eso-esmo 2nd international consensus guidelines for ... · eso-esmo 2nd international consensus...

lable at ScienceDirect

The Breast xxx (2014) 489e502

Contents lists avai

The Breast

journal homepage: www.elsevier .com/brst

ESO-ESMO 2nd international consensus guidelines for advancedbreast cancer (ABC2)*

F. Cardoso a, *, A. Costa b, c, L. Norton d, E. Senkus e, M. Aapro f, F. Andr�e g, C.H. Barrios h,J. Bergh i, L. Biganzoli j, K.L. Blackwell k, M.J. Cardoso l, T. Cufer m, N. El Saghir n,L. Fallowfield o, D. Fenech p, P. Francis q, K. Gelmon r, S.H. Giordano s, J. Gligorov t,A. Goldhirsch u, N. Harbeck v, N. Houssami w, C. Hudis x, B. Kaufman y, I. Krop z,S. Kyriakides aa, U.N. Lin z, M. Mayer ab, S.D. Merjaver ac, E.B. Nordstr€om ad, O. Pagani ae,A. Partridge af, F. Penault-Llorca ag, M.J. Piccart ah, H. Rugo ai, G. Sledge aj, C. Thomssen ak,L. van’t Veer al, D. Vorobiof am, C. Vrieling an, N. West ao, B. Xu ap, E. Winer z

a European School of Oncology & Breast Unit, Champalimaud Cancer Center, Lisbon, Portugalb European School of Oncology, Milan, Italyc European School of Oncology, Bellinzona, Switzerlandd Breast Cancer Program, Memorial Sloan-Kettering Cancer Centre, New York, USAe Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Polandf Division of Oncology, Institut Multidisciplinaire d'Oncologie, Genolier, Switzerlandg Department of Medical Oncology, Gustave-Roussy Institute, Villejuif, Franceh Department of Medicine, PUCRS School of Medicine, Porto Alegre, Brazili Department of Oncology/Radiumhemmet, Karolinska Institutet & Cancer Center Karolinska and Karolinska University Hospital, Stockholm, Swedenj Department of Medical Oncology, Sandro Pitigliani Oncology Centre, Prato, Italyk Breast Cancer Clinical Program, Duke Cancer Institute, Durham, USAl Breast Unit, Champalimaud Cancer Center, Lisbon, Portugalm University Clinic Golnik, Medical Faculty Ljubljana, Ljubljana, Slovenian NK Basile Cancer Institute Breast Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanono Brighton & Sussex Medical School, University of Sussex, Falmer, UKp Breast Care Support Group, Europa Donna Malta, Mtarfa, Maltaq Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australiar BC Cancer Agency, Vancouver, Canadas Departments of Health Services Research and Breast Medical Oncology, UT MD Anderson Cancer Center, Houston, USAt APHP Tenon, IUC-UPMC, Francilian Breast Intergroup, Arome, Paris, Franceu Program of Breast Health, European Institute of Oncology, Milan, Italyv Brustzentrum der Universit€at München, Munich, DE, USAw Screening and Test Evaluation Program, School of Public Health, Sydney Medical School, University of Sydney, Sydney, Australiax Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, USAy Sheba Medical Center, Tel Hashomer, Israelz Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USAaa Europa Donna Cyprus, Nicosa, Cyprusab Advanced BC.org, New York, USAac University of Michigan Medical School and School of Public Health, Ann Arbor, USAad Europa Donna Sweden & Br€ostcancerf€oreningarnas Riksorganisation, BRO, Sundbyberg, Swedenae Oncology Institute of Southern Switzerland and Breast Unit of Southern Switzerland, Bellinzona, Switzerlandaf Department Medical Oncology, Division of Women's Cancers, Dana-Farber Cancer Institute, Boston, USAag Jean Perrin Centre, Comprehensive Cancer Centre, Clermont Ferrand, Franceah Department of Medicine, Institut Jules Bordet, Brussels, Belgiumai Department of Medicine, Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USAaj Indiana University Medical CTR, Indianapolis, USAak Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle an der Saale, DE, Germanyal Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USAam Sandton Oncology Centre, Johannesburg, South Africa

* Important note: These Guidelines were developed by ESO and ESMO and are published simultaneously in The Breast (The Breast 2014, http://dx.doi.org/10.1016/j.breast.2014.08.009) and Annals of Oncology (Ann Oncol 2014; 25: http://dx.doi.org/10.1093/annonc/mdu385) and both must be cited.* Corresponding author. Director Breast Unit, Champalimaud Cancer Center, Av. De Brasília, s/n, 1400-048 Lisbon, Portugal. Tel.: þ351 (210) 480 002; fax: þ351 (210) 480

298.E-mail address: [email protected] (F. Cardoso).

http://dx.doi.org/10.1016/j.breast.2014.08.0090960-9776/© 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

http://dx.doi.org/10.1016/j.breast.2014.08.009


http://dx.doi.org/10.1093/annonc/mdu385

mailto:[email protected]

www.sciencedirect.com/science/journal/09609776

http://www.elsevier.com/brst


http://creativecommons.org/licenses/by-nc-nd/3.0/



F. Cardoso et al. / The Breast xxx (2014) 489e502490

an Department of Radiotherapy, Clinique des Grangettes, Geneva, Switzerlandao Nursing Division, Health Board, Cardiff and Vale University, Cardiff, UKap Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

a r t i c l e i n f o

Article history:Received 5 August 2014Available online xxx

Introduction

Advanced Breast Cancer (ABC) is a treatable but still generallyincurable disease. The goals of care are to optimize both length andquality of life. Due to continuous research, several advances havebeenmade, particularly for the HER-2-positive and for Luminal-likesubtypes. Notwithstanding these advances, median overall survivalof patients with ABC is still only 2e3 years, although the range iswide [1e5], and survival may be longer for patients treated inspecialized institutions [6]. Implementation of current knowledgeis highly variable among countries and within each country.

The use of treatment guidelines has been associated with asignificant improvement in survival [7e9]. This has been achievedmainly in early breast cancer. For ABC, and particularly metastaticbreast cancer (MBC), less level 1 evidence exists and only recentlyhave international consensus guidelines been developed (ABC1 e

[10]. The ABC Consensus Conference was created by the EuropeanSchool of Oncology (ESO) with the ambitious goal of improvingoutcomes for all patients with advanced breast cancer. Backed bystrong political advocacy, ABC guidelines are seeking to improvestandards of care, to raise awareness about how to best meet to theneeds of this underserved group of patients, and to identifyresearch priorities so that clinical research is focused on the mostimportant areas of unmet need.

Following the work of the ESO-ABC Task Force [11e14], createdin 2005, and the successful undertaking of the 1st InternationalConsensus Guidelines Conference on ABC (ABC1), held inNovember 2011, the 2nd International Consensus Conference forAdvanced Breast Cancer (ABC2) took place in Lisbon, Portugal, on

Table 1Levels of evidence grading system [15].

Grade of recommendation/description

Benefit vs. risk and burdens Methodolog

1 A/Strong recommendation,high quality evidence

Benefits clearly outweigh riskand burdens, or vice versa

RCTs withooverwhelmstudies

1 B/Strong recommendation,moderate quality evidence


RCTs with iresults, meimprecise)from obser

1 C/Strong recommendation,low quality evidence


Observation

2A/Weak recommendation,high quality evidence

Benefits closely balanced withrisks and burden

RCTs withooverwhelmstudies

2 B/Weak recommendation,moderate quality evidence


RCTs with iresults, meimprecise)from obser

2 C/Weak recommendation,low quality evidence


Observation

November 7e9, 2013. The conference brought together about 1100participants from 71 countries, including health professionals, pa-tient advocates and journalists. A series of guidelines were dis-cussed and agreed upon, based on the most up-to-date evidenceand can be used to guide treatment decision-making in diversehealth care settings globally. These guidelines are developed as ajoint effort from ESO and ESMO (European Society of MedicalOncology), are endorsed by EUSOMA (European Society of BreastCancer Specialists), SIS (Senologic International Society) and Flam(Federaci�on Latino Americana de Mastologia), and organized underthe auspices of UICC (Union Internationale Contre Le Cancer), OECI(Organization of European Cancer Institutes) and the BCRF (BreastCancer Research Foundation).

