxifen: Danish Breast Cancer Cooperative Group DBCG 82c random-ised trial. Lancet 353:1641-1648, 1999

3. Recht A, Gray R, Davidson NE, et al: Locoregional failure 10 years aftermastectomy and adjuvant chemotherapy with or without tamoxifenwithout irradiation: Experience of the Eastern Cooperative OncologyGroup. J Clin Oncol 17:1689-1700, 1999

4. Taghian A, Jeong JH, Mamounas E, et al: Patterns of locoregional failurein patients with operable breast cancer treated by mastectomy andadjuvant chemotherapy with or without tamoxifen and without radio-therapy: Results from five national surgical adjuvant breast and bowelproject randomized clinical trials. J Clin Oncol 22:4247-4254, 2004

5. Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinicalpractice guidelines of the American Society of Clinical Oncology. J ClinOncol 19:1539-1569, 2001

6. Ceilley E, Jagsi R, Goldberg S, et al: Radiotherapy for invasive breastcancer in North America and Europe: Results of a survey. Int J RadiatOncol Biol Phys 61:365-373, 2005

7. Overgaard M, Nielsen HM, Overgaard J: Is the benefit of postmastec-tomy irradiation limited to patients with four or more positive nodes, asrecommended by international consensus reports? A subgroup analysisof the DBCG 82 b & c randomized trials. Radiother Oncol 82:247-253,2007

8. Mignano JE, Gage I, Piantadosi S, et al: Local recurrence after mastec-tomy in patient with T3N0 breast carcinoma treated without postop-erative irradiation. Breast Cancer Res Treat 41:255, 1996 (abst)

9. Helinto M, Blomqvist C, Heikkila P, et al: Post-mastectomy radiother-apy in pT3N0M0 breast cancer: Is it needed? Radiother Oncol 52:213-217, 1999

0. Floyd SR, Buchholz TA, Haffty BG, et al: Low local recurrence ratewithout postmastectomy radiation in node-negative breast cancer pa-tients with tumors 5 cm and larger. Int J Radiat Oncol Biol Phys 66:358-364, 2006

1. Taghian AG, Jeong JH, Mamounas EP, et al: Low locoregional recur-rence rate among node-negative breast cancer patients with tumors 5 cmor larger treated by mastectomy, with or without adjuvant systemic ther-apy and without radiotherapy: Results from five national surgical adjuvantbreast and bowel project randomized clinical trials. J Clin Oncol 24:3927-3932, 2006

2. Wallgren A, Bonetti M, Gelber RD, et al: Risk factors for locoregionalrecurrence among breast cancer patients: Results from InternationalBreast Cancer Study Group Trials I through VII. J Clin Oncol 21:1205-1213, 2003

3. Jagsi R, Raad RA, Goldberg S, et al: Locoregional recurrence rates andprognostic factors for failure in node-negative patients treated withmastectomy: Implications for postmastectomy radiation. Int J RadiatOncol Biol Phys 62:1035-1039, 2005

4. Truong PT, Lesperance M, Culhaci A, et al: Patient subsets with T1-T2,node-negative breast cancer at high locoregional recurrence risk aftermastectomy. Int J Radiat Oncol Biol Phys 62:175-182, 2005

5. Medical Research Council: SUPREMO trial. Available at: http://www.supremo-trial.com/index.html. Accessed January 13, 2009

6. Huang EH, Tucker SL, Strom EA, et al: Postmastectomy radiation im-
proves local-regional control and survival for selected patients with
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locally advanced breast cancer treated with neoadjuvant chemotherapyand mastectomy. J Clin Oncol 22:4691-4699, 2004

7. Huang EH, Tucker SL, Strom EA, et al: Predictors of locoregional re-currence in patients with locally advanced breast cancer treated withneoadjuvant chemotherapy, mastectomy, and radiotherapy. Int J Ra-diat Oncol Biol Phys 62:351-357, 2005

8. Mamounas EP, Wang J, Bryant J, et al: Patterns of loco-regional failurein patients receiving neoadjuvant chemotherapy: Results from NSABPB18. Breast Cancer Res Treat 82:S17, 2003 (abstr 35)

9. Mamounas E: Sentinel node biopsy after neoadjuvant chemother-apy: The pros: Presented at Preoperative Therapy in Invasive BreastCancer: Reviewing the State of the Science and Exploring New Re-search Directions. National Cancer Institute. Bethesda, MD, March26, 2007

0. Buchholz TA, Lehman CD, Harris JR, et al: Statement of the science

concerning locoregional treatments after preoperative chemotherapyfor breast cancer: A National Cancer Institute conference. J Clin Oncol26:791-797, 2008

1. Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinicalpractice guidelines of the American Society of Clinical Oncology. J ClinOncol 19:1539-1569, 2001

2. Harris JR, Halpin-Murphy P, McNeese M, et al: Consensus statementon postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys44:989-990, 1999

3. Taylor ME, Haffty BG, Shank BM, et al: Postmastectomy radiotherapy;American College of Radiology, ACR: Appropriateness criteria. Radiol-ogy 215:1153-1170, 2000 (suppl)

4. Truong PT, Olivotto NA, Whelan TJ, et al: Clinical practice guidelinesfor the care and treatment of breast cancer. 16. Locoregional post-
mastectomy radiotherapy. CMAJ 170:1263-1273, 2004

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adiation Techniques andoxicities for Locally Advanced Breast Cancereena S. Moran, MD,* and Bruce G. Haffty, MD†,‡

Radiation therapy is used in the management of locally advanced breast cancer in thepostmastectomy or neoadjuvant chemotherapy and breast-conservation setting to improvelocal-regional control and survival. Using modern-day technology, the therapeutic ratio hasincreased and the potential morbidity has decreased. This article reviews the technicalaspects of radiation therapy for locally advanced breast cancer with emphasis on 3-dimen-sional radiotherapy techniques and discusses potential toxicities and how to reduce them.Semin Radiat Oncol 19:244-255 © 2009 Elsevier Inc. All rights reserved.

ts

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adiation therapy is an integral component in the multi-disciplinary management of locally advanced breast can-

er (LABC). In the postmastectomy setting, radiation haseen used for decades to reduce the risk of local-regionalecurrence; with modern-day techniques, postmastectomyadiation (PMRT) for advanced-disease stages has beenhown to improve overall survival. More recently, for se-ected patients with LABC wishing to conserve their breast,eoadjuvant chemotherapy is being used in an attempt tohrink the tumor/lymph nodes before breast-conservationherapy (conservative surgery followed by radiation to thentact breast). The techniques for radiation treatment to thehest wall and breast have evolved significantly since theirnitial use in the 1940s. Using computed tomography (CT)imulators, modern-day linear accelerators, computerizedreatment planning modalities, and on-board imaging tech-iques, the therapeutic ratio for radiation therapy in LABCas markedly improved, whereas the potential for side effectsas diminished significantly.In this article, the traditional tangential and more confor-al radiation techniques for chest wall radiation for LABC

re reviewed. We discuss the delineation of target volumes,oses, complications of radiation, and methods to maximize

ocoregional control and minimize toxicity in the postmas-ectomy setting. In addition, technical aspects of radiation

Department of Therapeutic Radiology, Yale University School of Medicine,New Haven, CT.

Department of Radiation Oncology, UMDNJ-Robert Wood Johnson Schoolof Medicine, New Brunswick, NJ.

The Cancer Institute of New Jersey, New Brunswick, NJ.ddress reprint requests to Meena S. Moran, MD, Yale University School of

Medicine, 333 Cedar Street, PO Box 208040, New Haven, CT 06520-
p8040. E-mail: [email protected]

herapy after neoadjuvant systemic therapy and breast-con-erving surgery for LABC are discussed.

arget Volumeslthough it is routinely accepted that the entire chest wallnd mastectomy scar be included for PMRT, there is no con-ensus among physicians who treat LABC as to which nodalasins to routinely include. Although most patients receivingMRT have lymph node-positive disease and therefore the

psilateral supraclavicular (SC) fossa is generally included inhe treatment volume, significant controversy exists as tohen to include the dissected axilla and internal mammary

IM) nodes in the radiation treatment volumes. Despite these of “comprehensive” radiation to include all lymph nodest risk in the 3 most recent and important randomized stud-es of PMRT,1-3 the inclusion of all lymph node basins is notniformly used in this country for several reasons. First, there

s often an added technical difficulty in treatment planning/elivery when attempting to include all nodal regions at risk.econd, the increase in the target volumes comes with theotential for adding toxicity. Furthermore, the additionalenefit of nodal radiation to chest wall radiation alone has yeto be shown in a randomized, prospective fashion. Because ofariations in the philosophies, the target volumes to be irra-iated for LABC are commonly generated based on the treat-

ng physician’s opinion regarding these issues and the clini-al/pathologic characteristics of each individual case andften are influenced by the institutional policies of the treat-ng facility. Patterns of care with respect to regional nodalrradiation are widely variable as reflected in a worldwideurvey of radiation oncologists published by Taghian et al.4

urthermore, the American College of Radiology ACR appro-
riateness criteria panel for PMRT did not reach uniform

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Radiation techniques and toxicities 245

onsensus on the treatment of IM nodes or full axillary radi-tion in the postmastectomy setting.5

The issue of whether or not to intentionally include the IModes in all LABC cases continues to be debated and remainsontroversial. The issue is currently being investigated in 2rospective, randomized studies conducted by the Europeanrganization for Research Treatment of Cancer (protocol2,922/10,925) and National Cancer Institute of Canada.rom a technical standpoint, treatment of the IM nodes isften challenging; inclusion of IM nodes in “deep” tangentialelds often results in excessive radiation to the lung and heartparticularly for left sided tumors) and other techniques,uch as the use of a matched medial electron field to moreateral tangent fields can result in a “cold triangle” in an areat risk for recurrence.

