Carcinoma In SituManagement Overview

Presented By: Dr Isha JaiswalModerated By: Dr Ritusha Mishra

Date:10th March 2015

AJCC 2010 TNM STAGING OF CA BREAST*• Primary Tumor• Definitions for classifying primary tumor (T) are same for clinical & pathologic

classification

Tx : Primary tumor cannot be assessed

T0: No evidence of primary tumor

Tis: Carcinoma in situ• Tis (DCIS): Ductal carcinoma in situ• Tis (LCIS) :Lobular carcinoma in situ• Tis (Paget’s) :Paget’s disease of the nipple

*AJCC VII Cancer Staging Manual 2010 springer

T1:Tumor ≤2 cm in greatest dimension• T1mic :Microinvasion ≤ 0.1 cm in greatest dimension• T1a :Tumor > 0.1 cm but ≤0.5cm in greatest dimension• T1b :Tumor > 0.5 cm but ≤1 cm in greatest dimension• T1c :Tumor > 1 cm but ≤ 2 cm in greatest dimension

T2 :Tumor > 2 cm but ≤ 5 cm in greatest dimension

T3 :Tumor >5 cm in greatest dimension

T4 :Tumor of any size with direct extension to chest wall &/or skin• T4a :Extension to chest wall, not including pectoralis muscle• T4b :Edema (including peau d’orange) /ulceration/ satellite skin nodules

confined to same breast) (Dimpling & nipple retraction are not t4b)• T4c: Both (T4a and T4b)• T4d :Inflammatory carcinoma.

Regional Lymph Nodes

Definitions for classifying regional lymph nodes (N) are different for clinical & pathologic classification.

Clinical lymph node classification based on clinical examination &/or imaging studies such as USG,CT but excluding lymhoscintigraphyClinically detected nodes are more than 1 cm with characteristic of macro metastasis confirmed by fnac or biopsy

pathological classification applies when lymph nodes are removed surgically & examined histopathologically

Clinical Lymph Node Classification (cN)

Nx :Regional lymph nodes cannot be assessed N0 :No regional lymph node metastases

N1 :Metastases to movable ipsilateral level I,II axillary lymph nodes

N2 : divided into N2a & N2b• N2a :Metastases in ipsilateral level I,II axillary lymph nodes fixed to one another (matted)

or to other structures• N2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary

lymph node metastases

N3: divided into N3a,N3b &N3c• N3a Metastases in ipsilateral infraclavicular lymph node(s) level III axillary• N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary• lymph node(s)• N3c Metastases in ipsilateral supraclavicular lymph node(s) irrespective of axillary &

internal mammary lymph node involvement

Pathologic Lymph Node Classification (pN)

pNx :Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study)

pN0 :No regional lymph node metastases histologically

pN0 (i-): No regional lymph node metastases histologically, negative IHCpN0 (i+): Malignant cells in regional lymph node(s) no greater than 0.2 mm

(detected by H&E or IHC including Isolated tumor cells)

pN0 (mol-) :No regional lymph node metastasis histologically,negative molecular findings (reverse transcriptase polymerase chain reaction [RT-PCR])

pN0 (mol+) :Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC

pN1 :

pN1mi :Micrometastases (greater than 0.2 mm, and/or more than 200 cells, but none greater than 2.0 mm)

pN1a :Metastases in 1-3 axillary l.ns, at least one metastasis greater than 2.0 mm

pN1b : Metastases in internal mammary l.ns with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected

pN1c :Metastases in 1–3 axillary l.ns and in internal mammary l.ns with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected

pN2

N2a: Metastases in 4-9 axillary l.n (at least one tumor deposit greater than 2.0 mm)

pN2b :Metastases in clinically detected internal mammary l.n in absence of axillary l.n metastasis

pN3

pN3a :Metastases in 10 or more axillary l.ns (at least one tumor deposit greater than 2.0 mm), or metastases to the infraclavicular (level III axillary lymph nodes)

pN3b :Metastases in clinically detected ipsilateral internal mammary l.ns in presence of one or more positive axillary l.ns,

or in more than three axillary l.ns and in internal mammary l.ns with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected

pN3c :Metastases in ipsilateral supraclavicular l.ns.

Distant Metastasis (M)

M0 :No clinical or radiographic evidence of distant metastases

cM0(i+) :No clinical or radiographic evidence of distant metastases, but deposits of molecular or microscopically detected tumor cells detected in circulating blood, bone marrow, or other nonregional nodal tissues, that are no larger than 0.2 mm in a patient without symptoms or signs of metastases

M1 :Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proved larger than 0.2 mm.

AJCC 7th Edition Staging for Breast Cancer

*T1 includes T1mi.** T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA & are classified Stage IB.

Carcinoma in situCIS represents non invasive cancer defined by confinement of malignant cells within basement membraneWidespread use of mammography has lead to an increase in overall incidence of in-situ lesionThey differ in natural history, pathologic appearances, biologic characteristics, clinical presentation & treatment CIS of the breast (stage 0) includes• Paget’s disease of the nipple• Lobular carcinoma in situ (LCIS)• Ductal carcinoma in situ (DCIS).