The present manuscript summarizes the guidelines developedat ABC2. The guidelines include the level of evidence, the per-centage of panel members who agreed with the consensus state-ments, and the supporting references for each recommendation.Importantly, the ABC guidelines are developed as clinical man-agement recommendations potentially applicable worldwide,albeit with the necessary adjustments for each country, dependingon access to therapies. The guidelines are based on the underlyingprinciples of modern oncology, emphasizing the crucial role of amultidisciplinary and individualized approach that respects thespecificities of the advanced setting and the preferences of eachpatient. The manuscript also clearly highlights areas whereresearch efforts are urgently needed.

Methodology

Prior to the ABC2 Conference, a set of preliminary recommen-dation statements on the treatment of ABC were prepared, basedon available published data and following the ESMO guidelinesmethodology. These recommendations were circulated to all 43panel members by email for comments and corrections on contentand wording. A final set of recommendations was presented, dis-cussed and voted upon during the consensus session of ABC2. All

ical quality of supporting evidence Implications

ut important limitations oring evidence from observational

Strong recommendation, can apply tomost patients in most circumstanceswithout reservation

mportant limitations (inconsistentthodological flaws, indirect, oror exceptionally strong evidencevational studies

Strong recommendation, can apply tomost patients in most circumstanceswithout reservation

al studies or case series Strong recommendation, but maychange when higher quality evidencebecomes available

ut important limitations oring evidence from observational

Weak recommendation, best actionmay differ depending on circumstancesor patients' or societal values

mportant limitations (inconsistentthodological flaws, indirect, oror exceptionally strong evidencevational studies

Weak recommendation, best actionmay differ depending on circumstancesor patients' or societal values

al studies or case series Very weak recommendation, otheralternatives may be equally reasonable

F. Cardoso et al. / The Breast xxx (2014) 489e502 491

panel members were instructed to vote on all questions, withmembers with a potential conflict of interest or who did not feelcomfortable answering the question (e.g. because it is not their areaof expertise) instructed to “abstain” from voting. Additionalchanges in the wording of statements were made during the ses-sion. The statement on Everolimus was updated after the presen-tation of the overall survival results of the BOLERO-2 trial and re-voted by email by all panel members.

Supplementary Table 1 lists all members of the ABC2 consensuspanel and their disclosure of any relationships that could beperceived as a potential conflict of interest.

Table 1 describes the grading system used [15].Three main issues were discussed at ABC2: inoperable locally

advanced breast cancer (LABC) both inflammatory and nonin-flammatory; MBC; and specific definitions for which a consensuswas deemed important.

For clarification, ABC comprises both inoperable LABC and MBCor stage IV. Some of the ABC guidelines apply to both LABC andMBC, while others are specific to each of the settings.

General guidelines

Guideline statement LoE Consensus

All ABC patients should be offeredcomprehensive, culturally sensitive, up-to-date and easy to understand informationabout their disease and its management.

I B 97.2% (36) Yes0% (0) Abstain(37 voters)

Specialized oncology nurses (if possiblespecialized breast nurses) should be part ofthe multidisciplinary team managing ABCpts. In some countries, this role may beplayed by a physician assistant or othertrained and specialized health carepractitioner.

Expertopinion

92.1% (35) Yes7.8% (3) Abstain(38 voters)

Strong consideration should be given to the useof validated instruments for patients toreport the symptoms of disease and sideeffects of treatment they experience as aregular part of their clinical care. These PRO(patient-reported outcomes) instrumentsshould be simple and user-friendly tofacilitate their use in clinical practice. Thissystematic monitoring will serve to facilitatecommunication between patients and theirtreatment teams, allow optimal quality oflife, and may better characterize thetoxicities of all anticancer therapies.

I C 89.4% (34) Yes5.2% (2) Abstain(38 voters)

The age of the patient should not be the solereason to withhold effective therapy (inelderly patients) nor to overtreat (in youngpatients). Age alone should not determinethe type and intensity of treatment.

I B 100% (38) Yes0% (0) Abstain(38 voters)

LoE: Available level of evidence; Consensus: Percentage of panel members inagreement with the statement.

ABC1 Guidelines had already emphasised the importance ofincluding the patient in all steps of the decision-making process[10]. For active and informed participation, patients must haveaccess to comprehensive, culturally sensitive, up-to-date and easyto understand information about their disease and itsmanagement.

A “patient navigator” can help the patient going through allphases of the cancer journey [16e20]. This is particularly relevantfor advanced cancer patients who are often overwhelmed withdifficult decisions to make, through complex information andavailable treatment options, and are frequently co-managed by thebreast cancer and the palliative care teams. This role is best takenby a specialized breast nurse, or at least a specialized oncology

nurse, who should be part of the multidisciplinary team managingABC patients. In some countries however, this role may be playedby a physician assistant or another trained and specialized healthcare practitioner. It is also recognized that in many centres it is notyet possible for each patient to have a navigator due to lack ofhuman resources.

There is an implicit assumption that the recording of adverseevents by clinicians reliably documents patients' side effects andsymptoms. However, there is an accumulating body of evidencesuggesting that the frequency and severity of many symptoms thatimpact upon an individual patient's quality of life go under-reported,under-recognised and consequently under-treated [21]. Since qual-ity of life is one of the main aims of ABC treatment, this poses animportant problem. It is also potentially dangerous from a drugsafety point of view. The inability of traditional methods forcapturing adverse events has led to renewed interest in incorpo-rating Patient Reported Outcomes (PROs/PROMs) with CommonTerminology Criteria for Adverse Events (CTC-AEs) in clinical trials,as well as utilising PROs outside a clinical trial setting to reflect andmonitor more accurately the harms and benefits of patient experi-ence. This may be particularly important for drugs approved basedsolely on progression-free survival (PFS) benefits or only modestoverall survival (OS) benefits, for which the balance between efficacyand toxicity may be more difficult to accurately determine. Manystandardised, well-validated instruments or PRO measures areavailable with translations into most languages. The most frequentlyused are the generic EORTC-QLQ-C3 (http://groups.eortc.be/qol/eortc-qlq-c30) and the FACT (http://www.facit.org/FACITOrg/Questionnaires). Both have breast cancer specific modules/sub-scales (EORTC QLQ-BR23 and FACT-B) and the FACT in particular hasseveral other specific subscales covering, for example, treatmentwith EGFR inhibitors, taxanes, anti-angiogenesis drugs, endocrineagents and monoclonal antibodies. Recently the FDA and EMA havepublished guidance for industry on how to utilise PROs in applica-tions for drug labelling claims. There has also been an importantinitiative, funded by the NCI, to produce a Patient-Reported Out-comes version of the Common Terminology Criteria for AdverseEvents (PRO-CTCAE), which is suggested for use in NCI sponsoredtrials (http://outcomes.cancer.gov/tools/pro-ctcae.html).

Although age is an important factor to consider in decision-making for ABC, it must not be the sole factor to determine the in-tensity and type of treatment. There is a tendency to withholdtherapy in some elderly patients because of fear of toxicity orconcern about co-morbidity. In some cases, however, such therapiesmay be highly effective and could improve both survival and qualityof life. At the same time, younger patients are often overtreated ortreated somewhat inappropriately. Age may influence breast cancertreatment, but it should not be the guiding force [10,22e24].

“Survivorship” in ABC

The complex needs of patients living with ABC, at times formany years, as well as their caregivers, should be addressed notonly in terms of supportive and palliative care but also regarding“survivorship” concerns. The multidisciplinary approach of ABCshould encompass early in the history of the disease not onlyphysical but also functional, social, psychological and spiritual do-mains [25e27].

It is important to clearly define the disease context with patientsand families, addressing the concept of uncertainty and tailoringthe treatment strategy according to individual priorities and dis-ease status [28]. Specific psychosocial needs of young and elderlypatients should also be recognized and supported, i.e. social secu-rity, job flexibility, rehabilitation, body image (including sexuality),home and child care.

http://groups.eortc.be/qol/eortc-qlq-c30

http://groups.eortc.be/qol/eortc-qlq-c30

http://www.facit.org/FACITOrg/Questionnaires

http://www.facit.org/FACITOrg/Questionnaires

http://outcomes.cancer.gov/tools/pro-ctcae.html

(continued )


Important ABC-related definitions


VISCERAL CRISIS is defined as severe organdysfunction as assessed by signs andsymptoms, laboratory studies, and rapidprogression of disease. Visceral crisis is notthe mere presence of visceral metastases, butimplies important visceral compromiseleading to a clinical indication for a morerapidly efficacious therapy, particularly sinceanother treatment option at progression willprobably not be possible.