At our institutions, the SC fossa and axillary apex (level III)re routinely included for all patients receiving PMRT forymph node-positive diseases, whereas the decisions regard-ng radiation to the IM nodes and dissected level I/II axilla are

ade on a case-by-case basis. Because most patients withABC will have undergone a level I/II axillary nodal dissec-ion (AND), and risk of axillary relapse in these patients isow,6 we only intentionally include the level I/II axilla after aodal dissection in the following circumstances: (1) the num-er of lymph nodes removed was inadequate/incomplete, (2)here is evidence of gross residual disease, (3) there is exten-ive extracapsular extension on pathology report suggestivef a high residual tumor burden, or (4) an incomplete ANDr an axillary sampling was performed. For IM nodes, theecision is individualized based on the risk of IM involve-ent and whether treatment would result in an excessive

mount of heart/lung based on the patient’s anatomy. Atome centers, “comprehensive” radiation is routinely deliv-red to all the regional nodes when PMRT is indicated, re-ardless of the potential technical difficulty of encompassingll these regions. As shown in the first patterns-of-care studyf PMRT, there remains no consensus regarding regionalodal radiation throughout the United States.7 Seventy-eightercent of the patients who received PMRT had regionalodal radiation. When RT to the nodes was delivered, SCodes were included in 98%, IM nodes in 23%, and a sup-lemental axillary field in 46%.7 Until results of the random-

zed trials become available, variability and individualizedreatment will continue to be based on the treating physi-ian’s preferences, normal tissue tolerance considerations,nd patient’s risk factors.

angential Chestall Radiation Techniques

he first step in radiation therapy treatment planning is pa-ient immobilization. Immobilization is necessary to repro-uce the patient’s position daily, avoid radiation to normalissue structures and ensure treatment of targeted regions.here are many commercially available devices for immobi-

ization; most commonly, a “breast board” or a customized
oam mold are used. During immobilization, the patient’s t
psilateral arm is abducted 90° to 120° and the shoulder isxternally rotated so the arm is out of the way of the radiationeams. Because the sternum in most patients slopes superiorly,hich can potentially make adequate coverage of the chest wallith the tangential beams technically difficult, the patient

hould be positioned so the sternum is parallel to the table, ifossible. Once immobilized, the specific setup parameters for

mmobilization are recorded for the patient to maximize theaily reproducibility. Tentative field borders can then be placedsing radiopaque catheters on the skin for better radiographicisualization of the field borders during the treatment planningrocess.The use of a CT simulator and virtual simulation is prefer-

ble for treatment planning purposes in that they permit-dimensional visualization of targets and normal tissues. Auoroscopic simulator can be used to set up the treatment forhe chest wall and regional nodes if CT technology is notvailable. In either case, the chest wall field borders should belinically determined and tentatively delineated by the radi-tion oncologist. The chest wall field is generally defineduperiorly by the inferior portion of the clavicular head, lat-rally at the midaxillary line, medially to the midsternum,nd inferiorly to 2 cm below the previous location of thenframammary fold (using the contralateral inframammaryold as a reference, if present). The anterior field edge shouldlear air by 2 to 3 cm over the chest wall, and the posteriordge should include from 1 to 3 cm of the lung, as measuredy the perpendicular distance of the posterior edge of theangential field edge to the posterior portion of the anteriorhest at the center of the field.8 The entire chest wall, theastectomy scar, and all drainage scars, if possible, should be

ncompassed in the radiation field.The posterior edges of the medial and lateral tangential

eams are aligned so that there is no divergence into the lungnd heart. We typically do not use a collimator angle, andlocking of the heart and lung are often achieved using mul-ileaf collimation to shape the posterior edge of the tangenteams. If blocks are placed, it is important to clinically re-heck the fields with blocks in place to ensure that the entirehest wall, mastectomy flap, and all scars are covered.

An alternative to tangential photon radiation is the use ofn face electrons to treat the chest wall. This technique haseen used in many centers throughout the world with com-arable outcomes and toxicity to tangential photon beams.9

here can be issues related to homogeneity dependent on thehest wall contour, patient anatomy, and difficulty in match-ng the electron fields to the IM and SC fields. Kirova et al10

ecently reported on a modified electron technique thathowed improved homogeneity and conformality over theirtandard electron technique.

Regardless of the technique used, it is important to avoidigh doses of radiation to the heart when considering differ-nt treatment techniques for left-sided lesions. In a compar-son of heart doses using various postmastectomy chest wallechniques, Pierce et al noted that the volume of heart receiv-ng �30 Gy was least using partially wide tangent fields (de-cribed later) and as expected, greatest when using cobalt
echniques.11

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The dose delivered to the chest wall is typically 50 Gy in-Gy fractions using 6-MV photons with a 0.5- to 1.0-cmolus placed on the entire chest wall field every other day oror the first 20 Gy during the treatment (Fig. 1). It is impor-ant to recognize that even in patients with a reconstructedreast, the use of bolus is recommended to ensure that thekin and immediate subcutaneous target tissues receive andequate dose of radiation. The use of a boost to the mastec-omy scar is variable. As reported in the American College ofadiology Appropriateness Criteria, there are no clear data toupport or discourage the use of a boost to the mastectomycar, and its use remains highly individualized.5 When used,t is typically delivered via en face electrons to a generous arearound the mastectomy scar to 60 Gy. If a patient has aositive margin, a higher boost dose is often used (64-66 Gy).

echnique of SC Fossa andxillary Treatment

n oblique anterior-posterior SC field can be matched to thehest wall fields to target the SC fossa and axillary apex. Theuperior clinical border of this field is typically placed at theevel of the cricoid cartilage, inferior border abutting the su-erior edge of the tangential fields, medial border on theedicles of the vertebral bodies, and lateral border extendingo the coracoid process (Fig. 2). If the dissected axilla is to bencluded, the lateral border of the SC field is extended to theateral aspect of the humeral head. The SC field gantry isngled 10° to 20°.

The geometric edges of the inferior border of the SC anduperior border of the tangential fields must be aligned sohat there is no divergence of the 3 beams, which would causehotspots” and overdosing in the regions of overlap. Variousechniques have been described to match these fields, all ofhich are effective in producing a uniform dose across theatch line. At our institutions, we generally use a single

socentric technique that half beam blocks the inferior aspectf the SC field and then the superior aspect of the tangentialelds (using the independent collimator jaws) so the beam

igure 1 A patient receiving postmastectomy chest wall radiationmmobilized on a breast board with bolus covering the entire chest
all field. (Color version of figure is available online.) v
dges are perfectly aligned.12 This technique requires that thelinical borders be tentatively determined and the isocenterocation be determined along the match line of the SC andangent fields in the superior to inferior, anterior to posterior,nd medial to lateral axis either during fluoroscopic or CTvirtual) simulation (Fig. 3). During treatment, the 3 fieldsre treated in succession without movement of the isocenter.lthough blocks can be used (ie, to block the lung or heart in

he tangential fields or the spinal cord and central structuresn the SC field), no blocks are required with this technique tochieve matching between the tangents and the SC field (Fig.). This technique is favored at our institutions because noovement of the treatment table is required between fields

ut has the limitation of a size of 20 � 20 cm for the tangentelds because of the standard beam width of 40 cm on cur-ent linear accelerators. Another commonly utilized tech-ique is the “rod-and-chain”13; this method uses tabletopotation, gantry and collimator angles, and corner blocks toatch the SC field to the tangents, and is not limited by the

igure 2 The supraclavicular/axillary field (SAF) in yellow and theosterior axillary boost (PAB) in red. (Color version of figure isvailable online.)

igure 3 A single isocentric technique to match SAF to the tangents.he isocenter is not moved, and matching is achieved by half beamlocking the superior and inferior portions of the treatment fieldsith the independent collimator jaws. Image shows the medial and

ateral chest wall field and the anterior SAF projected on skin. (Color
ersion of figure is available online.).

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0 cm tangent field size. Various other matching techniquessing different blocking methods14-18 have also been de-cribed in the literature. All the previously mentioned tech-iques adequately achieve the goal of preventing overlap ofhe SC and tangential fields and will provide a uniform doset the match line.

The level of the SC match line placement has recently beenhown to be an important consideration to ensure adequateoverage of the level III lymph nodes of the axillary apex.19

lacement of the superior tangential/SC match caudal to thelavicular head results in statistically improved coverage ofhe high axillary apex lymph nodes in comparison to patientsho have match lines that are more superior.The SC field has traditionally been treated using 6-MV

hotons, delivering 46 to 50 Gy to a depth of approximatelycm. Routine radiation prescriptions have been shown to

uboptimally cover intended targets across all body massndexes,20 and, therefore, optimized CT-based treatmentlanning should be used whenever possible to treat the SCodes. Using CT simulation, the depth of the SC and level III

ymph nodes can be more precisely assessed and contourednd treatment planning can be specified to the patient’s anat-my (Fig. 5). For instance, in a large patient, if the depth ofhe SC nodes is greater than 5 to 6 cm, the use of higher-nergy photons or an anterior-posterior/posterior-anterioreld can be considered. Furthermore, if the axillary treat-ent is warranted, the CT simulation scan allows for the

ccurate measurement of the dose to the axilla relative to theC nodes so that a boost to the axilla using a posterior-nterior field can be added if necessary.

osterior Axillary Boostistorically, before the CT-simulation era, a posterior axillaryoost (PAB) was routinely used at some institutions to ac-ount for the assumed difference in depth of the level I/IIxillary lymph nodes from the depth of the level III axilla andC nodes. The posterior PAB photon beam supplemented thenterior supraclavicular/axillary field (SAF) to boost the axilla

igure 4 Digital reconstructions of the beam’s eye view of the singlesocentric technique to match SAF to the tangents. The isocenter isepicted by the large dot. The 3 fields are treated in succession, andatching does not require blocks or a couch shift. Normal tissue

tructure blocking can be used as in the SAF above. (Color versionf figure is available online.)

o therapeutic doses. With the widespread use of CT simula- a

ion, we now know that the depths of the axillary and SCodes are similar in most patients.21 A PAB is still sometimes

ndicated when the maximal depths of the SC and axillaryodes differ significantly when a single anterior field alone isot adequate. A standard PAB is shown in Figure 2. The doseor the PAB is prescribed so that a point at the depth of thexillary nodes or the midplane of the axilla receives the fullrescribed dose. With modern CT-based treatment planningnd a broad range of external beam shaping and modulatingechniques available, contouring the target nodal volumes atisk and the use of field arrangements that optimally coverhe target are recommended over empiric prescriptions to thexilla.

M Node Treatmenthen the IM nodes are to be included with chest wall radi-

tion, visualization of the IM vessels on CT simulation willllow one to determine if these nodes can be encompassed inhe tangential fields without excessive radiation to the lungand heart). To achieve this, it is helpful to contour the easilyisualized IM artery and vein in the first 3 costal interspaces.lthough the precise position should be determined by a CTcan when available, traditional IM portals have been 5 to 6m in width, extending from midline medially, just below thelavicular head superiorly to include the first 3 intercostalpaces, with the inferior border at the fourth interspace. Thiseparate IM field can be treated with electrons alone or aombination of low-energy photons and electrons, with ainimum of 50% of the dose being delivered by electrons toinimize the dose to underlying heart and lung tissue. Aopular technique is to tilt the gantry angle of the electroneld 5° to 15° less than the medial tangent, minimizing theold triangle just below the skin match of the 2 fields ashown in Figure 6.

A common technique to treat the IM nodes is the use ofartially wide tangential fields.11 When using this technique,

igure 5 Typical dosimetry for a SC field. Isodose lines start at 105%,hen 100%, 98%, 95%, and 90%. CT simulation should be used tossess the depth of the nodes at risk. (Color version of figure is
vailable online.)

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locking is used on the deep edge of the tangent fields tollow deeper coverage of the IM nodes in the upper 3 inter-ostal spaces, while providing more blocking of the lungnd/or heart in the inferior portion of the field as shown inigure 7. This technique avoids the issue of matching fieldsnd, depending on the patients anatomy, offers an attractivelternative to a separate IM field in selected patients. Careust be taken to minimize overlap of dose into the contralat-

ral breast in the superior portion of the field and ensureomplete coverage of all target tissue and the entire mastec-

igure 6 A tangential chest wall field with a separate IM electroneld. The location of IM chain nodes is outlined in red. Electroneld is angled 5% less than tangential field, minimizing cold trianglet the match. (Color version of figure is available online.)

igure 7 Partially wide tangential radiation field to include IM nodesn the first 3 intercostal spaces in the superior aspect of the tangenteld, with a block to shield the lung and/or heart in the lowerortion of the tangential field. (Color version of figure is available

rnline.)

omy scar in the inferior portion of the field, in the region ofhe block.