Cancer Facts & Figures 2015 Special Section: Breast Carcinoma In Situ

In 2015, there will be an estimated 60,290 new cases of breast CIS diagnosed83% of them will be ductal carcinoma in situ (DCIS)12% of them will be lobular carcinoma in situ (LCIS).

This year’s special section reviews breast carcinoma in situ, including incidence rates and trends, risk factors, prognostic characteristics, and treatment patterns.

*Cancer Facts & Figures 2015 American Cancer Society

Paget's disease

• Paget’s disease is a rare entity • represents <5% of all breast

cancer cases & associated with an underlying malignancy in >95% of cases.

• characterised by crusting & eczematous appearance of nipple-areola complex

PATHOLOGY

• characterized by presence of Paget’s cells located throughout the epidermis.

• Paget’s cells are large ,hyperchromatic, round/oval nuclei with abundant cytoplasm found in clusters or individually

Epidermotropic Theory of Paget's disease

• belief that the disease originates from underlying in situ or invasive ca• also supported by histologic evidence of intraepithelial extension, • IHC studies & evidence suggest that epidermal keratinocytes release a motility

factor heregulin-α, that results in the chemotaxis of paget’s cells that migrate to overlying nipple epidermis.

Clinical presentation• Age:5th -6th decade• Gender: F>>M (male Paget’s have been reported)

• Usually U/L (synchronous b/l paget's have been reported)• Symptoms include:red, flaky,scaly rash which spread from nipple to

surrounding areola. tingling, itching, burning, over the rash. thin discharge may be present forming a crust as it dries. with more skin destruction, there may flattening of the

nipplepalpable mass bleeding, pain, and ulceration in advanced stage

Alternatively, can be asymptomatic and present as pathologic finding after surgical removal of the nipple–areolar complex.

Diagnosis • palpable mass detected in 50% pts.at diagnosis: in >90% of

cases, this will be an invasive carcinoma. • no palpable mass is detected: 66%- 86% will have an

underlying DCIS. • these associated malignancies are usually located centrally,

although they can occur elsewhere in the breast.

• Diagnostic Work Up Includes: bilateral breast examination, mammography, and biopsy• Mammographic findings are frequent in the presence of a

palpable mass; however, normal mammograms are reported in as many as 50% of case

Treatment of Paget's diseaseThe combination of limited surgical resection and postoperative radiotherapy is the most practical breast-conserving approach .

Surgical resection should include the nipple–areolar complex with microscopically clear margins surrounding both the Paget’s disease and the associated malignancy.

Whole-breast radiotherapy is delivered with standard techniques. 

a seven-institution collaborative review of 36 patients with Paget’s disease without a palpable mass or mammographic density treated with local excision & RT Surgery94% of patients underwent surgeryextent of surgical resection varied complete excision (69%), partial excision of nipple–areolar complex & underlying breast tissue (25%), & biopsy only in 6% The final margin status was documented as negative in 56%, positive in 6%, and unknown in 39%. Radiotherapyall patients received median EBRT dose of 50 Gy (range, 45–54 Gy) to whole breast. 97% of patients also received a boost to tumor bed, median total dose of 61.5 Gy (range:50.4 –70 Gy).

RESULTS.median follow-up =113 months (range, 18 –257 months)

Local control Actuarial local control rates for breast as only site of first recurrence were 91% at 5

and 87% at both 10 and 15 years. Actuarial local control rates for breast recurrence, as a component of first failure,

were 91% ,83% and 76% at 5, 10, and 15 years, respectively.

Failures:4/36 patients (11%) developed first recurrence in treated breast only:2 were DCIS only & 2 invasive with DCIS. Two additional patients had a recurrence in breast as a component of first failure

No clinical factors were identified as significant predictors for breast recurrence.

Survival:5-, 10- and 15-year actuarial rates for DFS was 97%actuarial rates of OS was 93 at 5 years and 90% at 10 and 15 years

CONCLUSIONS. excellent rates of LC,DFS & OS at 10 and 15 years following BCS and RT for Paget disease of the breast.

This study continues to support the recommendation of local excision and definitive breast irradiation in the treatment of patients with Paget disease presenting without a palpable mass or mammographic density

.

Lobular carcinoma in situ• comprise 15% of in situ disease• approximately 22-26% LCIS associated with DCIS or invasive

disease• not a precursor of invasive cancer instead, considered a marker

for increased risk of developing invasive breast cancer.• Exception :Pleomorphic LCIS -linked to a higher risk of

invasive cancer • Risk of development of invasive cancer is 20%–25% when

followed over a duration of 15 years• risk appears to be nearly equal for both breasts & is greatest for

high-grade or more extensive lesions.