Expertopinion

95.0% (38) Yes5.0% (2)Abstain(40 voters)

PRIMARY ENDOCRINE RESISTANCE is definedas: relapse while on the first 2 years ofadjuvant ET, or PD within first 6 months of1st line ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINERESISTANCE is defined as: relapse while onadjuvant ET but after the first 2 years, orrelapse within 12 months of completingadjuvant ET, or PD� 6months after initiatingET for MBC, while on ET.

Expertopinion

66.6% (22) Yes21.2% (7)Abstain(33 voters)

LoE: Available level of evidence; Consensus: Percentage of panel members inagreement with the statement; ET: endocrine therapy; PD: progressive disease;MBC: metastatic breast cancer.


A combined treatment modality based on amultidisciplinary approach (systemictherapy, surgery and radiotherapy) isstrongly indicated in the vast majority ofcases.

100% (39) Yes0% (0) Abstain(39 voters)

For TRIPLE NEGATIVE LABC, anthracycline- and-taxane-based chemotherapy isrecommended as initial treatment.

I A 85.3% (35) Yes9.7% (4) Abstain(41 voters)

For HER-2-POSITIVE LABC, concurrent taxaneand anti-HER-2 therapy is recommendedsince it increases the rate of pathologicalcomplete response (pCR).


For HER-2-POSITIVE LABC, anthracycline-basedchemotherapy should be incorporated in thetreatment regimen.


In HER-2-POSITIVE LABC, when ananthracycline is given, it should beadministered sequentially with the anti-HER-2 therapy.


Options for HORMONAL RECEPTOR POSITIVELABC include an anthracycline- and taxane-based chemotherapy regimen, or endocrinetherapy.

The choice of chemotherapy vs. endocrinetherapy, as initial treatment, will depend ontumour (grade, biomarker expression) andpatient (menopausal status, performancestatus, comorbidities, preference)considerations.


Following effective neoadjuvant systemictherapy with or without radiotherapy,surgery will be possible in many patients.This will consist of mastectomy with axillarydissection in the vast majority of cases, but inselected patients with a good response,breast conserving surgery may be possible.

II B 97.5% (39) Yes0% Abstain(40 voters)

LABC: locally advanced breast cancer; LoE: Available level of evidence; Consensus:Percentage of panel members in agreement with the statement; ER: oestrogen re-ceptor; PR: progesterone receptor.

Current terminology uses several ill-defined terms that often havedifferent meanings, leading to confusion and difficulty in adaptingclinical trial findings to current practice populations.

The ABC2 Panel tried to define two of these important terms,aiming at standardization of their use.

Regarding endocrine resistance, an attempt was made to beconsistent with a definition reached by a number of investigatorsinvolved in breast cancer clinical trials, at a meeting sponsored byNCI held in May 2012 and later approved by the North AmericanBreast Cancer Groups (NABCG).

It is also important to note that endocrine resistance is a con-tinuum and that strict definitions are mainly helpful for the clinicaltrials setting and not necessarily for routine clinical practice.


For inflammatory LABC, overall treatment I B 92.6% (38) Yes

Inoperable locally advanced, non-inflammatory, breast cancer


Before starting any therapy, a core biopsyproviding histology and biomarker (ER, PR,HER-2, proliferation/grade) expression isindispensable to guide treatment decisions.

I B 97.2% (36) Yes2.7% (1) Abstain(37 voters)

Since LABC patients have a significant risk ofmetastatic disease, a full staging workup,including a complete history, physicalexamination, lab tests and imaging of chestand abdomen (preferably CT scans) and bone,prior to initiation of systemic therapy ishighly recommended.


PET-CT, if available, may be used (instead of andnot on top of CT scans and bone scan).

II B 100% (37) Yes0% (0) Abstain(37 voters)

Systemic therapy (not surgery or radiotherapy)should be the initial treatment. If LABCremains inoperable after systemic therapyand eventual radiation, “palliative”mastectomy should not be done, unless thesurgery is likely to result in an overallimprovement in quality of life.

Expertopinion


I A

Inoperable locally advanced, inflammatory, breast cancer

recommendations are similar to those fornon-inflammatory LABC, with systemictherapy as first treatment.

4.8% (2) Abstain(41 voters)

Mastectomy with axillary dissection isrecommended in almost all cases, even whenthere is good response to primary systemictherapy.


Immediate reconstruction is generally notrecommended in patients with inflammatoryLABC.

Expertopinion


Loco-regional radiotherapy (chest wall andlymph nodes) is required, even when a pCR isachieved with systemic therapy.


MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-centage of panel members in agreement with the statement; pCR: pathologicalcomplete remission.

LABC occurs at first presentation in about one fifth of breastcancer patients worldwide, with lower incidence in countries withestablished screening programs but as high as 60% in some othercountries [29]. Usually, the definition of LABC includes large oper-able primary breast tumours (stage IIB, IIIA) and/or those involving

(continued )


For MALE PATIENTS WITH ABC who need toreceive an aromatase inhibitor, aconcomitant LHRH agonist or orchiectomy isthe preferred option. Aromatase inhibitormonotherapy may also be considered, withclose monitoring of response.

Clinical trials are needed in this patientpopulation.

Expertopinion


MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-centage of panel members in agreement with the statement.


the skin or chest wall and/or those with extensive lymphadenop-athies (stage IIIB, IIIC) [30]. For the purpose of ABC guidelines wedefine LABC as inoperable locally advanced disease that has not yetspread to distant sites.

Inoperable LABC is a heterogeneous designation encompassinga range of clinical situations from neglected low-grade ER-positivebreast cancers to rapidly progressing usually ER-negative disease[30e33].

A more homogenous form of LABC is inflammatory breast can-cer (IBC), a distinct clinic-pathologic entity. IBC has a greater as-sociation with younger age at diagnosis, higher tumour grade, andnegative oestrogen receptor (ER) status.

The first steps in the management of this disease are a corebiopsy to provide histology and biomarker assessment(including ER, PR, HER-2, proliferation/grade), and a full stagingworkup. Due to a relatively high risk of distant metastases [34],thoracic and abdominal CT scans are preferred to thorax X-rayand liver ultrasound, and a PET-CT is also an acceptable option[34].

A multimodality approach is key for loco-regional control andsurvival, including systemic therapies, surgery and radiation.

The type of systemic therapy is similar to the one used in the(neo)adjuvant setting, with anthracycline and taxanes as thebackbone of the chemotherapy regimes. For HER-2-positive LABC,anthracyclines should not be administered concurrently withtrastuzumab since this approach does not increase the pCR rate,and it could increase the risk of cardiac toxicity, based largely onstudies in the metastatic setting [35,36].

For luminal-like LABC, initial treatment options includechemotherapy (with sequential anthracyclines and taxanes) andendocrine therapy, depending on tumour (grade, biomarkerexpression) and patient characteristics (menopausal status,performance status, comorbidities) and preferences. A numberof studies have demonstrated significant activity of endocrinetherapy, particularly in luminal A-like disease [37e40]. Datapresented after ABC2 strongly suggest that this subset of breastcancer, especially lobular histology, is less sensitive to chemo-therapy (at least in terms of pCR rate) [41]. Very few data existon primary endocrine therapy in premenopausal women [42]and, therefore, it cannot be recommended outside of clinicaltrials.

Primary systemic therapy in inoperable LABC allows breastconserving surgery in variable percentages depending on tumour/patient characteristics [43]. Mastectomy remains the only optionbefore or after radiotherapy for those patients not amenable tobreast conservation and for all patients with IBC [44]. For the timebeing, axillary dissection is still standard of care in inoperable LABC[45].

As for all other stages of breast cancer, decision-making at amultidisciplinary tumour board is highly recommended.

Specific ABC populations


In patients with BRCAeASSOCIATED TRIPLENEGATIVE OR ENDOCRINEeRESISTANTMBC previously treated with ananthracycline and a taxane (in the adjuvantor metastatic setting), a platinum regimenmay be considered, if the patient is notincluded in a clinical trial.

All other treatment recommendations aresimilar to sporadic MBC.