Occasionally, the IM nodes can be treated by what is com-only referred to as deep tangents (Fig. 8). Using this tech-ique, the medial border of the tangential field is broughtcross the midline, such that the IM nodes are includedithin the tangential field. This technique, however, gener-

lly results in an excessive volume of lung and/or heart withinhe tangential field, and studies have shown the dose volumeistogram for heart and lung with this technique may benacceptably high. Depending on the patient’s anatomy,owever, this technique may be acceptable in some patients.

hree-Dimensionalonformal and Intensity-odulated Radiation Therapy:

he “More Conformal Techniques”he potential benefit of the newer generation of 3-dimen-ional CT-based treatment planning techniques is the po-ential to “sculpt the dose” to the tissue at risk and improveomogeneity in the target volumes while theoreticallyinimizing dose to surrounding normal tissue. Althoughprospective, randomized studies of 2-dimensional ver-

us 3-dimensional treatment techniques have shown aenefit in acute skin reactions and long-term side effects ofbrosis/cosmesis using the more conformal technique22,23

or the intact breast, the more conformal techniques haveot been prospectively studied for LABC in the post-mas-ectomy setting. Furthermore, the long-term toxicity toormal tissue (heart, lung, brachial plexus, ribs, and son) using the 3-dimensional techniques have not been

igure 8 A tangential chest wall field with the IM nodes intentionallyncluded. The location of IM chain is outlined and included in theangential field. Note that the amount of lung for this technique iscceptable (�3 cm) in this instance, but is not achievable in manyatients. (Color version of figure is available online.)

eported to date.

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Although the exact definitions of intensity-modulated ra-iation therapy (IMRT) versus 3-dimensional conformal ra-iation for breast cancer treatment have broad variability ineaning, the vast majority of published data on breast cancer

onformal radiation techniques use multiple, static “field-ithin-field” techniques with multileaf collimation and for-ard planning (as opposed to inverse planning). With IMRT,

he multisegment (segmental) fields make use of fixed fieldhaping to create intensity-modulated fields by adding theose from several different-shaped beam portals (segments)hat have the same beam direction,24 with the number ofegments varying based on the different types of planningnd optimization tools used to plan each case. Although in-ensity-modulated treatment planning is typically inverselanned in most tumor sites (ie, head and neck and prostate),MRT for breast cancer treatment planning is often done withorward planning. Therefore, the definitions of 3-dimen-ional conformal versus IMRT for breast cancer radiationreatment remain broad. Therefore, we will comprehensivelyefer to the newer generation of treatment planning with-dimensional conformal or IMRT as “the more conformalechniques.”

It is important to note that when using the more conformalechniques for LABC, the delivery of radiation is based onnatomic volumes from CT simulation scans; thus, all tissuet risk must be meticulously delineated to allow the dose ofadiation to be sculpted to the target structures (ie, chestall � regional nodes), while minimizing dose to the normal

tructures (ie, heart and lung). Although these techniquesmprove the homogeneity across the clinical target volume(s)nd have the potential to decrease the radiation doses toormal, unaffected tissue, a relatively in-depth knowledge ofhe anatomy and tissue at risk is critical to reproduce similarong-term outcomes as were achieved with the older 2-di-

ensional techniques. A recent study conducted by the Ra-iation Therapy Oncology Group (RTOG) has brought to

ight the variability that exists in contouring targets for breast

able 1 Breast and Chest Wall Contour: Anatomic Boundarie

Cranial Caudal

reast Clinical reference �second ribinsertion

Clinical reference � lossof CT apparent breast

reast � chestwalla Same Same

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Clinical reference � lossof CT apparentcontralateral breast

eprinted with permission from White J, Tai A, Arthur D, et al:Definitions.

Breast � chestwall CTV definitions should be utilized after appropclinical stage IIb/III who receive neoadjuvant chemotheraphy amastectomy radiation if a mastectomy had been performed.

CTV after mastectomy, lateral border to estimate the lateral bordepectoralis muscles but excludes the lattismus dorsi muscle. Sho

ancer radiation therapy and the need for consensus defini- d

ions to reduce interphysician variability in delineating theissue at risk and normal structures for breast cancer treat-ent planning.25 Based on the findings of their study, the

roup has created a breast cancer atlas to provide consensusuidelines for contouring of the chest wall/breast (Table 1),C nodes, axilla (level I, II, II), IM nodes (Table 2), andeart/lung volumes (Table 3). These guidelines were gener-ted from geometric averaging of contours performed by aanel of breast experts and should serve as a reference whenontouring the chest wall, regional nodes, and heart/lungolumes for 3-dimensional delivery techniques.

A relatively common conformal technique generated byorward planning is described. First, the tangential fields arereated in the standard fashion with matching to the SAF, ifndicated. Once the medial and lateral tangent fields are cre-ted with clinical and radiographic coverage of the targettructures and nondivergent posterior field edges, the dosim-try of the open fields is generated with the dose normalizedo a point at midseparation at the boundary between theectoralis major and chest wall tissue. The dose distributionf the tangent fields is then examined, and the fields areeighted to optimize the dosimetry. Then, a dose cloud of

he 115% isodose curve volume is projected in the beam’s eyeiew of the treatment fields. A new segment is generatedsing multileaf collimation onto the medial tangent field toccount for 15% of the dose. This process can then be re-eated for the 110% dose cloud, the 107% dose cloud, and son. Generally, 4 to 6 fields are required to achieve optimiza-ion of dose homogeneity, typically 1 open medial with 1 to 2ollimated medial and 1 open lateral with 1 to 2 collimatedateral (Fig. 9). Occasionally, higher-energy photons need toe considered when the patient separation is large.26 Figure0 compares isodose plans for a patient planned with tradi-ional tangential techniques versus a more conformal radia-ion therapy plan.

It is important to note that using the more conformal tech-iques in which the beam orientation remains tangential as

erior Posterior Lateral Medial

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Breast Cancer Atlas for Radiation Therapy Planning: Consensus

umpectomy for more locally advanced cases including those: withpectomy, who have sufficient high risk disease to require post-

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ittle to no improvement in dose conformality. If multipleeam arrangements are used, as in a noncoplanar plan or alanar but nontangential plan, improvements in the volumef high-dose regions may be seen with a further “sculpted”ose but needs to be weighted against the expense of expo-ure of significantly more normal tissue to lower doses ofadiation (ie, lung, heart, soft tissue and contralateral breast).

oxicity of Radiation Therapyhe potential side effects for PMRT therapy can be separated

nto acute and late toxicity categories. Acutely, a patient mayxperience some fatigue and radiation dermatitis/skin reac-ion in the treatment portals, which generally begins in theecond to third week of treatment and in some cases results intransient moist desquamation of the skin. The most com-on potential late sequelae of radiation therapy are chronic

hanges of the radiated skin and soft tissue (fibrosis, hyper-igmentation, and, rarely, telangectasias). In patients whondergo axillary node dissection and receive adjuvant irradi-tion to the axilla, the risk of lymphedema significantly in-reases with the addition of radiation beyond the risk of ANDlone. Although modern-day techniques have significantlyeduced the risk of lung and cardiac complications, careful-dimensional treatment planning should be used to mini-ize the radiation doses to these relatively sensitive organs.he risk of joint complications, rib fractures, and brachiallexus complications is relatively low with current treatmentechniques.

ardiac Toxicityeveral meta-analyses of the randomized studies of the firsteneration of PMRT therapy trials suggested that the benefitf radiation, with respect to survival, were counteracted byardiac mortality.27-30 Although postmastectomy, adjuvantadiation therapy for node-positive patients appears to pro-uce about a two thirds reduction in local recurrence andubsequently, an approximately 10% reduction in breastancer mortality rates, these favorable findings were offset byn increase in death from other causes, which appeared to beelated to vascular/coronary-associated deaths from the un-ntended radiation of the coronary and carotid arteries.31

hen analyzed further, these findings of cardiac deaths wereignificantly more apparent in the older trials from Eu-ope,32-34 which used outdated techniques and equipmentie, en face chest wall photon fields, cobalt units, larger frac-ionation size, and orthovoltage units). Further supportinghis observation, the risk of cardiac mortality has been showno be significantly higher in patients with radiation for left-ided breast cancers than right-sided breast cancers.35,36 Withegavoltage units replacing the previously used orthovoltage

nd cobalt-60 units and improved techniques, the doses tohe heart have been significantly reduced.37 Furthermore,sing modern-day techniques, the normal tissue complica-ion probability for late cardiac tissue toxicity has been de-reased by 30% to 50%.38-40 The risk of cardiac death after

adjuvant radiotherapy for breast cancer has also been sub-Tab

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tantially decreased over time.36 In that study, no differenceas noted in the incidence of mortality from ischemic heartisease between left- and right-sided tumor in the 1980 to984 or 1985 to 1989 timeframe, although large differenceere found in earlier time periods. With each succeedingear after 1979, the hazard of death from ischemic heartisease decreased by 6%. With these reductions of cardiacoses from the use of modern machines and techniques, theost recent data show an overall survival advantage in pa-

ients receiving PMRT therapy.1,2,41 Furthermore, data fromhe most modern postmastectomy trials suggest that com-ined modality treatment with mastectomy, systemic ther-py, and adjuvant radiation did not result in clinically rele-ant cardiotoxic effects.42

Comparison of the volume of heart irradiated and the doseeceived for the standard tangential versus newer, more con-ormal radiation techniques have been difficult to evaluate foreveral reasons. The definition of the “organ at risk” has noteen well defined or consistent (ie, whole heart v left ventricle

able 3 Heart and Lung Contours: Anatomic Boundaries

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earta Inferior aspect of the leftpulmonary artery

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eprinted with permission from White J, Tail A, Arthur D, et al:Definitions.

Heart caudal border: the heart blends with the diaphragm and liverheart versus these other organs.