LCIS incidence and trends

• The incidence rate of LCIS was 3.9/100,000 women during 2007-2011

• peaks in women ages 50-59• higher for non-Hispanic white women

LCIS:Pathology• LCIS represent abnormal cells growing within the walls of the

lobules• Pleomorphic LCIS: an aggressive variant that has a greater

potential for progressing to invasive cancer • Multicentric (90% of mastectomy specimens)• bilateral involvement (in 35%-59% of mastectomy specimens)• ER/PR+, Her 2 nue negative• loss of E-cadherin is often observed, and the absence of this

adhesion molecule may explain the growth pattern seen with LCIS.

• (Vos CB, et al. E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 1997;76:1131–1133.)

Clinical presentation age: varies with raceextremely rare in men.symptomsusually asymptomatic: no symptoms on clinical and

mammographyrarely may present as• breast lump:.• nipple discharge:• pain

Diagnosis of LCIS

• no clinical or mammographic indicators that are characteristic• often detected asan incidental biopsy finding.mammographic calcifications in excisional biopsy specimens ( dcis or invasive carcinoma

are frequently identified even when lcis is the sole histologic entity seen on core biopsy)

mastectomy specimens

The only definitive way to diagnose LCIS is by a breast biopsy

GOAL OF TREATMENT LCIS

• Treatment of LCIS emphasizes medical surveillance and risk reduction strategies for both breasts rather than local treatment, such as BCS plus radiation therapy

LCIS : sole histologic diagnosismedical

surveillance and risk reduction

strategies

a/w another malignancy (DCIS or invasive

carcinoma)manage the breast

according to dominant

malignant histology

Management of LCIS: sole histologic diagnosis

Role of SURGERYLocal Excision & Subsequent Surveillance Complete removal with negative margins is considered important

for more histologically aggressive pleomorphic LCIS.unilateral mastectomy: inadequate and illogical.Bilateral prophylactic mastectomy in high risk: young age, diffuse high-grade lesionsignificant family history. BRCA1/2 mutation

*Fisher ER et al. Pathologic findings from NSABP—12 year observations concerning lobular carcinoma in situ. Cancer 2004;100:238–244

Medical surveillance recommendations NCCN recommend annual mammography and clinical breast exam every 6-12 months.(National Comprehensive Cancer Network. Breast Cancer Screening and Diagnosis (Version 1.2014).

Role of MRI in LCISIn 2009, NCCN published guidelines reflecting a panel consensus opinion

that annual breast MRI can be considered in patients with LCIS.three studies have been published evaluating the role of MRI in patients

with LCIS.1. Friedlander LC, Roth SO, Gavenonis SC. Results of MR imaging screening for breast cancer

in high-risk patients with lobular carcinoma in situ. Radiology 2011;261(2):421–427.

2. Port ER, et al. Results of MRI screening for breast cancer in high risk patients with LCIS and atypical hyperplasia Ann Surg Oncol 2007;14:1051–1057.

3. Sung JS, et al. Screening breast MR imaging in women with a history of lobular carcinoma in situ. Radiology 2011;261(2):414–420

Each document revealed a small but defined 3.8% to 4.5% breast cancer detection rate with MRI

cohort comprised of 182 women with LCIS who were enrolled in NSABP Protocol B-17 but received no treatment other than lumpectomy.

Nineteen pathologic features were assessed & related to i/l breast tumor recurrence(IBTR) & c/l breast tumor recurrence (CBTR) at a mean time 5 years.

Results were published at 5 years & updated at 12 years

4 CBTR 2 invasive& 2 CIS 1invasive CBTR :lobular type

other mucinous carcinoma 1 non invasive CBTR were

LCIS&DCIS. 1 CBTR were LCIS only.

NSABP B-17: results at 5 years

13 IBTR All IBTR occurred in same quadrant 9 were CIS & 4 invasive recurrences All 4 invasive IBTR were lobular type 3 non invasive IBTR were pure DCIS 5 non invasive IBTR were LCIS only 1 non invasive IBTR were LCIS&DCIS

All examples tested were found to be c-erb B-2 negative, and estrogen receptor and progesterone receptor positive.

NSABP B-17results at median follow-up of 12 years.

• 26(14.4%) in-breast tumor recurrence (IBTR) rate9 IBTRs (5% of the total cohort) were invasive carcinoma17 (9% of the total cohort) were DCIS

• 14(7.8%) contralateral breast tumor recurrence rate. • 10 CBTR (5.6% of total cohort) were invasive carcinoma

• Although the frequency of contralateral breast tumor recurrence rate was less than that of IBTR, frequency of invasive contralateral breast tumor recurrence rate (5.6% of total cohort) was similar to invasive IBTR (5% of total cohort).

• Of note, all of the IBTR were documented to be at the site of the index lesion except for one, characterized as pure LCIS, that was found at a remote site.

Hormonal therapyBoth the American Society of Clinical Oncology (ASCO) and

NCCN recommend chemoprevention therapy tamoxifen: for premenopausal women tamoxifen or raloxifene: for postmenopausal women,

depending on other health conditions.• (ref:Allred DC, Anderson SJ, Paik S, et al. Adjuvant tamoxifen reduces subsequent

breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30: 1268-1273)

ASCO also lists exemestane, an aromatase inhibitor, as an option in postmenopausal women; however, this is not FDA-approved indication

• (ref:Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31: 2942-2962.)