As predicted by their DNA-damaging mechanism of action,platinum compounds are expected to be particularly active in tu-mours deficient of mechanisms responsible for DNA damage repair,e.g. those without active BRCA1/2 proteins. Due to rarity of suchpatients, little evidence exists on the clinical activity of these drugsin BRCA1/2 mutation carriers in the metastatic setting. However,available data suggest their promising activity mostly in the neo-adjuvant setting [46,47], and to a lesser degree in advanced disease[48].

In triple-negative breast cancer (TNBC), another putativelyBRCA-deficient population, a relatively large amount of datafrom prospective studies, recently summarized in a meta-analysis, demonstrated improved pCR rates in patients whoseneoadjuvant treatment included a platinum compound[49e51]. However, which patients definitely benefit is not yetclear since there is also one negative GEICAM study addingcarboplatin to EC-Docetaxel in basal-like breast cancer [52].Fewer data exist for inclusion of platinum in the treatment ofmetastatic disease, although the benefit in the TNBC popula-tion seems to be larger than in other breast cancer patients[53].

Taking available evidence into account, most of the ABC2panel supported the inclusion of platinum-containing regimensin the treatment of BRCA1/2 mutant patients pretreated withanthracyclines and taxanes and demonstrated to be endocrine-resistant.

ABC1 issued several recommendations for the treatment ofmale patients with ABC [10] that still remain valid for ABC2 (seeTable 2). One additional recommendation is added at this point,related to the use of aromatase inhibitors in this patientpopulation.

There are concerns about the efficacy of these agents when usedin monotherapy in male patients, due to the hypothalamic-pituitary negative feedback.

Important differences exist in the physiology of oestrogenproduction between men and women. In men, 80% of circu-lating oestrogens result from the peripheral aromatization ofandrogens, whereas 20% are directly secreted in the testicles[54e56]. Adrenals secrete less than 1% of circulating sex ste-roids, but precursors can undergo peripheral aromatization. Soperipheral conversion results in less than 5% of all testos-terone, 80% of all dihydrotestosterone and oestradiol, andnearly all of estrone (98%) [56,57]. Additionally, oestradiollevels are 3e4 times higher in older males than in post-menopausal females.

For these reasons, and despite the lack of prospective and ran-domized data, the majority of panel members recommend thatwhen an aromatase inhibitor needs to be used in male ABC pa-tients, a concomitant LHRH agonist or orchiectomy should be addedto further down-regulate testicular function.


Specific sites of metastases


Prospective randomized clinical trials of localtherapy for breast cancer LIVERMETASTASES are urgently needed, sinceavailable evidence comes only from seriesin highly selected patients. Since there areno randomized data supporting the effectof local therapy on survival, every patientmust be informed of this when discussing apotential local therapy technique. Localtherapy should only be proposed in veryselected cases of good performance status,with limited liver involvement, no extra-hepatic lesions, after adequate systemictherapy has demonstrated control of thedisease. Currently, there are no data toselect the best technique for the individualpatient (surgery, stereotactic RT, intra-hepatic CT or other).

Expertopinion

83.3% (25) Yes16.6% (5)(30 voters)

MALIGNANT PLEURAL EFFUSIONS requiresystemic treatment with/without localmanagement. Thoracentesis for diagnosisshould be performed if it is likely that thiswill change clinical management. Falsenegative results are common. Drainage isrecommended in patients withsymptomatic, clinically significant pleuraleffusion. Use of an intrapleural catheter orintrapleural administration of talc or drugs(e.g. bleomycin, biological responsemodifiers) can be helpful.

Clinical trials evaluating the best techniqueare needed.

II B 86.4% (32) Yes10.8% (4) Abstain(37 voters)

Chest wall and regional (nodal) recurrencesDue to the high risk of concomitant distant

metastases, patients with chest wall orregional (nodal) recurrence shouldundergo full restaging, includingassessment of chest, abdomen and bone.

Expertopinion


Chest wall and regional recurrences should betreated with surgical excision whenfeasible with limited risk of morbidity.


Locoregional radiotherapy is indicated forpatients not previously irradiated.


For patients previously irradiated, re-irradiation of all or part of the chest wallmay be considered in selected cases.

Expertopinion


In addition to local therapy (surgery and/orRT), in the absence of distant metastases,the use of systemic therapy (CT, ET and/oranti-HER-2 therapy) should be considered.

CT after first local or regional recurrenceimproves long-term outcomes primarily inER negative disease.

ET in this setting improves long-termoutcomes for ER positive disease.

The choice of systemic treatment depends ontumour biology, previous treatments,length of disease free interval, and patient-related factors (co-morbidities,preferences, etc).


In patients with disease not amenable toradical local treatment, the choice ofpalliative systemic therapy should bemadeaccording to principles previously definedfor metastatic BC. These patients may stillbe considered for palliative local therapy.

Expertopinion


MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-centage of panel members in agreement with the statement; CT: chemotherapy; RT:radiotherapy; ET: endocrine therapy.

Due to the lack of prospective randomized data for the man-agement of liver metastases from breast cancer, and the existenceof several loco-regional techniques, local therapy of liver metasta-ses should only be considered in highly selected patients. Each caseshould be discussed with a multidisciplinary tumour board, beforea decision is made. Inclusion in a clinical trial, when available, isconsidered the best option.

When breast cancer recurs only on the chest wall after mastec-tomy, the use of intensive local-regional therapy should be consid-ered. Therapy can include surgical excision alone, surgical excisionfollowed by radiation therapy, radiation therapy alone (when sur-gical excision is not feasible) or concurrent chemotherapy and ra-diation. Complete surgical resection reduces the total required doseof radiation therapy and also maximizes the likelihood of long-termdisease control. Complete excision alone can lead to a 5-year diseasefree survival rate of 35% [58]. Complete resection followed by loco-regional radiotherapy results in a 5-year local regional controlranging from 60 to 77% [59,60]. Long-term predictors of disease freesurvival after a local regional recurrence include a disease-free in-terval greater than 24 months and a complete excision [59].

With modern radiotherapy techniques it is often possible to re-irradiate with full dose without too many side effects [61]. The firstresults of retreatment with stereotactic body radiotherapy (SBRT)techniques have been published recently, describing promisinglocal control rates [62].

Concurrent chemoradiation has both preclinical rationale andclinical efficacy in many solid tumour types. Potential mechanismsof chemotherapy and radiotherapy interactions include increasingradiation damage, inhibition of DNA repair processes, enhancedactivity against hypoxic and radioresistant cells, and prevention ofregrowth of tumour after radiation [63]. In patients who havereceived prior radiation, chemoradiation can be considered, as theresidual tumour should be considered radioresistant unless com-bined with a potentiating agent, provided that the patient is judgeda candidate and can tolerate additional radiation therapy. Agentshaving shown potential synergy with radiation include platinumanalogs [64], antimetabolites [65e67], and taxanes [68]. Severalnovel therapeutics are also being studied in the trial setting incombination with radiation, including EGFR inhibitors [69], HER-2inhibitors [70], and PARP inhibitors [71]. Patients who have resid-ual isolated local-regional recurrence after attempted resection, orminimal systemic disease, might derive benefit from considerationof this multi-modality approach.

Hyperthermia has a proven benefit for the treatment of super-ficial malignancies, acting as a radiosensitizer. Trials evaluating therole of hyperthermia in combination with radiotherapy in patientswith chest wall recurrences have shown a significant improvementin complete response rates with the addition of hyperthermia,especially in previously irradiated patients (e.g. CR: 24%e31% in theno-hyperthermia arm vs. 57%e68% in the hyperthermia arm)[72,73]. However, there was no difference in survival between thetwo treatment arms. Recent studies have analysed the combinationof radiotherapy, hyperthermia and concurrent chemotherapy inthis patient population [74].

Finally, systemic therapy (both endocrine and chemotherapy)has been shown to benefit patients after complete resection of afirst locoregional isolated recurrence [75,76]. The CALOR study [76],a randomized Phase 3 study, allocated 162 patients to either phy-sician's choice chemotherapy or no chemotherapy. The use ofchemotherapy after surgery resulted in a significant reduction insystemic recurrence (HR ¼ 0.59; p ¼ 0.046). In the subgroup ofpatients with ER-negative tumours, there was also a significantimprovement in survival. This study provides important data insupport of use of systemic chemotherapy after surgical resection ofisolated locoregional recurrence of ER-negative breast cancer.