Lung volumes: the lung volume within the pleural surface excludingsystems.

igure 9 Digital radiographs showing a field-within-field, “moreonformal” technique in which the (a) the optimized open lateralangent is treated (b) first and (c) 2 additional lateral fields usingultileaf collimation are delivered to improve homogeneity. (Color

ersion of figure is available online.) 1

myocardium); the dosimetric data for historic techniquesave not been well reported; the clinical manifestations ofardiac toxicity often occur with a latency period of greaterhan 10 years after treatment with endpoints that are oftenifficult to measure (ie, pericarditis, coronary artery disease

eading to angina, myocardial infarction, and thromboem-oli), with no established surrogates for clinical toxicity (ie,erfusion studies) other than death from cardiac causes.here is significant controversy regarding the threshold for

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cceptable low and intermediate doses for the heart and whathe heart volume to be contoured should be. Based on theew guidelines in the RTOG breast atlas,25 the entire hearthould be contoured. The cardiac doses should be measuredo generate a dose-volume histogram to allow for accuratessessment of the dose to various portions of the heart. Theaximum heart distance (MHD) is the maximum distance

etween the anterior cardiac contour and the posterior tan-ential views,39,40,43 which is measured on the beam’s eyeiew on CT-simulator or traditional simulation film. TheHD has been found to be a reliable predictor of the mean

eart dose and mean left anterior descending artery dose andan potentially be useful in clinical practice. When the MHDs �1 cm, the risk probability is reported to be less than%.39,40,44 For these reasons, the use of CT-based treatmentlanning and conformal radiation techniques for chest walladiotherapy should be used whenever possible in an attempto decrease normal tissue exposure, with the goal of sparinghe heart as best as possible, without conceding to a subop-imal coverage of the planning target volume and homogene-ty. Three-dimensional planning with CT-generated contoursan be more precisely customized to the individual patientith analysis of the dose volumes for critical structures.Several modern maneuvers for chest wall radiation have

een shown to reduce the volume of the heart irradiated.reath-holding techniques (using “active breathing control”evices or unassisted) and respiratory gating have beenhown as effective techniques to reduce cardiac volumes45-47;n addition, advancements in patient treatment positioningave made a significant difference in the amount of heart

rradiated. An inclined breast board has been shown to de-rease the mean cardiac dose, the maximal dose to the heart,nd the cardiac volume in the 50% isodose curve comparedith positioning patients flat.48,49 Several studies also suggest

hat treatment in the prone position allow for sparing of theeart and lung tissue.50,51

There are several treatment-related factors that have beenhown to increase cardiac toxicity including intentional treat-ent of the lower IM nodes, anthracycline-based systemic

herapy, and potentially trastuzamab. When the lower IModes are intentionally included with chest wall radiation,he volume of heart irradiated has been shown to increase,articularly when an additional IM field is added.52 Whendding a separate IM field it is prudent to use a combinationf electrons and photons or electrons alone (as opposed to ann face photon field) and to obtain a treatment plan in whichhe cardiac doses are minimized. Anthracycline-based che-otherapeutic drugs are well known to be cardiotoxic; al-

hough the mechanisms of cardiac damage with the drugersus radiotherapy differ, the potentiation of the toxicity ishought to be additive.53 Again, in patients receiving anthra-ycline drugs at higher risk for cardiotoxicity, meticulousttention is needed to minimize cardiac volumes irradiated.lthough trastuzamab is commonly delivered concomitantlyith radiation and is also known to be cardiotoxic, there is aaucity of data on the safety of delivering these 2 treatmentodalities together. A recent study showed that trastuzamab,
hen delivered weekly with radiation therapy, was an inde- a
endent prognostic factor for left ventricular ejection fractionecrease.54 Although the median follow-up was only 16onths and additional follow-up to assess long-term toxicity

s warranted, the authors concluded that cardiac volumeparing and careful selection of patients for IM irradiation beonsidered in patients receiving trastuzamab with RT.

ung Toxicityhe incidence of pulmonary toxicity after radiation therapy

or breast cancer varies significantly in the literature but isypically well under 10% with modern treatment units andechniques. Although most of the studies assessing radiation-nduced pneumonitis have been performed in patients afterreast-conservation therapy and not specifically in the post-astectomy setting, the acute and long-term effects are sim-

lar in that they are primarily dependent on the volume ofung irradiated and thus higher with the addition of SC or IMelds. Furthermore, the use and sequencing of systemic ther-py clearly impact the rate of pneumonitis, with a signifi-antly higher risk when concurrent versus sequential radia-ion therapy is delivered.55

Although the ultimate endpoint of “incidence of pulmo-ary toxicity” differs significantly based on the method usedo quantify pulmonary complications, whether it be patientymptoms’ assessment, chest radiographs, pulmonary func-ion testing, perfusion studies, or CT scans, several studiesave suggested that the frequency of pulmonary toxicity cane predicted based on the amount of lung in the tangentialelds.56-58 Although various models for predicting lung tox-

city after breast radiation therapy have been proposed in theiterature, no specific model has been consistently used inlinical practice or in the literature.

It is generally recommended that the amount of lung in theadiation field be kept under 3.0. When this is not possibleecause of anatomic limitations, the more conformal radia-ion techniques should be considered.

ymphedemafter treatment for LABC, upper-extremity arm edema is aommonly experienced complication, particularly for thoseatients who have undergone AND followed by radiationherapy to the full axilla. Similar to the issues regarding lungoxicity measurements, the frequency of lymphedema is vari-ble depending on the definition used, whether it be patientersus lymphedema specialists’ assessment and subjective se-erity versus quantitative measurements. The risk ofymphedema increases with the extent of lymph nodes ex-ised and is higher after radiotherapy is administered to theissected axilla versus AND alone.59,60 Other known risk fac-ors include older age and obesity (high body mass index).here are some data suggesting that the addition of a SC field

o tangential fields and the use of a posterior axillary boosteld may increase the risk of lymphedema in node positiveatients.61 For patients who are being managed with a fullND and comprehensive PMRT to intentionally include the
xilla, it is recommended that conventional fractionation

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1.8-2.0 Gy/d) and doses of 45 to 50 Gy be used. Sparing thekin at the top of the shoulder allows for collateral lymphaticrainage; therefore, whenever SC radiation is delivered, it isecommended that a strip of skin be spared, if possible.62

astly, in patients for whom only high (level 3) axillary radi-tion is warranted, the use of surgical clips to mark the area ofissection will help in treatment planning, so the portion ofhe axilla that has been dissected can be avoided with con-ormal radiation techniques.

rachial Plexopathyecause the brachial plexus transverses through the SC field

nto the axilla, it needs to be considered an organ at risk, withhe potential for significant toxicity. The effects of dose, vol-me, and fractionation need to be well thought through, justs with the other organs at risk. The long-term sequela ofadiation to the brachial plexus is radiation-induced brachiallexopathy, a clinical syndrome in which patients who havead previous SC fossa/axillary radiation present with symp-oms of arm numbness, tingling, pain, or motor weaknessonths to years after treatment. When these symptoms oc-

ur, workup to rule out neoplastic infiltration of tumor re-urrence is imperative. Although the incidence of brachiallexopathy is relatively low in patients who undergo confor-al treatment planning techniques and standard fraction-

tion schemas (46-50 Gy in 1.8-2-Gy fractions), older studiessing outdated techniques have shown that the doses to therachial plexus can be as high as 130% of the prescribedose, therefore significantly increasing the risk of brachiallexus injury.63 To ensure minimizing the risk of radiation-

nduced brachial plexopathy, it is important to (1) reduceignificant hotspots in the SAF, (2) avoid usage of large doseser fraction, and (3) place the match line for the SAF belowhe level of the brachial plexus whenever possible.64

adiation Aftereoadjuvant Chemotherapynd Breast Conservationor LABChe management of LABC treated with neoadjuvant therapynd breast conservation is reviewed by Taghian et al in thisssue of Seminars in Radiation Oncology. Herein, we describehe technical aspects appropriate for this treatment approach.or patients with LABC in which breast preservation is at-empted, it is imperative that a multidisciplinary approach isaken upfront with involvement of the surgeon, medical on-ologist, and radiation oncologist. The location of the pri-ary tumor should be marked with radiopaque clips insertedercutaneously before initiating chemotherapy so the tumored can be readily located for surgical excision if there is aomplete clinical regression of disease. All patients shouldndergo surgical excision to obtain negative margins, evenhose who achieve complete clinical response. Furthermore,ll patients should receive whole-breast irradiation followed
y a radiation boost to the lumpectomy cavity. fi
The simulation, treatment planning, and delivery of radi-tion to the intact breast do not differ significantly from thatf the chest wall radiation. Similar to PMRT, the role of add-ng regional nodal radiation to that of the intact breast (IModes and axilla after an AND) have yet to be evaluated in arospective, randomized setting. Contrary to what is typicallyone for early-stage breast cancer treated with breast conserva-ion, the threshold for including the regional lymph nodes isigher in patients with LABCs, and therefore the target volume isften extended beyond the intact breast in these patientsFig. 11). There are also controversies specific to the neoadju-ant approach that warrant further investigation, for instance,hether to irradiate the full axilla in a patient who initially had aositive sentinel lymph node, received neoadjuvant chemother-py, and subsequently has a negative axillary dissection orhether to add a radiation boost in a patient who has had a

omplete pathologic response with no residual disease at theime of lumpectomy.

Again, treatment planning should be performed with CTuidance whenever possible, and all attempts should beade to deliver a homogeneous dose to the breast and re-

ional nodes (if treating) and minimize the dose to the organst risk. If contouring for conformal treatment planning,uidelines set forth by the RTOG are useful.25 The breastypically receives 50 Gy in 2-Gy fractions delivered with stan-ard tangential fields or more conformal methods as de-cribed earlier.

At our institution, a boost is typically delivered for allatients who are treated with neoadjuvant chemotherapynd breast-conserving surgery, regardless of pathologic re-ponse. For the boost field, the second set of clips placed atime of lumpectomy will help to localize the tumor cavity.lthough the boost can be treated with tangential photon

igure 11 The dosimetry for a patient who underwent neoadjuvanthemotherapy, breast-conserving surgery, and axillary node dissec-ion. The technique incorporates a electron/photon IM field with theconformal field-in-field tangents and a matched SC field. Note the

dded dose to the heart with the addition of the IM field. (Colorersion of figure is available online.)

elds in very large-breasted women, electrons are generally

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sed in most cases. Often, repositioning of the patient isequired (different position than the whole-breast radiation)n an attempt to align the skin over the clips parallel to thereatment table so the electron field can be delivered en face.nce the clips are visualized, a 2- to 3-cm margin is placed in

ll directions to define the boost field. The energy of thelectrons should be determined by the thickness of the breastrom the skin to the chest wall in the treatment position andrescribed to the 90% isodose line. The boost dose is typi-ally 10 to 16 Gy in 2.0-Gy fractions.

onclusionsadiation therapy is an important component of the multi-isciplinary management of LABC. The treatment units andechniques have evolved significantly over the years, with aubsequent decrease in the long-term cardiac complicationsnd cardiac-related deaths and improvements in overall sur-ival. The current technology mandates an in-depth knowl-dge of the anatomy and treatment techniques to improveomogeneity in the treatment field while minimizing theose to organs at risk. Only with optimal radiation treatmentlanning and delivery can the survival benefit with adjuvantadiation therapy for LABC continue to be achieved.

eferences1. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemo-

therapy in node-positive premenopausal women with breast cancer.N Engl J Med 337:956-962, 1997

2. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapyin high-risk premenopausal women with breast Cancer who receiveadjuvant chemotherapy. Danish Breast Cancer Cooperative Group, p82b Trial. N Engl J Med 337:949-955, 1997

3. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapyin high-risk postmenopausal breast-cancer patients given adjuvant ta-moxifen: Danish Breast Cancer Cooperative Group DBCG 82c random-ized trial. Lancet 353:1641-1648, 1999

4. Taghian A, Jagsi R, Makris A, et al: Results of a survey regarding irra-diation of internal mammary chain in patients with breast cancer: Prac-tice is culture driven rather than evidence based. Int J Radiat Oncol BiolPhys 60:706-714, 2004

5. Taylor ME, Haffty BG, Shank BM, et al: Postmastectomy radiotherapy;American College of Radiology, ACR: Appropriateness criteria. Radiol-ogy 215:1153-1170, 2000 (suppl)

6. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a ran-domized trial comparing total mastectomy, lumpectomy, and lumpec-tomy plus irradiation for the treatment of invasive breast cancer. N EnglJ Med 347:1233-1241, 2002