• N = 13 388 • patients at elevated risk for breast cancer >60 years old, 35–59 yrs with 5-year predicted risk of at least 1.66% based on Gail model,history of LCIS

• Randomly assigned into 2 groups • Group 1: (n = 6707) recieve placebo • Group 2: (n = 6681) tamoxifen 20 mg/day for 5 yrs

*Fisher B, Costantino J, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–1388.

Results:

Tamoxifen reduced risk of : invasive breast cancer by 49% (two-sided P<.00001)non-invasive breast cancer by 50% (two-sided P<.002).reduced occurrence of ER+tumors by 69%no difference in occurrence of ER-tumors age related decreased risk occurred in women aged 49 years or younger (44%), 50–59 years (51%), 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in

situ (56%) or atypical hyperplasia (86%)

Cumulative rates of invasive breast cancer

Side Effects In The Tamoxifen Group rate of endometrial cancer increased in the tamoxifen group risk ratio = 2.53increased risk occurred predominantly in women aged 50 yrs or older

Cumulative rates of invasive endometrial cancer

rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women 50 years or older

reduction in hip, radius (Colles’) & spine fractures

No increase in liver, colon, rectal, ovarian or other tumors

No alteration in the average annual rate of ischemic heart disease;

NSABP-P2 STAR (vogel et al 2006).Tamoxifen vs raloxifene• 19,747 postmenopausal women at increased risk of breast CA• Randomized to Tamoxifen 20 mg qd vs. Raloxifene 60 mg qd ×

5 years.• Incidence of invasive breast CA 0.4% both arms, but fewer

noninvasive cases (DCIS/LCIS) with Tamoxifen (0.15 vs. 0.21%).

• Raloxifene reduced risk of uterine cancer (absolute 0.7→0.5%) cataracts,and thromboembolic events.

• Similar number of osteoporotic fractures, other cancers, stroke, and heart disease.

Vogel VG, Costantino JP, Wickerham DL, et al. NSABP: prevention trials and endocrine therapy of ductal carcinoma in situ. Clin Cancer Res 2003;9:495 S–501 S.

Ductal carcinoma in situ• Constitute 80% of CIS• DCIS is a precursor lesion to invasive ductal carcinoma  • It is confined to ductal system of breast lacks histologic

evidence of invasion into basement membrane & surrounding stroma.

• lacks the ability to metastasize• axillary node involvement is rare (0% to 5%) and most likely is

associated with an undetected focus of invasive carcinoma.

Pathobiologic Events Associated with DCIS

majority of changes that give rise to cancer, including genetic changes, & loss of normal cell-cycle regulation, occurred by the time DCIS is present

Most of clinical features of subsequent invasive cancer are already determined although additional events, including tissue invasion and changes in surrounding stroma characterize the invasive tumor

Natural History of DCISprimary consideration in DCIS is the risk of progression to invasive

carcinomafew published long-term follow-up studies after biopsy only document

overall incidence of subsequent invasive carcinoma of >36%.  Most of these subsequent malignancies occur within 10 years although as many as one-third may develop after 15 years.

• (ref:betsill wl, rosen pp, lieberman ph, et al. intraductal carcinoma: long-term follow-up after treatment by biopsy alone. jama 1978;239:1863–1867)

Women with DCIS in one breast are at risk for a second tumor (either invasive or in situ) in the contralateral breast

rate at which such tumors develop is similar to that among women with primary invasive breast cancer at approximately 0.5% to 1% per year. 

• (ref:Habel LA, Moe RE, Daling JR, et al. Risk of contralateral breast cancer among women with carcinoma in situ of the breast. Ann Surg 1997;225:69–75.)

Pathology DCIS• Traditionally, classification of DCIS has followed its

architectural or morphologic appearance. • The five subtypes of DCIS are

Risk Factors

DCIS Invasive Cancer

Peak Age 60 -74 75 – 79Race Caucasian CaucasianFamily History Yes YesMammographic Density Yes YesObesity No YesNo children Yes YesLate age at childbirth Yes YesHormone replacement No Yes

Risk factors for the development of DCIS are the same as those identified for invasive carcinoma*

*Trentham-Dietz A, Newcomb PA, Storer BE, et al. Risk factors for carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 2000;9:697–703.

Clinical presentation• Before the use of screening mammography, DCIS presented as a palpable mass/ nipple discharge.invasive component commonly was found, and pure DCIS

rarely was encountered.

• The widespread use of mammography now routinely detects DCIS <1 cm in diameter

• Studies have shown that the rate of screen-detected DCIS increases with age

• The rate of DCIS detection increase from 0.56 per 1,000 mammograms among women aged 40 to 49 years to 1.07 per 1,000 mammograms among women aged 70 to 84 years.

DCIS incidence trends

Diagnostic workup• Screening mammography• Diagnostic mammography• Biopsy

• MRI• Galactography

Mammographic findings of DCIS

• 95 % present with mammographic abnormalities• Most common finding is microcalcifications seen in 76% • Noncalcified mammographic findings (24%) includesasymmetric densities identified in 10%, dominant masses in 8%,abnormal galactograms in 6%.