Update on ER positive/HER-2 negative ABC


The preferred 1st line ET for postmenopausalpatients is an aromatase inhibitor or tamoxifen,depending on type and duration of adjuvant ET.


Fulvestrant HD is also an option. I B 83.3% (30) Yes16.6% (6) Abstain(36 voters)

The addition of everolimus to an aromataseinhibitor is a valid option for some post-menopausal patients with disease progressionafter a non-steroidal aromatase inhibitor, since itsignificantly prolongs PFS by a median interval of5 months. There is a survival prolongation ofsimilar magnitude (4.4 months) although thisdifference is not statistically significant. Thedecision to treat must take into account therelevant toxicities associated with thiscombination and should be made on a case bycase basis.

At present, no predictive biomarker exists toidentify those patients who will benefit from thisapproach.

I B 100% Yes(30 voters)

LoE: Available level of evidence; Consensus: Percentage of panel members inagreement with the statement; ET: endocrine therapy; PFS: progression-freesurvival.


In the 1st line setting, for HER-2þ MBC previouslytreated (in the adjuvant setting) or untreatedwith trastuzumab, combinations ofCT þ trastuzumab are superior to combinationsof CT þ lapatinib in terms of PFS and OS.


In 1st line therapy, the combination ofCT þ trastuzumab and pertuzumab is superior toCT þ trastuzumab, primarily for previouslyuntreated HER-2þ MBC, making it the preferredtreatment option since it is associated with OSbenefit.

It is currently unknown how this treatmentcompares to other anti-HER-2 options such as T-DM1.


There are currently no data supporting the use ofdual blockade with trastuzumab þ pertuzumabassociated with CT beyond 1st line, aftertreatment with trastuzumab þ pertuzumab þ CTin 1st line (i.e. continuing dual blockade beyondprogression) and therefore this 3 drug regimenshould not be given beyond 1st line outsideclinical trials.


In a HER-2þMBC patient previously untreated withpertuzumab, it is acceptable to use pertuzumabbeyond 1st line.

II C 43.7% (14) Yes21.8% (7) Abstain(32 voters)

After 1st line trastuzumab-based therapy, T-DM1provides superior efficacy relative to other HER-2-based therapies in the 2nd line (vs.lapatinib þ capecitabine) and beyond (vs.treatment of physician's choice).

T-DM1 should be preferred in patients who haveprogressed through at least 1 line oftrastuzumab-based therapy, since it provides anOS benefit.


All patients with HER-2þ MBC who relapse afteradjuvant anti-HER-2 therapy should beconsidered for further anti-HER-2 therapy,except in the presence of contraindications.

The choice of the anti-HER-2 agent will depend oncountry-specific availability, the specific anti-HER-2 therapy previously administered, and therelapse free interval.

The optimal sequence of all available anti-HER-2therapies is currently unknown.


Because patients with HER-2-positive MBC andbrain metastases can live for several years,consideration of long-term toxicity is importantand less toxic local therapy options (e.g.stereotactic RT) should be preferred to wholebrain RT, when available and appropriate (e.g. inthe setting of a limited number of brainmetastases).


MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-centage of panel members in agreement with the statement; CT: chemotherapy, RT:radiotherapy; T-DM1: Trastuzumab Emtansine.

ABC2 reinforces the ABC1 recommendations for ER-positive/HER-2-negative advanced breast cancer regarding the preferentialuse of endocrine therapy, even in the presence of visceral metas-tases. Chemotherapy should be reserved for cases of rapidly pro-gressive disease or proven endocrine-resistance. Most ABC1recommendations remain unchanged (see Table 2). The twochanges refer to the preferred 1st line endocrine therapy forpostmenopausal women and the use of everolimus.

The preferred 1st line endocrine therapy for postmenopausalwomen depends on the type and duration of adjuvant endocrinetherapy. Available data supports the use of an aromatase inhibitor,tamoxifen or fulvestrant HD (i.e. 500 mg, every 4 weeks)[31,77e88]. Fulvestrant HD is well tolerated and numericallyassociated with a 4.1-month difference in median OS comparedwith fulvestrant 250 mg [80]. Only the lower, less efficacious dose,was compared to aromatase inhibitors and found to have similarefficacy; so far, no data directly comparing fulvestrant HD with anaromatase inhibitor exist.

Endocrine resistance is a common and important clinicalproblem. It may be primary or secondary (see above ABC defini-tions). The main identified mechanisms of endocrine resistance arerelated to ESR alterations (mutations, amplifications or trans-locations), and upregulation of alternative pathways, such as theHER growth factor pathways and the PI3K/Akt/mTOR pathway.

The mTOR inhibitor everolimus when added to exemestane, inpatients progressing on non-steroidal aromatase inhibitor, pro-vided a significant PFS prolongation of about 5 months [89,90]. Theoverall survival data, presented after ABC2, demonstrated a non-significant 4-month increase in median survival (HR 0.89) [91].Overall survival prolongation was also observed, in an exploratoryanalysis of the randomized phase II TAMRAD study comparingcombination of tamoxifen and everolimus to tamoxifen alone in AI-resistant patients [92]. These benefits must be weighed againstrelevant toxicities associated with this compound, particularlystomatitis, pneumonitis and hyperglycemia. Decisions on ever-olimus use must thus be made on a case-by-case basis, after dis-cussion with a well-informed patient, and administered byphysicians experienced in managing adverse effects of thiscompound.

Update on Her-2-Positive ABC

In the last two years, several trials in HER-2-positive ABC havebeen reported, which led to an update on several ABC1 recom-mendations regarding this specific subtype.

Evidence from three trials, two in advanced and one in earlybreast cancer, support the recommendation that combinations ofchemotherapy with trastuzumab are superior to chemotherapy andlapatinib.

The MA.31 trial [93] randomly compared taxanes plus trastu-zumab (weekly paclitaxel or three weekly docetaxel) or the sametaxane plus lapatinib, as first line treatment of 636 HER-2 positiveMBC patients, a substantial percentage of whom had de novo MBC.With a median follow-up of 13.6 months, the taxane-lapatinib armhad inferior PFS compared to the taxane-trastuzumab (8.8 vs. 11.4

(continued )


Additional choices include gemcitabine, platinumagents, taxanes, and liposomal anthracyclines.

The decision should be individualized and take intoaccount different toxicity profiles, previousexposure, patient preferences, and countryavailability.

LoE: Available level of evidence; Consensus: Percentage of panel members inagreement with the statement; CT: chemotherapy.


The true value of the removal of the primarytumour in patients with de novo stage IVbreast cancer is currently unknown.However, it can be considered in selectedpatients. Of note, some studies suggest thatsurgery is only valuable if performed withthe same attention to detail (e.g. attainingclear margins and addressing disease in theaxilla) as in patients with early stage disease.

II B 100% (29) Yes0% (0) Abstain(29 voters)

LoE: Available level of evidence; Consensus: Percentage of panel members inagreement with the statement.


months). There was no difference in OS and toxicity was signifi-cantly higher in the lapatinib arm.

The CEREBEL trial [94], compared lapatinib plus capecitabine totrastuzumab plus capecitabine, as 1st line therapy for HER-2-positive MBC with no evidence of CNS disease. The primaryendpoint was incidence of CNS metastases as first site of relapse.With a planned population of 475 patients, the study was termi-nated at the time of the interim analysis due to a low number ofCNS events (3% and 5% respectively). PFS, a secondary endpoint,was lower in the lapatinib arm (6.6 vs. 8.0 months).

Additional evidence comes from the adjuvant ALTTO trial,where the lapatinib alone arm was closed early, due to futility in anon-inferiority comparison to trastuzumab, and patients offeredcross-over to receive trastuzumab [95].

The CLEOPATRA trial [96,97]; showed superior results, in terms ofPFS (18.5 vs. 12.4 months) and 1-year survival (23.6% vs. 17.2), of thetriplet trastuzumab þ pertuzumab þ docetaxel compared totrastuzumabþ docetaxel as 1st line therapy. Importantly, themajority(z90%) of the patients were trastuzumab-naive; if previously treatedwith trastuzumab, a 12 months disease-free interval was required.Therefore, this trial did not address, and therefore cannot support, theuse of this combination in patients with truly trastuzumab-resistanttumours. There are also no data supporting the use of the dualblockade with trastuzumab þ pertuzumab with CT beyond 1st line,after treatment with trastuzumab þ pertuzumab þ CT in 1st line (i.e.continuing dual blockade beyond progression) and therefore thisregimen should not be given beyond 1st line outside clinical trials.