7. White J, Moughan J, Pierce LJ, et al: Status of post-mastectomy radio-therapy in the United States: A patterns of care study. Int J Radiat OncolBiol Phys 60:77-85, 2004

8. Bornstein BA, Cheng CW, Rhodes LM, et al: Can simulation measure-ments be used to predict the irradiated lung volume in the tangentialfields in patients treated for breast cancer? Int J Radiat Oncol Biol Phys18:181-187, 1990

9. Kirova YM, Campana F, Fournier-Bidoz N, et al: Postmastectomy elec-tron beam chest wall irradiation in women with breast cancer: A clinicalstep toward conformal electron therapy. Int J Radiat Oncol Biol Phys69:1139-1144, 2007

0. Kirova YM, Campana F, Fournier-Bidoz N, et al: Post-mastectomy elec-tron beam chest wall irradiation in women with breast cancer: A clinicalstep toward conformal electron therapy. Int J Radiat Oncol Biol Phys69:1139-1144, 2007

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2. Hartsell WF, Kelly CA, Schneider L, et al: A single isocenter three-fieldbreast irradiation technique using an empiric simulation and a sym-metric collimator. Med Dosimetry 19:169-173, 1994

3. Chu JC, Solin LJ, Hwang CC, et al: A nondivergent three field matchingtechnique for breast irradiation. Int J Radiat Oncol Biol Phys 19:1037-1040, 1990

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5. Svensson GK, Chin LM, Siddon RL, et al: Breast treatment techniques atthe Joint Center for Radiation Therapy, in Harris JR, Hellman S andSilen W (eds): Conservative Management of Breast Cancer: New Sur-gical and Radiotherapeutic Techniques. Philadelphia, JB Lippincott,1983, pp 239-255

6. Siddon RL, Buck BA, Harris JR, et al: Three-field technique for breastirradiation using tangential field corner blocks. Int J Radiat Oncol BiolPhys 9:583-588, 1983

7. Lebesque JV: Field matching in breast irradiation: An exact solution toa geometrical problem. Radiother Oncol 5:47-57, 1986

8. Podgorsak EB, Gosselin M, Kim TH, et al: A simple isocentric techniquefor irradiation of the breast, chest wall and peripheral lymphatics. Br JRadiol 57:57-63, 1984

9. Garg AK, Frija EK, Sun TL, et al: Effects of variable placement ofsuperior tangential/supraclavicular match line on dosimetric coverageof level III axilla/axillary apex in patients treated with breast and supra-clavicular radiotherapy. Int J Radiat Oncol Biol Phys 73:370-374, 2009

0. Liengsawangwong R, Yu TK, Sun TL, et al: Treatment optimizationusing computed tomography-delineated targets should be used for su-praclavicular irradiation for breast cancer. Int J Radiat Oncol Biol Phys69:711-715, 2007

1. Bentel GC, Marks LB, Hardenbergh PH, et al: Variability of the depth ofsupraclavicular and axillary lymph nodes in patients with breast cancer:Is a posterior axillary boost field necessary? Int J Radiat Oncol Biol Phys47:755-758, 2000

2. Pignol JP, Olivotto I, Rakovitch E, et al: A multicenter randomized trialof breast intensity-modulated radiation therapy to reduce acute radia-tion dermatitis. J Clin Oncol 26:2085-2092, 2008

3. Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT)in patients prescribed breast radiotherapy. Radiother Oncol 82:254-264, 2007

4. Fraass BA, Kessler ML, McShan DL, et al: Optimization and clinical useof multisegment intensity-modulated radiation therapy for high-doseconformal therapy. Semin Radiat Oncol 9:60-77, 1999

5. White J, Tai A, Arthur D, et al: RTOG breast cancer atlas for radiationtherapy planning: Consensus definitions: Presented at the ASCO 2008Breast Cancer Symposium, Washington DC, 2008

6. Buchholtz TA: Breast cancer, in Chao C, Apisrathanarax S, Ozyigit G(eds): Practical Essentials of Intensity Modulated Radiation Therapy.Philadelphia, PA, Lippincott, Williams & Wilkins, 2005, p 248

7. Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiother-apy. J Clin Oncol 12:447-453, 1994

8. Early Breast Cancer Realists Collaborative Group: Effects of radiother-apy and surgery in early breast cancer: An overview of the randomizedtrials. N Engl J Med 333:1444-1455, 1995

9. Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardialinfarction after adjuvant radiotherapy for breast cancer in the surveil-lance, epidemiology, and end-results cancer registries. J Clin Oncol16:2625-2631, 1998

0. Rutqvist LE, Johansson H: Mortality by laterality of the primary tumouramong 55,000 breast cancer patients from the Swedish Cancer Regis-try. Br J Cancer 61:866-868, 1990

1. EBCTCG: Favourable and unfavourable effects on long-term survival ofradiotherapy for early breast cancer: An overview of the randomisedtrials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 355:
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2. Host H, Brennhovd IO, Loeb M: Postoperative radiotherapy in breastcancer—Long-term results from the Oslo study. Int J Radiat Oncol BiolPhys 12:727-732. 1986

3. Early Breast Cancer Trialists’ Collaborative Group: Treatment of EarlyBreast Cancer: Worldwide Evidence 1985-1990 (vol 1). Oxford, Ox-ford University Press, 1990

4. Jones J, Ribeiro G: Mortality patterns over 34 years of breast cancerpatients in a clinical trial of post-operative radiotherapy. Clin Radiol40:204-208, 1989

5. Haybittle JL, Brinkley D, Houghton J, et al: Postoperative radiotherapyand late mortality: Evidence from the cancer research campaign trial forearly breast cancer. BMJ 298:1611-1614, 1989

6. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death afteradjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424,2005

7. Fuller SA, Haybittle JL, Smith RE, et al: Cardiac doses in post-operativebreast irradiation. Radiother Oncol 25:19-24, 1992

8. Muren LP, Maurstad G, Hafslund R, et al: Cardiac and pulmonary dosesand complication probabilities in standard and conformal tangentialirradiation in conservative management of breast cancer. RadiotherOncol 62:173-183, 2002

9. Hurkmans CW, Borger JH, Bos LJ, et al: Cardiac and lung complicationprobabilities after breast cancer irradiation. Radiother Oncol 55:145-151, 2000

0. Hurkmans CW, Cho BC, Damen E, et al: Reduction of cardiac and lungcomplication probabilities after breast irradiation using conformal ra-diotherapy with or without intensity modulation. Radiother Oncol 62:163-171, 2002

1. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and ofdifferences in the extent of surgery for early breast cancer on localrecurrence and 15-year survival: An overview of the randomised trials.Lancet 366:2087-2106, 2005

2. Hojris I, Overgaard M, Christensen JJ, et al: Morbidity and mortality ofischemic heart disease in high-risk breast-cancer after adjuvant post-mastectomy systemic treatment with or without radiotherapy: Analysisof DBCG 82b and 82c randomized trails. Lancet 354:1425-1430, 1999

3. Taylor C, McGale P, Povall J, et al: Estimating cardiac exposure frombreast cancer radiotherapy in clinical practice. Int J Radiat Oncol BiolPhys Octoer 73:1061-1068, 2009

4. Gagliardi G, Lax I, Rutqvist LE: Partial irradiation of the heart. SeminRadiat Oncol 11:224-233, 2001

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7. Remouchamps VM, Vicini FA, Sharpe MB, et al: Significant reductionsin heart and lung doses using deep inspiration breath hold with activebreathing control and intensity modulated radiation therapy for pa-tients treated with locoregional breast irradiation. Int J Radiat Oncol
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8. Canney PA, Deehan C, Glegg M, et al: Reducing cardiac dose in post-operative irradiation of breast cancer patients: The relative importanceof patient positioning and CT scan planning. Br J Radiol 72:986-993,1999

9. Canney PA, Sanderson R, Deehan C, et al: Variation in the probabilityof cardiac complications with radiation technique in early breast can-cer. Br J Radiol 74:262-265, 2001

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1. Griem KL, Fetherston P, Kuznetsova M, et al: Three-dimensional photondosimetry: A comparison of treatment of the intact breast in the supine andprone position. Int J Radiat Oncol Biol Phys 57:891-899, 2003

2. Gyenes G, Gagliardi G, Lax I, et al: Evaluation of irradiated heart vol-umes in stage I breast cancer patients treated with postoperative adju-vant radiotherapy. J Clin Oncol 15:1348-1353, 1997

3. Yahalom J, Portlock CS: Cancer: Principles and Practice of Oncology(ed 7). Philadelphia, PA, Lippincott/Williams & Wilkins, 2005

4. Belkacemi Y, Gligorov J, Ozsahin M, et al: Concurrent trastuzamab withadjuvant radiotherapy in HER2-positive breast cancer patients: Acutetoxicity analyses from the French multicentric study. Ann Oncol 19:1110-1116, 2008

5. Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breastcancer patients treated with conservative surgery and radiation therapy.Int J Radiat Oncol Biol Phys 21:355-360, 1991

6. Kimsey FC, Mendenhall NP, Ewald LM, et al: Is radiation treatmentvolume a predictor for acute or late effects on pulmonary function? Aprospective study of patients treated with breast-conserving surgeryand post-operative irradiation. Cancer 73:2549-2555, 1994

7. Lind P, Wennberg B, Gagliardi G, et al: Pulmonary complications fol-lowing different radiotherapy techniques for breast cancer, and theassociation to irradiated lung volume and dose. Br Cancer Res Treat68:199-210, 2001

8. Krengli M, Sacco M, Loi G, et al: Pulmonary changes after radiotherapyfor conservative treatment of breast cancer: A prospective study. Int JRadiat Oncol Biol Phys 70:1460-1467, 2008

9. Kissin MW, Querci della Rovere G, Easton D, et al: Risk of lymphedemafollowing treatment for breast cancer. Br J Surg 73:580-584, 1986

0. Dewar JA, Sarrazin D, Benhamou E, et al: Management of the axilla inconservatively treated breast cancer: 592 patients treated at the institueGustave-Roussy. Int J Radiat Oncol Biol Phys 13:475-481, 1987

1. Hayes SB, Freedman GM, Li T, et al: Does axillary boost increaselymphedema compared with supraclavicular radiation alone afterbreast conservation? Int J Radiat Oncol Biol Phys 72:1449-1455, 2008

2. Leitch A, Meek A, Smith R, et al: Workgroup I: Treatment of the axillawith surgery and radiation-preoperative and postoperative risk assess-ment. Cancer S83:2877-2879, 1998

3. Svensson H, Westling P, Larsson L-G: Radiation-induced lesions of thebrachial plexus correlated to the dose-time-fractionation schedule.Acta Radiol Ther Phys Biol 14:228-238, 1975

4. Benson S, Dische S: Morbidity related to axillary irradiation in the
treatment of breast cancer. Acta Oncol 39:337-347, 2000

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nflammatory Breast Cancerendy A. Woodward, MD, PhD,* and Massimo Cristofanilli, MD†

Inflammatory breast cancer (IBC) represents the most virulent form of breast cancer,characterized by involvement of the skin and rapid progression of the disease. Manage-ment involves careful coordination of all multidisciplinary modalities, including imaging,systemic chemotherapy, surgery, and radiation therapy. The use of neoadjuvant chemo-therapy has contributed significantly to improvement in overall survival since the firstdescriptions of this entity and has made the role of locoregional therapy, including surgeryand radiation critical to continued improvements in this disease. In this article, we examinethe unique epidemiology and pathology of IBC and review the various treatment modalitiesnoting the significance of a multimodality approach and delineating each of the specificcomponents. Moreover, we briefly describe the current research in IBC that will hopefullycontribute further to improve systemic therapies.Semin Radiat Oncol 19:256-265 © 2009 Published by Elsevier Inc.