Calcification in DCIS• all forms of calcifications that that

can be related to DCIS. : Amorphous, coarse, fine pleomorphic, fine linear

• Linear and segmental calcifications are associated with DCIS in up to 80% of cases.

Linear and branching calcifications associated with high-grade (DCIS).

Fine and granular calcifications associated with low-grade DCIS

Role of MRI• Size of lesion is underestimated in mammography by 1-2 cm when

compared with pathological specimen• MRI now presents as the imaging modality with the highest

sensitivity to detect DCIS, particularly high-grade DCIS. • MRI better establish the extent of DCIS, thus aiding treatment

planning• Lehman CD. Magnetic resonance imaging in the evaluation of ductal carcinoma in situ. J Natl Cancer Inst

Monogr 2010;(4):214–217.

• Berg WA, Gutierrez L, Nessairer MS, et al. Diagnositic accuracy of mammography, US, and MR imaging in preoperative assessment of breast cancer.Radiology 2004;133:830–849

• In cases that present with nipple discharge and a negative mammogram, galactography may be helpful in determining the likelihood of underlying DCIS versus papilloma

Role of galactography

ACR-ASS-CAP-SSO 2006 practice guideline

• The role of other image modalities, especially MRI, has yet to be established in DCIS.

• Berg found that MRI was more sensitive than mammography and sonography in detecting DCIS; however, disease extent was overestimated in 50% of involved breasts.

• The impact of MRI on clinical outcomes such as local recurrence in the preserved breast remains to be demonstrated.

Goal of treatment: DCIS• Eradication of initial cancer• prevent progression to invasive/noninvasive cancer.

DCIS: management options• Surgery• Radiotherapy• Hormonal therapy

Breast Conservation for DCIS• Breast conservation surgery (BCS) may consist of

quadrantectomy, wide excision, lumpectomy (local excision).• A primary goal of BCS for DCIS is to achieve the best possible

cosmetic outcome along with negative margins• microscopic complete excision is essential for optimal local

control in breast-conserving therapy for DCIS. • 1 cm margin is considered adequate• 1–2 mm post-BCS require re excision as up to 1/2 will have

residual DCIS• even in the group of DCIS cases who underwent a surgical re-

excision a 4-year local recurrence rate of 18% was observed when these patients were treated with surgery alone.

Contraindications to BCT• Repeatedly positive margins• Multicentric disease ( >2 quadrants)• Diffuse malignant calcifications on mammogram• Prior RT to breast• Pregnancy• History of scleroderma• Large tumor in small breast: cosmetically undesirable

Additional tests done after BCS*• Specimen mammography• Post excision mammography• Frozen section analysis• Complete histopathological assessment of

specimen

*Standard for the Management of Ductal Carcinoma In Situ of the BreastCA Cancer J Clin 2002;52:256-276

• Specimen mammography of lumpectomy specimenRadiologicalintraoperative

• ADVANTAGES:• Allows surgeons to asses the adequacy of excision• Reduce the no of reexcisions required to achieve margin –ve resections• less tissue excised : better cosmesis• Reduces frequency of missed lesions: hard copy confirmation reduces

litigations• DISADVANTAGES:• Prolongs surgical procedure• Increases cost• False + & false - results• Limited ability to predict margin status due to magnification & compression

views• Discordance between SM & pathological & post excision mammography

results

Post excision mammography

• Done post excision & pre radiotherapy• obtained to document complete removal of calcifications.• can be performed as soon as the patient can tolerate compression

however, a large seroma may obscure small residual calcifications. • Magnification views taken( may show calcifications not evident

on nonmagnified views)• It is used as a complementary means of assessing the

completeness of excision. • If reexcision is performed for residual calcifications, specimen

radiography and a post-excision mammogram should again be obtained to reassess the tumorectomy site.

Frozen section examination• *Frozen sections should be avoided if possible especially on lesions,

which measure <1cm. in diameter• Advantages:• Indicated when information is necessary for immediate therapeutic

decisions • reduction in the rate of reexcision• Disadvantages• Methodological difficulties• Ductal carcinoma in situ is more difficult to identify in FSA • small foci of microinvasion may be lost or rendered uninterpretable

by freezing artifact.

* Association of Directors of Anatomic and Surgical Pathology. Immediate management of mammographically detected breast lesions. Am J Surg Pathol 1993;17:850-851

PATHOLOGIC EVALUATION• Following should be included in the pathology report nuclear grade, presence/absence of necrosis architectural pattern(s)size/extent distance to excision margins/margin statusCalcification in the Tumour (or DCIS): Yes/ NoEstrogen Receptor Status: PR Status/Her-2 neu Status

risk factors for local recurrence after breast-conservation therapy for DCIS• Through multiple retrospective studies, several factors have

been identified that may be important in defining local failure risk. These include

• patient age• symptomatic presentation• lesion size• multifocality

• histopathologic subtype• nuclear/cytologic grade• central necrosis• margin status

Mastectomy for DCIS• Mastectomy is a highly effective treatment for DCIS• locoregional control rate of 96% to 100% • cancer-specific mortality rates of ≤4%.• No randomized study has compared mastectomy with BCS for

DCIS.• Data from some surgical series and large treatment registries

suggest that rates of local or regional recurrence are significantly lower after mastectomy than after breast-conserving surgery,

• although there have been no significant differences in overall survival.