The panel could not reach a consensus regarding the possibleuse of pertuzumab beyond 1st line in patients previously untreatedwith this drug (14 votes “yes”, 11 “no”, 7 “abstain”). The onlyavailable data regarding this issue come from a phase II single armstudy [98]. This phase II also showed that pertuzumab does notwork by itself but needs to be combined with trastuzumab.

T-DM1 (Trastuzumab Emtansine) has shown consistent andsubstantial benefits in terms of PFS and OS, both in the 2nd line (vs.lapatinib þ capecitabine, in the EMILIA trial) [99,100]; and beyond(vs. treatment of physician's choice, in the TH3RESA trial) [101].These results make T-DM1 the preferred choice for patients withdisease progression after treatment with at least one line oftrastuzumab-based therapy.

There are almost no data regarding the treatment of patients withHER-2-positive ABC who relapse on or shortly after adjuvant tras-tuzumab and urgent trials are needed for this poor prognosis pop-ulation. In the EMILIA trial, the overall survival advantage (hazardratio) for T-DM1 vs. lapatinib plus capecitabine in the subset of 118patients who were randomized in the first-line setting, havingrelapsed on or within 6 months of adjuvant trastuzumab, appearedsimilar to the effect seen in the overall trial [100].

Several ABC1 recommendations for HER-2-positive ABC remainunchanged and are listed in Table 2.

Update on HER-2-negative ABC


Sequential monotherapy is the preferred choice forMBC. Combination CT should be reserved forpatients with rapid clinical progression, life-threatening visceral metastases, or need for rapidsymptom and/or disease control.

I A 96% (25) Yes4% (1) Abstain(26 voters)

In patients pre-treated (in the adjuvant ormetastatic setting) with an anthracycline and ataxane, and who do not need combinationchemotherapy, single agent capecitabine,vinorelbine or eribulin are the preferred choices.


Regarding the use of chemotherapy, the main recommendationremains unchanged and relates to the sequential use of singleagents, with combination chemotherapy reserved for situations ofvisceral crisis, rapidly progressive or highly symptomatic disease.Available literature has been previously reviewed [12] and a recentCochrane meta-analysis [102] confirms and provides level 1 evi-dence for this recommendation.

Although taxanes can be used as first line therapy, they have notshown superior benefit to anthracyclines in a meta-analysis per-formed in a mostly taxane-naive, anthracycline-pretreated patientpopulation [103]. Considerations regarding toxicity and patientpreferences (namely wish to avoid alopecia) should be taken intoconsideration in the choice of cytotoxic agent.

Capecitabine has shown consistent results as first and secondline therapy [104e112].

Vinorelbine yielded equal or superior results to both paclitaxeland docetaxel, when combined with trastuzumab in the HER-2positive ABC in the HERNATA [113] and TRAVIOTA trials [114].

Eribulin has provided an OS benefit in heavily pretreated pa-tients (up to 5 lines of treatment) [115] and similar PFS and OSresults to capecitabine after prior treatment with an anthracyclineand taxane [116].

Update on surgery of the primary tumour in stage IV atdiagnosis

Available data regarding the value of removal of the primarytumour in patients with stage IV at diagnosis were extensivelyreviewed and published in one of the ESO ABC Task Force manu-scripts [13]. All but one study published after this 2010 papersupport the surgical removal of the primary tumour in patientswith stage IV disease, reinforcing the importance of the ongoingprospective trials evaluating this approach since existing data comealmost exclusively from retrospective studies [117e121,124]. In thebeginning of 2012, the British Columbia large retrospective seriesreinforced the importance of treating the primary with the mostfavourable survival rates observed in subsets of patients with youngage, good performance status, ER-positive disease, distant diseaselimited to one site, bone-only involvement, or fewer than five

Table 2ABC1 statements [10] with minor update or with no update.


The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (includingbut not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gynaecologists, psycho-oncologists,social workers, nurses and palliative care specialists), is crucial.

Expertopinion


From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care, supportive care, and symptom-relatedinterventions as a routine part of their care. The approach must be personalized to meet the needs of the individual patient.

Expertopinion


Following a thorough assessment and confirmation of MBC, the potential treatment goals of care should be discussed. Patientsshould be told that MBC is incurable but treatable, and that some patients can live with MBC for extended periods of time (manyyears in some circumstances).

This conversation should be conducted in accessible language, respecting patient privacy and cultural differences, and wheneverpossible, written information should be provided.

Expertopinion


Patients (and their families, caregivers or support network, if the patient agrees) should be invited to participate in the decision-making process at all times. When possible, patients should be encouraged to be accompanied by persons who can support themand share treatment decisions (e.g. family members, caregivers, support network).

Expertopinion


There are few proven standards of care in ABC management. After appropriate informed consent, inclusion of patients in well-designed, prospective, randomized independent trials must be a priority whenever such trials are available and the patient iswilling to participate.

Expertopinion


The medical community is aware of the problems raised by the cost of ABC treatment. Balanced decisions should be made in allinstances; patients' well being, length of life and preferences should always guide decisions.

Expertopinion


Assessment guidelinesMinimal staging workup for MBC includes a history and physical examination, haematology and biochemistry tests, and imaging of

chest, abdomen and bone.2 C 67% (20) Yes

3% (1) Abstain(30 voters)

Brain imaging should not be routinely performed in asymptomatic patients. This approach is applicable to all patients with MBCincluding those patients with HER-2þ and/or triple negative MBC.

Expertopinion

94% (30) Yes0% Abstain(32 voters)

The clinical value of tumour markers is not well established for diagnosis or follow-up after adjuvant therapy, but their use isreasonable (if elevated) as an aid to evaluate response to treatment, particularly in patients with non-measurable metastaticdisease. A change in tumour markers alone should not be used to initiate a change in treatment.

2 C 89% (24) Yes4% (1) Abstain(27 voters)

Evaluation of response to therapy should generally occur every 2e4 months for ET or after 2 to 4 cycles for CT, depending on thedynamics of the disease, the location and extent of metastatic involvement, and type of treatment.

Imaging of a target lesion may be sufficient in many patients. In certain patients, such as those with indolent disease, less frequentmonitoring is acceptable.

Additional testing should be performed in a timely manner, irrespective of the planned intervals, if PD is suspected or newsymptoms appear. Thorough history and physical examination must always be performed.

Expertopinion


A biopsy (preferably providing histology) of a metastatic lesion should be performed, if easily accessible, to confirm diagnosisparticularly when metastasis is diagnosed for the first time.

1 C* 96% (27) Yes0% (0) Abstain(28 voters)

Biological markers (especially HR and HER-2) should be reassessed at least once in the metastatic setting, if clinically feasible. 2 C 90% (26) Yes7% (2) Abstain(29 voters)

If the results of tumour biology in the metastatic lesion differ from the primary tumour, it is currently unknownwhich result shouldbe used for treatment-decision making. Since a clinical trial addressing this issue is difficult to undertake, we recommendconsidering the use of targeted therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at least one biopsy,regardless of timing.

Expertopinion


Treatment general guidelinesTreatment choice should take into account at least these factors: HR and HER-2 status, previous therapies and toxicities, disease-free

interval, tumour burden (defined as number and site of metastases), biological age, performance status, co-morbidities (includingorgan dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychologicalfactors, available therapies in the patient's country and patient preference.

Expertopinion


A small but very important subset of patients with MBC, for example those with oligo-metastatic disease, can achieve completeremission and a long survival. A multimodal approach should be considered for these selected patients.

A prospective clinical trial addressing this specific situation is needed.

Expertopinion

96% (25) Yes0% Abstain(26 voters)

ER þ/HER-2 negative ABCEndocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless

there is concern or proof of endocrine resistance, or there is disease needing a fast response.I A 100% (29) Yes


For pre-menopausal women, ovarian suppression/ablation combined with additional endocrine therapy is the first choice. I A 97% (29) Yes0% (0) Abstain(30 voters)

The additional endocrine agent should be tamoxifen unless tamoxifen resistance is proven.An aromatase inhibitor is also a viable option, but absolutely mandates the use of ovarian suppression/ablation.Fulvestrant has not been adequately studied in premenopausal women.