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he historic background of inflammatory breast cancer(IBC), recently reviewed,1 apparently begins with Sir

harles Bell in 1814 who observed that “a purple color on thekin over the tumor accompanied by shooting pains is a verynpropitious beginning.”2 The term “inflammatory carci-oma of the breast” was first used by Lee and Tannenbaum in924,3 noting that “as the disease progresses, the skin be-omes deep red or reddish-purple, and to the touch israwny and infiltrated.” The inflamed area presents a distinctaised periphery after the fashion of erysipelas (Fig. 1). Cur-ently, the most widely referenced definition is that of themerican Joint Committee on Cancer,4 which states in part

hat “inflammatory carcinoma is a clinicopathologic entity char-cterized by diffuse erythema and edema (peau d’orange) of thereast, often without an underlying mass. These clinical findingshould involve the majority of the breast . . . It is important toemember that inflammatory carcinoma is primarily a clinicaliagnosis. Involvement of the dermal lymphatics alone doesot indicate inflammatory carcinoma in the absence of clin-

cal findings.”

Department of Radiation Oncology, The University of Texas M. D. Ander-son Cancer Center, Houston, TX.

Department of Breast Medical Oncology, The University of Texas M. D.Anderson Cancer Center, Houston, TX.

upported by Komen Foundation Promise grant KGO81287, the Universityof Texas Institutional Research grants K12-5611B through the Universityof Texas Health Sciences Centre from the National Institute of Health,and the University of Texas M. D. Anderson Cancer Center grant no.R01CA138239-01; IRG.

ddress reprint requests to Massimo Cristofanilli, MD, Department of BreastMedical Oncology, Unit 1354, The University of Texas M. D. AndersonCancer Center, 1515 Holcombe Blvd., Houston, TX. E-mail: mcristof@

ymdanderson.org

56 1053-4296/09/$-see front matter © 2009 Published by Elsevier Inc.doi:10.1016/j.semradonc.2009.05.008

An apparently useful model for the consideration of thepectrum of disease manifestations leading to IBC was pro-osed by Denoix5 who used the term pousee evolutive (PEV)r rapidly progressing breast cancer in which the most ad-anced form, PEV 3, as used in the Tunisian IBC studies,6 isefined as “a designation given to patients with inflammationovering more than half the breast surface,” which is clearlyompatible with the American Joint Committee on Cancerase definition. Cases with PEV 2 in Tunisia that have inflam-atory signs affecting less than half the breast did slightly

etter than PEV 3 cases in the first 3 years but had virtuallydentical poor survival at four years and beyond.7

pidemiologic Featureslthough there are some differences among the 4 large pop-lation-based studies,8-11 many of the features are similar.he specific details differ considerably for several reasons.hey cover different time periods ranging from 1975 to9819 to 1988 to 2000.8 They use different databases includ-

ng the Surveillance, Epidemiology and End Results Programor 38-10 and the North American Association of Central Can-er Registries for 1.11 Most importantly, they select differentatients with 28,9 using both clinical and pathologic criteria toelect patients and 210,11 restricting cases to those definedathologically as IBC. For pathologic definition, all 4 usednternational Classification of Diseases for Oncology mor-hology code 8530/3.Despite these differences in analysis, all reports document

hat IBC has a higher incidence in black women comparedith white women and that in both groups IBC occurs at a
ounger age than non-IBC breast cancer. Regarding racial/


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Radiotherapy for IBC 257

thnic differences, blacks had at least a 50% higher incidencehan whites, were diagnosed at an earlier age, and had ahorter survival, as also seen in non-IBC breast cancer.

ingo et al11 also looked at other racial-ethnic groups andoted that Hispanic women had the youngest mean age ofnset (50.5 years) compared with 55.2 for black women and8.1 for white women. Other findings of interest include theuggestion that the incidence of IBC in the United States hasncreased over time.8,10 These studies also confirm a poorurvival in clinically and pathologically defined cases8,9 butave noted an improving survival in recent years with impor-ant advances in chemotherapy.8,10 The increasing incidencen IBC contrasts markedly with non-IBC breast cancer, whichas leveled off since 2001 to 2003.12 In addition, IBC tumors

nclude a generally higher tumor grade and more estrogeneceptor (ER)-negative tumors than non-IBC breast cancer,ith the ER-negative disease making well more than 50% of

ll cancers in IBC.8 In regard to the incidence of IBC, the usef the clinical codes (EOD-E 70 for tumor extension andOD-S 998 for tumor size), which are now available in Sur-eillance, Epidemiology and End Results, indicate that IBComprises 2.5% of all incident breast cancer cases,8 which ishigher rate than reported in the 2 studies using only patho-

Figure 1 (A) Clinical and pathologic signs of IBC. Erythembreast (arrows). (B) Prominent ridging is present in theprior mammoplasty. (C) Peau d’orange encompassingimmediately outside the radiation field evident as hyperin a patient with clinical signs of IBC.

ogically diagnosed IBC. a

isk Factorst has been reported that women with aggressive breast can-er were more likely to have had their first child at a youngerge than non-IBC patients. This was noted in the TunisianEV patients; 14 of 15 premenopausal women with firstirths at the age of 18 or earlier were diagnosed as PEVositive. This finding was weakly supported by the study ofhang et al,13 who compared 68 IBC patients with 143 non-

BC breast cancer patients and 134 patients with cancer atther sites and found the lowest median age at first live birthn the IBC patients, but the difference was not statisticallyignificant. In a comparison of 116 patients with aggressivereast cancer as defined by tumor grade, 99 patients withonaggressive breast cancer, and 135 patients from our IBCegistry, both IBC patients and the non-IBC patients withggressive breast cancer were more likely to have a first childefore age 20 than the breast cancer patients with nonaggres-ive breast cancer, and the patients with aggressive breastancer were 3 times more likely to have their first child beforege 20 than the patients with nonaggressive breast cancer.14

A high body mass index has consistently been reported asrisk factor in premenopausal and postmenopausal women

he breast with tumor nodules extending to the oppositected breast and represents a postoperative change afterf the breast. (D) Inflammatory recurrence on the backtation of the skin (arrows). Dermal lymphatic invasion

a of tunaffemost opigmen

s well.13 Because relative weight is associated with a reduced

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258 W.A. Woodward and M. Cristofanilli

r similar risk of breast cancer in premenopausal women ineneral,15 this appears to be another example of a differenceetween IBC and non-IBC aggressive breast cancer versusonaggressive breast cancer.

linical Inflammatory Signshe histologic hallmark of IBC is the presence of dermal

ymphatic invasion in which numerous dilated dermal lym-hatics filled with tumor emboli that are usually retractedway from the surrounding endothelial lining (Fig. 1).16 Der-al lymphatic invasion and the subsequent lymphatic ob-

truction, rather than infiltration by inflammatory cells, isurported to be responsible for clinical inflammatory signsnd symptoms and, ultimately, for the highly metastatic po-ential of IBC. Likely because of sampling heterogeneity,owever, DLI is identified in fewer than 75% of IBC tumorsnd is not required for the diagnosis. Importantly, althoughhe diagnosis of IBC versus non-IBC can be made based onlinical signs and does not require pathologic evidence ofLI, pathologic confirmation of breast cancer is required toistinguish IBC from benign disease.

dhesion Moleculest has been proposed that the molecular basis of dermal lym-hatic invasion might involve adhesion molecules, either onumor cells or endothelial cells, or angiogenic growth factorsnd proteolytic enzymes elaborated by tumor cells that en-ble intravasation. E-cadherin is a calcium-dependent trans-embrane glycoprotein and, as part of a membrane complexith �-catenin and �-catenin, is essential in maintaining ad-esion between epithelial cells.17 In most epithelial malig-ancies, including breast carcinoma, decreased or lost E-adherin expression is associated with malignant progressionncluding high histologic grade, increased proliferation, in-asion, metastasis, and poor prognosis.18-24 Using immuno-istochemistry on 20 IBC and 22 stage-matched non-IBCumors, Kleer et al18 found that E-cadherin was preferentiallyxpressed in IBC tumors (100% IBC v 68% non-IBC). Nossociation was found between E-cadherin expression andormonal receptors or Her-2 status.18 Colpaert et al25 re-orted a strong E-cadherin expression in 33 of 35 IBC tu-ors. In particular, intralymphatic tumor emboli of IBC also

trongly expressed E-cadherin. These findings indicated that-cadherin is required for tumor emboli formation by en-ancing tumor cell–tumor cell adhesion and maintaining the

ntegrity of IBC tumor emboli in the dermal lymphatics. Inddition to an intact and overexpression of E-cadherin/�,-catenin axis,26 sialyl-Lewis X/A-deficient MUC1 appears toe another key factor that contributes to lymphovascular me-astasis of IBC.27,28 MUC1 is a glycoprotein in the cell surfaceucin family and is the ligand of E-selectin (a cell adhesion

eceptor) on the surface of endothelial cells. The sialyl-Lewis/A carbohydrate ligand-binding epitope on MUC1 facili-

ates the ligand-receptor interaction.27 Nonsialylated MUC1oes not bind E-selectin, resulting in epithelial cell–endothe-

ial cell aversion. Notably, the overexpression of E-cadherin c

nd MUC1 were included as part of “inflammatory signature”f IBC in a study by Charafe-Jauffret et al.29

IBC is further characterized by extensive angiolymphaticnvasion and early lymph node involvement. Using immuno-istochemical staining, McCarthy et al30 found that intratu-oral microvessel density in IBC was significantly higher

han in non-IBC. In a study with 35 IBC and 104 non-IBCumors, Colpaert et al25 observed intense angiogenesis in IBCumors that was manifested not only by increased vascularensity but also high endothelial cell proliferation rate. More-ver, the same study showed a significant positive correlationetween carbonic anhydrase IX, a hypoxia marker, and en-othelial cell proliferation in IBC, implying that the angio-enesis is at least partly hypoxia driven.

onventional BiomarkersBC more frequently shows negative ER and progesteroneeceptor (PR) status than non-IBC.29,31-33 Up to 83% of IBCumors lack ER expression compared with other forms ofABCs that are mostly ER positive.31,34-37 IBC has a higher

ncidence of EGFR and Her-2 overexpression than non-BC.29,38-40 Her-2 overexpression and/or amplification rateas been reported in up to 100% of IBC tumors tested but

s generally reported within the 40% to 50% positivityange.38-43 Also, Her-2 and C-myc proto-oncogene overex-ression is mutually exclusive in IBC38 and c-myb proto-ncogene expression was lower in IBC than non-IBC.40 The-myb expression was found to be directly associated withood prognostic factors (ie, lowest histopathologic grade,ositive ER and PR status, and pS2 gene expression)40,44 andegatively correlated with poorer prognosis in both IBC andon-IBC, suggesting a biological link with molecular featuresf less aggressive disease. The difference of Her-2 status be-ween IBC and non-IBC tumors has also been observed atolecular level, with IBC tumors more frequently showing gene

mplification (by Southern blotting) and messenger RNA ex-ression (by Northern blotting and reverse transcription poly-erase chain reaction) relative to non-IBC tumors.38,39,45 Theseata indicated that the newer Her-2–directed therapies are

ikely to improve the outcome of the population of patients withBC compared with historic standards.