Indications for total mastectomy

• If BCS is contraindicated• Repeatedly positive margins after BCS• patient desire. minimize the chance of ipsilateral recurrence

or for other reasons• Recurrent disease

Age at diagnosis was strongly associated with the type of treatment received younger women: more likely to undergo mastectomy. 53% pts younger than 40 underwent mastectomy bilateral mastectomy 28% unilateral mastectomy 25% proportion of DCIS pts undergoing bilateral mastectomy has increased over the past 2

decades, from 2% of patients in 1998 to 8% in 2011.

Lymph node dissection in DCIS• Axillary lymph node dissection & sentinel lymph node

mapping not routinely warranted • 3-13% of patients with DCIS have isolated tumor cells in

sentinel axillary lymph nodes

• sentinel lymph node mapping may be used in selected patients with a higher likelihood of occult invasive cancer—

those with extensive dshigh-grade DCIS palpable massesthose undergoing mastectomy

POSTOPERATIVE RADIOTHERAPY

• Breast irradiation reduces the risk of subsequent invasive or noninvasive carcinoma in the treated breast

• Four prospective randomized studies of excision only versus excision plus breast irradiation for DCIS have been performed

• all have shown that the rate of local recurrence was reduced with the addition of radiation

NSABP B-17 trial EORTC 10853 trialUnited Kingdom, Australia, and New Zealand (UK/ANZ)

DCISSwedish Breast Cancer Group SweDCIS study

NSABP B-17(Fisher et al.1998c, 2001b)

first randomized trial which confirmed the effectiveness of RT in decreasing local recurrence after lumpectomy with negative resection margins in DCIS

• 813 pts. stratified by age (≤49 years vs. >49 years), DCIS versus DCIS plus LCIS, method of detection, and whether an axillary dissection was performed.

• Mean follow-up time was 90 months (range, 67 to 130).• Of the patients enrolled, 83% had nonpalpable tumors

813 patients

The updated analysis with 15-year follow-up showed a decreased cumulative incidence of both invasive and non-invasive ipsilateral breast recurrences from 35% to 19.8% with the addition of radiation therapy. The incidence of invasive ipsilateral breast recurrence was also decreased from 19.4 to 8.9% with the addition of radiation therapy to lumpectomy.

Increased LR with: +margins, moderate/marked comedonecrosis ,and microcalcifications>1 cm

EORTC 10853(Julien et al. 2000;Bijker et al. 2006)

PATIENTS AND METHODS: Between March 1986 and July 1996, 1,010 women were randomly assigned to

no further treatment (503 patients) or to RT(507 patients) after LE analysis performed in August 2005, at median duration of follow-up: 10.5 years The median age of the women was 53 years; 71% of them were mammographically detected. Extent of free margins was not specified other than that DCIS should not be

present at microscopic examination of margins. irradiation dose was 50 Gy in 25 fractions to the whole breast. No boost was

advised .Tamoxifen not recommended. primary end points were both invasive and DCIS LR in the treated breast. Secondary end points included metastasis, death, and contralateral breast

Cancer

RESULTS: The 10-year LR-free rate was 74% in the group treated with LE alone compared with

85% in the women treated by LE plus RT The risk of DCIS and invasive LR was reduced by 48% (P = .0011) and 42% (P

= .0065) respectively. Both groups had similar low risks of metastases and death. The effect of RT was homogeneous across all assessed risk factors.

At multivariate analysis, factors significantly associated

with an increased LR risk were young age symptomatic detection intermediately or poorly

differentiated DCIS cribriform or solid growth

pattern doubtful margins treatment by LE alone

2x2 factorial designed randomised controlled trial.

Aim: to compare excision alone versus excision plus tamoxifen versus excision plus radiotherapy versus excision plus radiotherapy and tamoxifen in completely excised DCIS complete surgical excision was confirmed by specimen radiography and histology tamoxifen was prescribed as 20 mg per day radiotherapy was delivered through whole-breast tangential fields to a total dose of 50

Gy. Boost was not recommended

Between May, 1990, and August, 1998, 1701 patients recruited from screening programmes were randomised to 4 armsArm 1: excision aloneArm 2 : excision plus tamoxifen Arm 3: excision plus radiotherapy Arm 4:excision plus radiotherapy and tamoxifen

.

UKANZ(2003)

primary endpoint: incidence of ipsilateral invasive disease

Resultsmedian follow-up 53 months:rates of all breast events were 8, 18, 22, and 6%, respectively.