Optimal post-aromatase inhibitor treatment is uncertain. Available options include, but are not limited to, tamoxifen, anotheraromatase inhibitor (with a different mechanism of action), fulvestrant HD, megestrol acetate and everolimus þ aromataseinhibitor.


(continued on next page)


Table 2 (continued )


Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable option, although this approach has not beenassessed in randomized trials.

I C 88% (28) Yes9% (3) Abstain(32 voters)

Concomitant CT þ ET has not shown a survival benefit and should not be administered outside of a clinical trial. I B 100% (30) Yes0% (0) Abstain(30 voters)

HER-2-positive ABCAnti-HER-2 therapy should be offered early to all patients with HER-2þMBC, except in the presence of contra-indications to the use

of such therapy.I A 91% (30) Yes


For patients with ERþ/HER-2þ MBC for whom ET was chosen over CT, anti-HER-2 therapy þ ET should be considered with theinitiation of endocrine therapy (provided that further anti-HER-2 therapy is available) since anti-HER-2 therapy (eithertrastuzumab or lapatinib) in combinationwith ET has shown substantial PFS benefit (i.e. “timewithout CT”) compared to ET alone.The addition of anti-HER-2 therapy in this setting has not led to a survival benefit.


Patients whose tumours progress on an anti-HER-2 therapy combined with a cytotoxic or endocrine agent should be offeredadditional anti-HER-2 therapy with subsequent treatment since it is beneficial to continue suppression of the HER-2 pathway.

The optimal duration of anti-HER-2 therapy for MBC (i.e. when to stop these agents) is currently unknown.


Patients who have received any type of (neo)adjuvant anti-HER-2 therapy should not be excluded from clinical trials for HER-2þMBC.


In case of progression on trastuzumab, the combination of trastuzumab þ lapatinib is also a reasonable treatment option in thecourse of the disease.


Chemotherapy and biological therapyIn the absence of medical contraindications or patient concerns, anthracycline or taxane based regimens, preferably as single agents,

would usually be considered as first line CT for HER-2 negative MBC, in those patients who have not received these regimens asadjuvant treatment and for whom chemotherapy is appropriate. Other options are, however, available and effective, such ascapecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient.


In patients with taxane-naive and anthracycline-resistant MBC or with anthracycline cumulative dose or toxicity (i.e. cardiac) whoare being considered for further CT, taxane-based therapy, preferably as single agents, would usually be considered as treatmentof choice. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoidingalopecia is a priority for the patient.


If given in the adjuvant setting, a taxane can be re-used in the metastatic setting, particularly if there has been at least one year ofdisease-free survival.


Duration of each regimen and the number of regimens should be tailored to each individual patient. Expertopinion


Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity.What is considered unacceptable should be defined together with the patient.


Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides only a moderate benefit in PFS and nobenefit in OS. The absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult.Bevacizumab can only therefore be considered as an option in selected cases in these settings and is not recommended after 1st/2nd line.


Specific sites of metastases: bone and brainA bone modifying agent (bisphosphonate or denosumab) should be routinely used in combination with other systemic therapy in

patients with MBC and bone metastases.I A 96% (26) Yes


Radiological assessments are required in patients with persistent and localized pain due to bone metastases to determine whetherthere are impending or actual pathological fractures. If a fracture of a long bone is likely or has occurred, an orthopaedicassessment is required as the treatment of choice may be surgical stabilization, which is generally followed by RT. In the absenceof a clear fracture risk, RT is the treatment of choice.


Neurological symptoms and signs which suggest the possibility of spinal cord compression must be investigated as a matter ofurgency. This requires a full radiological assessment of potentially affected area as well as adjacent areas of the spine. MRI is themethod of choice. An emergency surgical opinion (neurosurgical or orthopaedic) may be required for surgical decompression. Ifno decompression/stabilization is feasible, emergency radiotherapy is the treatment of choice and vertebroplasty is also anoption.


Patients with a single or small number of potentially resectable brain metastases should be treated with surgery or radiosurgery.Radiosurgery is an option for some unresectable brain metastases.


If surgery/radiosurgery is performed it may be followed by whole brain radiotherapy but this should be discussed in detail with thepatient, balancing the longer duration of intracranial disease control against the risk of neurocognitive effects.


Supportive and palliative careSupportive care allowing safer and more tolerable delivery of appropriate treatments should always be part of the treatment plan. I A 100% (26) Yes


Early introduction of expert palliative care, including effective control of pain and other symptoms, should be a priority. I A 100% (26) Yes0% (0) Abstain(26 voters)


Table 2 (continued )


Access to effective pain treatment (including morphine, which is inexpensive) is necessary for all patients in need of pain relief. I A 100% (27) Yes0% (0) Abstain(27 voters)

Optimally, discussions about patient preferences at the end of life should begin early in the course of metastatic disease. However,when active treatment no longer is able to control widespread and life-threatening disease, and the toxicities of remainingoptions outweigh benefits, physicians and other members of the healthcare team should initiate discussions with the patient (andfamily members/friends, if the patient agrees) about end-of-life care.

Expertopinion


Metastatic male breast cancerFor ER þMale MBC, which represents the majority of cases, ET is the preferred option, unless there is concern or proof of endocrine

resistance or rapidly progressive disease needing a fast response.Expertopinion


For ER þ Male MBC, tamoxifen is the preferred option. Expertopinion


*LoE changed since ABC1 from 2 C to 1 C based on new published data [128e130].


metastatic lesions [122]. A meta-analysis of 15 publications alsopublished in 2012 reinforced the idea that surgery of the primarytumour appeared to be an independent factor for improved survivalin the multivariate analyses from the individual studies, with an HRof 0.69 (p < 0.00001) [123].

Since 2011 several randomized trials have started accrualcomparing loco-regional treatment of primary vs. no treatment instage IV patients at presentation [124,125].

In 2013, very early data from 2 prospectively randomized trialspresented at San Antonio Breast Cancer Symposium could notconfirm the previous conclusions. In these two studies, only alimited subgroup of patients with solitary bone metastases seemedto profit from surgery, while patients with multiple visceral me-tastases showed a worse prognosis with initial surgery. However,these trials were small, had short follow-up time and included all-comers [126,127].

More studies and better patient selection are necessary toresolve this question, and several other prospective randomizedtrials are ongoing. Until these results are available, ABC2 retains theABC1 recommendation, which considers that surgery of the pri-mary should not be offered as a routine practice but can be dis-cussed on a case-by-case basis and offered to selected patients.

Conclusions

Advances in survival outcomes for ABC, particularly for MBC,have been frustratingly slow. MBC remains a virtually incurabledisease and LABC patients generally have a poor prognosis with ahigh risk of distant recurrence.

In the last few years, a deeper focus on this historicallyneglected patient population has occurred, with new and betterdesigned clinical trials, a dedicated conference and the develop-ment of international consensus guidelines. Patient surveys haveshown a slight improvement in patient satisfaction about theseveral steps of their care but emphasize that much remains to bedone. Implementation of guidelines is very heterogeneous betweencountries but also within countries, according to the environmentwhere the patient is treated and cost of treatment.

The complexity of this disease, the multiple factors that must betaken into account, the lack of high-level evidence for severalclinical situations, and new highly specialized techniques availablefor local management of specific sites of metastases, all constitutestrong reasons for the treatment of these patients by a specializedmultidisciplinary team, rather than management by an isolatedoncologist regardless of his/her skills or experience.

Our plea for a strong commitment of all involved parties(academia, pharmaceutical industry, independent funding sources,

advocacy groups) to develop well designed, high quality multidis-ciplinary (involving other issues than drug-development) trials forABC remains of critical importance. Many questions are stillunanswered, related to management strategies, optimal drug use,and individualized treatment (based on predictive markers andeventually new technologies aiming at better characterization ofthe individual tumour).

Research and education are the two pillars for advances inoncology today. Research is indispensible for improving the man-agement and outcome of patients with cancer, now and in thefuture. Education, including implementation of carefully developedhigh quality guidelines such as the current ABC InternationalConsensus Guidelines, allows the appropriate application of cur-rent knowledge to patient care, which will substantially improvethe long-term outcomes of current ABC patients worldwide.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.breast.2014.08.009.