In many studies, p53 gene mutation and/or nuclear over-xpression of mutated p53 protein was found to be associ-ted with the advanced stage of the disease (ie, large tumorize, high grade, and early metastasis) and poor overall sur-ival.37,46-48 Riou et al37 showed that IBC patients with tumorsarrying a p53 gene mutation and nuclear overexpression ofhe p53 protein had an 8.6-fold higher risk of death com-ared with patients with tumors having neither mutation norhe protein overexpression. The prognosis was even worsehen the tumors were also ER negative.37 Data on associationetween p53 status and response to primary systemic ther-py are somewhat controversial.46,47,49,50

ther Biological Factorsan Golen et al51 identified 2 genes whose expression was
oncomitantly altered. With in situ hybridization, RhoC

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TPase, a breast-specific oncogene, was overexpressed in0% of the IBC tumors compared with 38% of the stage-atched non-IBC tumors, whereas WISP3 (also known as

ost in IBC) was lost in 80% of IBC tumors versus in only 21%f non-IBC tumors. RhoC GTPase is involved in cytoskeletaleorganization and contributes to the metastatic potential byncreasing cellular motility and invasion and inducing actintress fiber and focal adhesion complex formation.52 Kleer etl53,54 showed that RhoC overexpression is associated withigh histologic grade, positive lymph nodes, and negativeormonal receptor status. In addition, high RhoC expressionas shown to be a predictor of poor overall survival in pa-

ients with breast cancer and an independent predictor ofoor response to doxorubicin-based chemotherapy. Tran-cription factor nuclear factor kB (NF-kB) is an importantediator of cell proliferation, apoptosis, and migration. Van

aere et al55,56 reported a significant overexpression of manyF-�B target genes in the IBC tumors compared with non-

BC tumors by complementary DNA microarray, which wasonfirmed by reverse transcription polymerase chain reac-ion. In addition, they observed a significant increase in themount of positively stained nuclear in IBC for 2 NF-kBubunits (RelB and NF-kB1). The immunostaining result waserified by NF-kB DNA-binding experiments. NF-kB targetenes were also found to be significantly elevated in ER-egative breast cancers. Their findings suggested that theF-kB transcription factor pathway may play an important

ole in the aggressive behavior of IBC.

urvival Trends Over Time andistory of the Treatment of IBC

efore the availability of combination chemotherapy, IBCas almost uniformly fatal. Fewer than 5% of patients treatedith surgery and/or radiotherapy survived past 5 years, and

he expected median survival time for such patients was lesshan 15 months.57 Local recurrence rates with surgery and/oradiotherapy were also high at approximately 50%,58,59 andost patients were not surgical candidates at all. One of therst successful efforts to improve locoregional control beforerole for surgery in this disease was made by researchers at

he University of Texas M. D. Anderson Cancer Center. IBCas recognized to have a rapid proliferative potential, and as

uch, 1 mechanism for displaying resistance to radiation washe repopulation of tumor cells during the interval betweenadiation treatments. Based on this principle,60 investigatorsought to circumvent this rapid tumor cell growth rate byncorporating accelerated hyperfractionated radiotherapynto the definitive treatment of these patients.61 This short-ned the overall radiotherapy course from 6 to 7 weeks to aittle more than 4 weeks (51 to 54 Gy in twice-daily fractionsf 1.5 Gy followed by a boost to the highest-risk volume of 15o 20 Gy). Although this strategy was successful in improvingocoregional control, most patients still died from distant

etastatic disease. s

rimodality Therapy for IBCuring the 1970s, doxorubicin-based chemotherapy was in-

roduced into the management of this disease, and in the late970s neoadjuvant chemotherapy was introduced.62 Highates of tumor response were noted. Four prospective trialsonducted at the M.D. Anderson Cancer Center that enrolledatients with IBC between 1974 and 200163-67 compared 4nthracycline-containing regimen in combination with lo-oregional therapies, all of which showed equivalent efficacyith overall clinical response and complete clinical response

ates of 72% and 12%, respectively. Baldini et al68 reportedn a cohort of 68 patients with IBC treated on 2 prospectiveandomized trials in which patients received primary sys-emic chemotherapy with 3 cycles of cyclophosphamide,oxorubicin, and 5-fluorouracil or cyclophosphamide, epi-ubicin, and 5-fluorouracil followed by surgery, adjuvanthemotherapy, and finally radiotherapy. In this study, 5- and0-year disease-free survival rates were reported at 29% and0%, respectively, and overall survival rates were reported toe 44% and 32%, respectively. Again, both outcomes werear superior to outcomes reported before the introduction ofnthracycline-containing primary systemic treatment. Theseesults in combination with those observed for other breastancer types established anthracycline-containing primaryystemic regimens as a standard in the combined modalityreatment of IBC.

eoadjuvant Chemotherapy for IBChe prognostic impact of neoadjuvant systemic therapy cane assessed by the percentage of patients who achieve aathologic complete response (defined as the absence of dis-ase in both the breast and the axilla).69 Furthermore, Hen-essy et al70 evaluated the prognostic significance of attainingpathologic complete response in the axillary lymph nodes

n a cohort of 61 IBC patients with cytologically confirmedxillary lymph node metastases. In this study, the 5-yearverall and disease-free survival rates were higher in theroup that attained a pathologic complete response (82.5%nd 78.6%, respectively) in the axillary lymph nodes com-ared with those who had evidence of residual disease37.1% and 25.4%, respectively). These results served to ex-end the prognostic significance of response to treatment inatients with IBC.In the subsequent years, there were efforts to investigate

ovel chemotherapy regimens that would increase the rate ofathologic complete response in patients with IBC. There-ore, several studies introduced taxanes, such as paclitaxelnd docetaxel, to anthracycline-containing primary systemicreatment regimens. The results of a cohort of 44 patientsith IBC treated with 4 cycles of fluorouracil, adriamycin,

yclophosphamide (FAC)-based primary systemic chemo-herapy, 16 of whom crossed over to receive paclitaxel after aess than partial response to first-line chemotherapy, wereeported by Cristofanilli et al.71 Of the 16 patients who re-eived paclitaxel, 7 achieved a partial response and under-ent mastectomies. In a subsequent follow-up retrospective

tudy,72 the investigators compared 178 patients with IBC

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reated with FAC alone with 62 patients with IBC who werereated with FAC followed by paclitaxel (either every 3 weeksr on a high-dose weekly schedule). The investigators re-orted significantly higher pathologic complete responseates with the addition of paclitaxel compared with FAClone (25% v 10%, P � .012) with a higher median overallurvival and progression-free survival rates in the group re-eiving paclitaxel.

Among the several molecular determinants of IBC, partic-larly significant is the overexpression and/or amplificationf members of the HER-1 (ErbB1) and Her-2 (erbB2) familyf receptors. Trastuzumab, a humanized monoclonal anti-ody-targeted against the Her-2 protein, has recently beenhown to significantly improve survival outcomes in patientsith early73,74 and advanced-stage breast cancer.75 In addi-

ion, Buzdar et al76 reported pathologic response rates as highs 60% when trastuzumab was incorporated into an anthra-ycline/taxane-based primary systemic chemotherapy regi-en in a cohort of women with non-IBC early-stage breast

ancer. Similar pathologic complete response rates were sub-equently reported by Dawood et al77 in a cohort of patientsith locally advanced breast cancer (that included IBC) when

reated with the same regimen as used by Buzdar et al76 inperable disease.Several studies have reported a higher incidence of Her-2

verexpression in patients with IBC,38,41 making trastu-umab an ideal agent to incorporate into the treatment par-digm of IBC. Hurley et al78 reported on a cohort of 48atients with Her-2–positive locally advanced breast cancerincluding IBC) who were treated with 12 weeks of do-etaxel, cisplatin, and trastuzumab followed by surgery, ad-uvant chemotherapy, and radiation therapy. The study re-orted a pathologic response rate (breast and axilla) of 17%or the entire cohort with 4-year progression-free and overallurvival rates reported as 100% for those who attained aathologic complete response and 83% and 76%, respec-ively, for those who had evidence of residual disease. Vanelt et al79 reported on a cohort of 22 patients (9 of whom hadBC) who were treated with a combination of docetaxel andrastuzumab as part of their primary systemic regimen. In thisohort, a complete response of 40% was observed. Limentanit al80 evaluated a primary systemic regimen that was com-osed of docetaxel, vinorelbine, and trastuzumab on a cohortf 31 patients with Her-2–amplified breast carcinomas (in-luding IBC) and reported clinical and pathologic responseates of 94% and 39%, respectively. Burstein et al81 reportedn a pilot study that evaluated a cohort of 40 women withtage II and III breast cancer (including 6 who had IBC) whoere treated with a primary systemic regimen of trastuzumab

nd paclitaxel that was followed by surgery and adjuvantnthracycline-based chemotherapy. In this cohort, completelinical response and pathologic complete response rates of0% and 18% were reported, respectively. The results ofhese studies when taken in combination with the knownurvival advantage observed when trastuzumab is adminis-ered to patients with early-stage breast cancer and the sur-
ival advantage attained by obtaining a pathologic complete a
esponse suggest that trastuzumab may indeed be a vitalomponent in the treatment of Her-2–positive IBC.