When analysing those randomized to RT vs. no RT, RT reduced LF (invasive or noninvasive) in ipsilateral breast from 14 to

6% but there was no effect on the occurrence of contralateral disease. Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of

overall ductal carcinoma in situ (i/l & c/l )was decreased (hazard ratio 0.68 [0.49-0.96]; p=0.03).

Conclusion: Radiotherapy can be recommended for patients with ductal carcinoma in situ treated by complete local excision; however, there is little evidence for the use of tamoxifen in these women

Cusck J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial Lancet Oncol 2011;12:21–29

median follow-up of 12.7 years.addition of radiotherapy was demonstrated to reduce the risk of IBTR.

Of the 1,030 patients randomized between no radiotherapy versus radiotherapy, ipsilateral IBTR was 19.4% versus 7.1%, respectively (p <.0001).

The addition of tamoxifen offered no benefit toward overall ipsilateral local control when administered in addition to radiotherapy;

however, tamoxifen did appear to reduce the ipsilateral recurrence rate of DCIS (but not invasive carcinoma) in the absence of radiotherapy.

Long term results of United Kingdom, Australia, and New Zealand (UK/ANZ) DCIS trial*

randomized trialenrolled 1,067 patients from 1987 to 1999, with 1,046 of these patients followed for a mean of 8 years. Patients randomized between lumpectomy f/b RT & lumpectomy only

Following a sector resection, microscopic clear resection was not required, and 50 Gy in 25 fractions to the whole breast was delivered in the majority of patients.

A split course, 54 Gy in 2-Gy fractions, delivered in two treatment series separated by a 2 week break was allowed.

No boost dose was delivered.

The in-breast failure risk reduction reported as 16% at 10 years (95% confidence interval [CI] 10.3% to 21.6%) with a relative risk of 0.40 (95% CI 0.30 to 0.54).

Detailed analysis did not identify any patient or tumor characteristic subgroups that did not benefit of postoperative radiotherapy.

Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast J Clin Oncol 2008;26:1247–125

SweDCIS trial (JCO2008)

Four randomized trials of BCS ±RT (EORTC 2006; NSABP 1998; SweDCIS 2008; UKCCCR 2003). 3,925 patients.Analysis confirmed a statistically significant benefit from the

addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI

0.41 to 0.59, P < 0.00001) ipsilateral DCIS recurrence (HR 0.64; 95% CI 0.41 to 1.01, P =

0.05).All the subgroups analysed benefited from addition of RT No significant long-term toxicity from radiotherapy was found.

(Goodwin et al. 2009).

.

Early Breast Cancer Trialists’ Collaborative Group, Correa C, McGale P, Taylor C, et al. Overview of the randomized trials of radiotherapy in dictal carcinoma in situ of the breast. J Natl Cancer Inst Mongr 2010;(41):162–167.

meta-analysis of the four randomized trials total of 3,729 women eligible for analysis RT reduced the absolute 10-year risk of any ipsilateral breast event (recurrent

DCIS or invasive disease) by 15.2% (standard error [SE] 1.6%, 12.9% vs. 28.1%, 2 p <.00001).

approximately reduces the risk of IBTR by 50%. Subgroup analyses demonstrated that the absolute benefits of radiotherapy are

greater in women at increased risk for tumor recurrence, such as with involved surgical margins. younger women, tumors that have high-grade or comedonecrotic

little impact of RT on contralateral or distant events

RT IN DCIS• Indication: after breast-conserving surgery• Not Indicated :for post mastectomy & nodal irradiation

• Benefit of addition of RT to BCS more in Young women +marginHigh grade & comedonecrosis

• Fields: tangential fields to the whole breast • Dose: 45 to 50 Gy delivered in daily fractions of 180 to 200 cGy. • Radiation Boost :to the tumor bed may be added particularly for

close surgical margins, although the benefit of a boost not established.

Van nuys prognostic index

• scoring system using histopathologic features in an attempt to stratify patients according to local failure risk after excision plus or minus whole-breast irradiation.

• There are 3 variables. Each variable is assigned a score of 1 to 3, and the sum total defined the Van Nuys Prognostic Index.

• This scheme is drawn from the retrospective analysis of a patient cohort in which there exist several methodologic shortcomings, and it has not been independently validated.

333 patients with pure DCIS treated with breast preservation were studied with detection of local recurrence as the end point.

195 treated by excision only and 138 by excision plus radiation therapy

Score # 1 # 2 # 3

Path Other Comedo High Grade

Size <15mm 16-40mm >40mm

Margins >10mm 1-9mm < 1mm

Conclusions:Score 3 – 4 : Lumpectomy alone (local control is 100% vs 97%)Score 5 – 7: Lumpectomy + Radiation (local control from 68%- 85%)Score 8-9: Mastectomy

Cancer 1996 Jun 1;77(11):2267-74

RESULTS:

no statistical difference in 8 year LRFS in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant).

Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% LRFS benefit when treated with radiation therapy (85% vs. 68%; P = 0.017).

Patients with scores of 8 or 9, showed the greatest relative benefit from radiation therapy, however had recurrence rates in excess of 60% at 8 years regardless of irradiation, and should be considered for mastectomy.