Lapatinib (Tykerb, GlaxoSmithKline, Research Triangleark, NC 27709) is a reversible inhibitor of the ErbB1 andrbB2 tyrosine kinases that has been shown in ErbB1/ErbB2-ependent tumor cell lines to induce growth arrest and/orell apoptosis.82 Partial responses to lapatinib in women withxtensively pretreated IBC have been reported.83,84 Based onuch observations, Cristofanilli et al85 evaluated the combi-ation of lapatinib and paclitaxel as part of the primary sys-emic therapy regimen in a cohort of 21 chemo-naive patientsho had Her-2–overexpressing IBC. In this study, patients

eceived daily lapatinib at a dose of, 1500 mg initially asonotherapy for 14 days after which it was given in combi-ation with weekly paclitaxel, 80 mg/m, for 12 weeks. Inddition to good tolerance to this regimen, the authors noted95% clinical response rate. Because of the remarkable clin-

cal activity observed, these results will be prospectively val-dated.

urgery for IBCn important issue in reviewing reports about treatment ef-cacy has to do with the criteria used in selecting patients forurgery. Various studies that have not found a benefit fromhe addition of surgery have reserved mastectomy only forhose patients who did not respond well to primary chemo-herapy with or without radiation.86-88 In these cases, surgerys performed as a debulking procedure, rather than with cur-tive intent. These studies have had mixed results, in partecause there is residual disease in a significant percentage ofatients who are disease free by clinical examination after theompletion of chemotherapy.89,90

In contrast, multiple studies have shown that surgery isspecially important for patients who respond well to che-otherapy, with the combination of therapies giving theseatients a real chance at long-term survival. Two studies pub-

ished in 1989 showed that in patients receiving primaryhemotherapy, surgery, and radiation therapy, 5-year dis-ase-free survival was significantly higher in patients with aomplete clinical response to primary chemotherapy com-ared with patients showing only a partial response or noesponse.62,91 More recently, Fleming et al92 reviewed treat-ent outcomes in 178 women with IBC treated with doxo-

ubicin-based multimodality therapy. They found that theddition of mastectomy to chemotherapy and radiotherapymproved local control. Also, the addition of mastectomymproved distant disease-free survival and overall survivalut only in patients with a clinical complete or partial re-ponse to primary chemotherapy. There was no survival orocal control benefit from the addition of mastectomy foratients who showed no significant response to primary che-otherapy.A primary concern in surgical planning is that the opera-

ive field needs to be wide enough to encompass all the sec-ndary skin changes. This is true even if surgery is under-aken only as a palliative measure. If this is not possible,
dditional chemotherapy may be considered. Although as

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uch skin as necessary should be removed, tension must bevoided in closing the skin flaps because this would make theite unsuitable for radiotherapy. If necessary, repair with au-ologous tissue flaps should be used to ensure a healthy, flathest wall. This will usually be a latissimus dorsi myocutane-us flap, unless extremely broad coverage is needed.Another major concern in surgical planning is the diffi-

ulty in determining the extent of surgical resection neces-ary in a patient with a significant clinical response to neoad-uvant chemotherapy. Clinical response as judged by physicalxamination or imaging may underestimate the extent of re-idual disease in more than 60% of patients.89,90 Intuitively,he extent of residual disease will be directly related to margintatus, and outcomes in patients with IBC are strongly influ-nced by margin status as reported by Curcio et al.93 Thesenvestigators performed a 25-year review of outcome datarom 90 patients with IBC. In stage IIIB patients treated withurgery, negative margin status was associated with 3-yearverall survival, disease-free survivavl, and local control ratesf 47.4%, 37.5%, and 60.3%, respectively, compared with%, 16.7%, and 31.3% in patients with positive margins.

adiation for IBChe addition of neoadjuvant chemotherapy to the treatmentegimen made mastectomy an appropriate treatment optionor most patients and proved to be a significant therapeuticdvance in locoregional management. With the addition ofastectomy, the dose for the twice-daily fractionation

cheme was reduced to 45 Gy delivered over 3 weeks, with a5-Gy boost to the chest wall. An analysis of the first 61atients with clinically diagnosed IBC who were treated at. D. Anderson Cancer Center using this trimodality ap-

roach was published in 1989.62 Thirty-seven patients (61%)howed some clinical response to induction chemotherapy;0 of them (16%) experienced clinical complete response (6atients with confirmed pathologic complete response), and7 of them (45%) experienced at least a 50% reduction inlinical signs of disease. Only 24 patients (39%) had no re-ponse. Mastectomy was performed on 56 patients (92%)fter neoadjuvant chemotherapy. Among the patients treatedith mastectomy, 9 had pathologically positive margins andnderwent immediate postoperative radiation. The remain-

ng 46 patients completed planned adjuvant chemotherapyefore beginning radiation using once-daily (n � 14) orwice-daily (n � 32) radiation. As noted previously, thistudy showed that the initial clinical response to chemother-py was associated with improved 5-year actuarial disease-ree survival rates, and the initial clinical response to chemo-herapy also correlated with the probability of locoregionalontrol. The 5-year actuarial locoregional control rates were9% in the patients experiencing a complete response, 68%

n those with a partial response, and 33% those with noesponse; the overall rate was 58%. Most local failures oc-urred in the irradiated volume of the chest wall and oc-urred more frequently among patients who did not achieverisk erythema or moist desquamation from the radiation. In
he 46 patients who completed treatment as initially planned w
excluding the 9 patients who had immediate postmastec-omy radiation secondary to positive margins), no differencen local control was noted between the 2 radiation fraction-tion schedules, with 3 of 14 patients (21%) treated daily andof 32 patients (22%) treated twice each day failing locally.ecause the locoregional recurrence in both arms was high,hese results provided the rationale to conduct dose-escala-ion studies using the twice-daily fractionation schema.

The next study built on these results attempted to escalatehe dose of hyperfractionated radiation by approximately0%.94 The twice-daily regimen was delivered in 34 fractionsver 3.5 weeks to fields encompassing the chest wall and theupraclavicular, infraclavicular, and internal mammary lymphodes to a total dose of 51 Gy. Subsequently, a 15-Gy boostas delivered to the chest wall in a dosage of 1.5 Gy twiceaily over 5 days, yielding a total dose of 66 Gy. From 1986hrough 1993, 39 patients with IBC were treated postmastec-omy with this fractionation schedule. During this period, 8atients were treated preoperatively with twice-daily radia-ion to a dose of 51 Gy, and 7 others were treated postoper-tively with a daily radiation to 60 Gy. A comparison ofatients treated before 1986 (n � 61) versus those treatedfter 1986 (n � 54) revealed significant improvement inocoregional control rates in the latter group with trends to-ard better disease-free and overall survival as well. To eval-ate the effects of dose escalation, a specific comparison wasade between the 32 patients who were treated postmastec-

omy with twice-daily radiation to a total dose of 60 Gy andhe 39 patients treated similarly but to a total dose of 66 Gy.here was a significant improvement in locoregional control

n the high-dose group compared with the low-dose group,4% versus 58% and 77% versus 58% at 5 and 10 years,espectively (P � .04). A statistically significant improvementlso occurred in 5- and 10-year overall survival rates betweenhese 2 groups (P � .03), and a trend toward improvement in- and 10-year disease-free survival rates was noted (P �

06). As also noted in other studies,68,92,95-97 the degree of thenitial response to chemotherapy predicted for significantlyetter local control, overall survival, and disease-free sur-ival. Patients whose disease did not respond to chemother-py had extremely poor outcomes regardless of treatment,ith 5-year overall survival and disease-free survival rates of% and 3%, respectively. Late toxicity occurred in 23 pa-ients (20%). This complication rate was similar in the pa-ients treated before 1986 and those treated after 1986.

Studies from other institutions have also compared doseractionation schedules and/or dose escalation and haveome to similar conclusions.98-100 For example, Pisansky etl100 compared once-daily radiation given preoperatively to aose of 50.4 Gy over 28 days in 16 patients with twice-dailyadiation given preoperatively to a dose of 44.2 Gy over 13ays in 13 patients. Patients given the twice-daily treatmentppeared less likely to fail locally than patients treated withaily irradiation, with an 8% local recurrence risk at 5 yearsnd a median time to progression of 17 months in the twice-aily group versus 26% and 13 months in the once-dailyroup. In addition, Liauw et al98 reported their experience
ith 61 patients with IBC who were treated curatively from

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982 through 2001. Although postmastectomy radiotherapyas delivered using once-daily fractionation schedules, the

uthors concluded that total radiation doses greater than 60y resulted in better freedom from locoregional disease pro-ression and that local control was strongly predictive ofetter cause-specific survival (P � .0003). However, 22% ofhe patients in this study developed locally recurrent diseases a component of failure. In an attempt to further decreasehese local recurrence rates, these authors have now adoptedhe use of hyperfractionated radiotherapy for their patientsith IBC.98

The most recent update of the M. D. Anderson experienceith twice-a-day radiation reports data with increased pa-

ient numbers and more mature follow-up. This report con-rmed that treatment to a chest wall cumulative dose of 66y was of clinical value for patients with a poor response tohemotherapy, patients with close or positive surgical mar-ins, patients with 4 or more positive lymph nodes aftereoadjuvant chemotherapy, and patients under 45 years old.mportantly, excellent locoregional control rates were achievedith a dose of 60 Gy dose for patients without any of these

eatures. Stratification of patients according to these featuresay be warranted in that there was a trend for increased

ignificant late toxicity associated with dose escalation to 66y. The actuarial risk of developing a grade 3 to 4 late com-lication as a function of radiation dose (29% in the 66-Gyroup v 15% in the 60-Gy group, P � .08). From these data,t was concluded that hyperfractionated dose escalationould be reserved for the patient cohorts with high-risk fea-ures as described earlier.

ngoing IBC Researchatients whose disease does not respond initially to chemo-herapy remain a therapeutic challenge. Despite clear advan-ages to adjuvant chemoradiation strategies in other diseaseites, such as gynecologic, gastrointestinal, and head andeck malignancies,101,102 this strategy has not been exten-ively explored in breast cancer therapy. An unpublishedeview of 42 IBC patients treated preoperatively with radia-ion alone at UT MdACC led to a 5-year local control andistant metastasis-free survival rate of 75% and 20%, respec-ively. Eight patients were alive without distant disease at

40 months. Although preliminary, the MDACC experiencesing concurrent capecitibine and radiation in 55 patientsith inoperable non-IBC breast cancer was favorable, with1% of these patients converting to operable. The clinical com-lete response rate was 33%; moreover, the overall pathologicomplete response rate was 20% (unpublished data, SABCS,007). In general, patients have tolerated this treatment wellith very few additional acute side effects, and, as such, thisay represent an alternative strategy to dose acceleration/

scalation in patients with IBC at a high risk for local failure.Despite advances optimizing trimodality therapy for IBC,

o date, no IBC specific therapy is available clinically in partecause of the few models exist to study IBC. Two cell lines,um 149 and SUM190, which can be transplanted into im-
unocompromised mice to generate human xenografts have
een developed and used for in vitro and in vivo studies,103

nd 2 orthotopic animal models, Mary-X104 and WIBC-9,105

ave been established by transplanting cells derived fromuman IBC into the cleared mammary fat pads of immuno-ompromised mice. Clinically, most IBC tumors are ER neg-tive31 and Her-2/neu (H2N) positive,40 but IBC can be ob-erved in tumors of any receptor combination. Mary-X tumorsriginate from a tumor negative for ER, PR, and Her-2-neu,104

hereas WIBC-9 tumors are ER, PR, H2N positive.105 Addingo these models, we have developed a third orthotopic humanenograft, MDA-IBC-1 (unpublished data, WAW, MC) that isR positive (low), PR negative, and H2Neu negative, andhich unlike Sum 149, actively secretes WISP3, an insulin-

ike growth factor binding protein described as an IBC tumoruppressor gene.51,106 Although it is presumed that the failureo identify tumor emboli in the dermal lymphatics is clini-ally simply a sampling error in the biopsy, this xenograft cananifest significant skin erythema as expected in IBC with

nly rare tumor emboli noted, suggesting that other factorsay mediate skin change in addition to congested lymphatic

mboli. It is hoped that expanding the array of models avail-ble to study IBC will hasten the development of targeted IBCherapy and increase overall survival for this aggressive dis-ase.

cknowledgmentsr S. Krishnamurthy for providing DLI images, The Morganelch Inflammatory Breast Cancer Research Program and

linic, The State of Texas Grant for Rare and Aggressiveancers, and The American Airlines.

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4. Greene FL, Page DL, Fritz A, et al: Breast, in AJCC Cancer StagingManual. New York, NY, Springer-Verlag, 2002, pp 255-281

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