Modified VNPI (Silverstein 2003).

• Retrospective review of 706 patients status post-BCT with or without RT• scored based on four parameters: 1. tumor size (≤1.5, 1.6–4.0, >4.1 cm)2. Pathology (non high-grade without necrosis, nonhigh-grade with necrosis, high

grade)3. margins (≥1, 0.1–0.9, <0.1 cm)4. age (>60, 40–60, <40 years)

For low-risk (score 4, 5, 6), no significant difference in 12-year local RFS (>90–95%) with or without RT.

For intermediate-risk (score 7, 8, 9), addition of RT provided 12–15% 12-year local RFS benefit.

For high-risk (score 10, 11, 12), mastectomy recommended due to high 5-year LR (~50%) with or without RT.

Updated Van Nuys Prognostic IndexParameter 1 Point 2 Points 3 Points

Size <15mm 16-40mm >40mm

Grade I/IInon high-grade without necrosis,

I/II Necrosisnonhigh-grade with necrosis,

IIIhigh grade

Margin 10mm 1-9mm <1mm

Age >60 40-60 <40

4,5, 6 = Lumpectomy Alone7, 8, 9 = Lumpectomy + Radiation10, 11, 12 = Mastectomy

2003 Update PMID 14682107 -- "An argument against routine use of radiotherapy for ductal carcinoma in situ." (Silverstein MJ, Oncology (Williston Park). 2003 Nov;17(11):1511-33; discussion 1533-4, 1539, 1542 passim.)

LIMITATIONS OF VNPI INDEX• Attempts to validate the VNPI scoring system have yielded mixed results

in various retrospective studies MacAusland et al. 2007; Di Saverio et al. 2008; Gilleard et al. 2008 Altintas et al. 2011; Lee et al. 2013;).

• Such studies have had uneven population distributions, most patients having low to intermediate scores.

• Although patient age, tumor size, and tumor grade were set at patient diagnosis, margin width may be downgraded by re-excision or TM.

• Such efforts to salvage treatment have resulted in a disproportionately low rate of patients with high VNPI scores

A New Test for Estimating Recurrence Risk After Lumpectomy with No Radiation

analyzes the activity of 21 genes that can influence how likely a cancer is to grow and respond to treatment.

Oncotype DX test is both a prognostic test and predictive test

Oncotype DX test results assign a Recurrence Score — a number between 0 and 100

http://www.genomichealth.com/en-US/OncotypeDX.aspx

recurrence Score Any Recurrence Invasive Recurrence

Low Risk less than 18 12% 5%

Intermediate Risk:18-31 25% 9%

High Risk: more than 31 27% 19%

Subset of patients in which RT can be avoided• Van Nuys Prognostic Index :4-6

• DCIS size < 1.5 cm• Negative margin > 1 cm• Not high grade• No comedo necrosis• Age > 61• ER + tumors

To date, prospective data have failed to validate the elimination of RT for women completing BCS for DCIS

Few prospective trials have attempted to identify a subset of patients with low-risk DCIS who may not benefit from the addition of radiation therapy following a local excision

Confirmatory results are yet not available because either the trials stopped early due to poor accrual or high LR or their results are awaited

Hormonal therapy The use of tamoxifen in the treatment of DCIS treated with BCS & RT is

unclear due to conflicting results.  The NSABP B-24 updated results showed that with a median follow-up of 163

months, the addition of tamoxifen translated into a significant 32% reduction in invasive IBTR (9.0% vs. 6.6%, p = .025), a nonsignificant 16% reduction in DCIS-IBTR (7.6% vs. 6.7%, p = .33), and a significant 32% reduction in contralateral breast cancer (8.1% vs. 4.9%, p = .023); however, no survival benefit was found

In contrast to the findings of the NSABP B-24 trial, the UK/ANZ DCIS trial found that tamoxifen had no effect in reducing local recurrence rate when combined with whole-breast radiation therapy

Because DCIS is a precursor to invasive breast cancer, tamoxifen is used as target for preventive measures

Additional studies are being conducted evaluating the role of aromatase inhibitors and Her2Neu targeted treatment in DCIS

NCCN recommendation on hormonal therapy

Follow-Up

• CBE & baseline mammogram 6 to 12 months after initial therapy and at least annually thereafter

• Ipsilateral tumor recurrences usually detected on surveillance mammography, although one-quarter may be detected on the basis of changes on physical examination of the breast or chest wall.

• Distant breast cancer metastases in the absence of regional recurrence are unusual.

Management of Recurrence• Local recurrences • After excision only: local excision & RT• After BCT+RT: treated with mastectomy.

• The clinical outcome of ipsilateral tumor recurrence is governed by the nature of the recurrence.

• Patients with recurrent DCIS have an excellent prognosis, with <1% risk of further recurrence after salvage mastectomy.

• Patients with invasive recurrence after breast-conserving surgery for DCIS have a prognosis similar to those with early-stage breast cancer, with a 15% to 20% risk of metastatic recurrence at 8 years.

Thank you