References

[1] Cardoso F. Metastatic breast cancer patients: the forgotten heroes! Breast2009;18:271e2 [Editorial)].

[2] Largillier R, Ferrero J-M, Doyen J, Barriere J, Namer M, Mari V, et al. Prog-nostic factors in 1038 women with metastatic breast cancer. Ann Oncol2008;19:2012e9.

[3] Andre Fabrice, Slimane Khemaies, Bachelot Thomas, Dunant Arianne,Namer Moise, Barrelier Alain, et al. Breast cancer with synchronous metas-tases: trends in survival during a 14-year period. J Clin Oncol 2004;22:3302e8.

[4] Sundquist M, Eriksson Z, Tejler G, Brudin L. Trends in survival in metastaticbreast cancer [abstract 453] Eur J Cancer 2010;8(3):191.

[5] Foukakis Theodoros, Fornander Tommy, Lekberg Tobias, Hellborg Henrik,Adolfsson Jan, Bergh Jonas. Age-specific trends of survival in metastaticbreast cancer: 26 years longitudinal data from a population-based cancerregistry in Stockholm, Sweden. Breast Cancer Res Treat 2011. http://dx.doi.org/10.1007/s10549-011-1594-z.

[6] Fiteni F, Villanueva C, Bazan F, Perrin S, Chaigneau L, Dobi E, et al. Long-termfollow-up of patients with metastatic breast cancer treated by trastuzumab:impact of institutions. The Breast 2014;23(2):165e9.

[7] H�ebert-Croteau N, Brisson J, Latreille J, Rivard M, Abdelaziz N, Martin G.Compliance with consensus recommendations for systemic therapy isassociated with improved survival of women with node-negative breastcancer. J Clin Oncol 2004;22(18):3685e93.

[8] Griggs JJ, Culakova E, Sorbero ME, Poniewierski MS, Wolff DA, Crawford J,et al. Social and racial differences in selection of breast cancer adjuvantchemotherapy regimens. J Clin Oncol 2007;25(18):2522e7.

[9] Hassett MJ, Hughes ME, Niland JC, Ottesen R, Edge SB, Bookman MA, et al.Selecting high priority quality measures for breast cancer quality improve-ment. Med Care 2008;46(8):762e70.

[10] Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, et al. 1stinternational consensus guidelines for advanced breast cancer (ABC1). Breast2012;21(3):242e52.



http://refhub.elsevier.com/S0960-9776(14)00158-1/sref1














http://dx.doi.org/10.1007/s10549-011-1594-z

http://dx.doi.org/10.1007/s10549-011-1594-z

http://refhub.elsevier.com/S0960-9776(14)00158-1/sref1a























[11] Metastatic breast cancer: recommendations proposal from the Europeanschool of oncology (ESO)eMBC task force. Breast 2007;16:9e10.

[12] Cardoso F*, Bedard PL*, Winer EP, Pagani O, Senkus-Konefka E, Fallowfield LJ,et al., On Behalf of the ESO-MBC Task Force. *Co-first authors. Internationalguidelines for management of metastatic breast cancer: combination vssequential single-agent chemotherapy. J Natl Cancer Inst 2009;101:1174e81.

[13] Pagani* Olivia, Senkus-Konefka* El _zbieta, Wood William, Colleoni Marco,Cufer Tanja, Kyri-akides Stella, et al., OnBehalf of the ESO-MBCTask Force. *Co-first authors. International guidelines for management of metastatic breastcancer (MBC) from the European school of oncology (ESO)eMBC task force:can metastatic breast cancer be cured? J Natl Cancer Inst 2010;102:1e8.

[14] Lin* Nancy U, Thomssen* Christoph, Cardoso Fatima, Cameron David,Cufer Tanja, Fallowfield Lesley, et al., On Behalf of the ESO-MBC Task Force.International guidelines for management of metastatic breast cancer (MBC)from the European school of oncology (ESO)eMBC task force: surveillance,staging, and evaluation of patients with early-stage and metastatic breastcancer. Breast 2013;22(3):203e10.

[15] Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EM,Phillips B, et al. Grading strength of recommendations and quality of evi-dence in clinical guidelines: report from an american college of chest phy-sicians task force. Chest 2006;129(1):174e81.

[16] Freeman HP. Patient navigation: a community centered approach toreducing cancer mortality. J Cancer Educ 2006;21(Suppl. 1):S11e4.

[17] Freund KM, Battaglia TA, Calhoun E, Dudley DJ, Fiscella K, Paskett E, et al.National Cancer Institute Patient Navigation Research Program: methods,protocol, and measures. Cancer 2008;113(12):3391e9.

[18] Hopkins J, Mumber MD. Patient navigation through the cancer care contin-uum: an overview. J Oncol Pract 2009;5(4):150e1525.

[19] Robinson-White S, Conroy B, Slavish KH, Rosenzweig M. Patient navigationin breast cancer: a systematic review. Cancer Nurs 2010;33(2):127e40.

[20] Ko NY, Darnell JS, Calhoun E, Freund KM, Wells KJ, Shapiro CL, et al. Canpatient navigation improve receipt of recommended breast cancer care?evidence from the national patient navigation research program. J Clin Oncol2014 Jul 28. pii: JCO.2013.53.6037. [Epub ahead of print].

[21] Basch E. The missing voice of patients in drug-safety reporting. N Engl J MedMarch 11 2010;362:865e9. http://dx.doi.org/10.1056/NEJMp0911494.

[22] Biganzoli L, Wildiers H, Oakman C, Marottu L, Loibl S, reed M, et al. Man-agement of elderly patients with breast cancer: updated recommendationsof the International Society of Geriatric Oncology (SIOG) and European So-ciety of Breast Specialists (EUSOMA). Lancet Oncol 2012;13:e148e60.

[23] Cardoso Fatima, Loibl Sibylle, Pagani Olivia, Graziottin Alessandra,Panizza Pietro, Martincich Laura, et al. The EUSOMA recommendations forthe management of young women with breast cancer. Eur J Cancer2012;48(18):3355e77.

[24] *Co-first authors; #Co-last authors Partridge* Ann H, Pagani* Olivia,Abulkhair Omalkhair, Aebi Stefan, Amant Fr�ed�eric, Azim Jr Hatem A, et al.First international consensus guidelines for breast Cancer in young women(BCY1). Breast 2014. published online, http://dx.doi.org/10.1016/j.breast.2014.03.011.

[25] Zimmermann C, Swami N, Krzyzanowska M, Hannon B, Leighl N, Oza A, et al.Early palliative care for patients with advanced cancer: a cluster-randomisedcontrolled trial. Lancet 2014;383(9930):1721e30.

[26] Ganz PA, Yip CH, Gralow JR, Distelhorst SR, Albain KS, Andersen BL, et al.Supportive care after curative treatment for breast cancer (survivorship care):resource allocations in low- and middle-income countries. A Breast HealthGlobal Initiative 2013 consensus statement. Breast 2013;22(5):606e15.

[27] Cardoso F, Bese N, Distelhorst SR, Bevilacqua JL, Ginsburg O, Grunberg SM,et al. Supportive care during treatment for breast cancer: resource alloca-tions in low- and middle-income countries. A Breast Health Global Initiative2013 consensus statement. Breast 2013;22(5):593e605.

[28] Silverman R, Smith L, Sundar S. 'Is it my last christmas dinner?' survival ofcancer patients having palliative chemotherapy during christmas period.BMJ Support Palliat Care 2014 Mar;4(Suppl. 1):A56. http://dx.doi.org/10.1136/bmjspcare-2014-000654.159.

[29] El SaghirNS, AdebamowoCA, AndersonBO, CarlsonRW,BirdPA, CorbexM, et al.Breast cancer management in low resource countries (LRCs): consensus state-ment from the Breast Health Global Initiative. Breast 2011;20(Suppl. 2):S3e11.

[30] Macdonald SM, Harris EE, Arthur DW, Bailey L, Bellon JR, Carey L, et al. ACRappropriateness criteria® locally advanced breast cancer. Breast J2011;17(6):579e85.

[31] Chia S, Swain SM, Byrd DR, Mankoff DA. Locally advanced and inflammatorybreast cancer. J Clin Oncol 2008;26:786e90.

[32] Giordano SH. Update on locally advanced breast cancer. Oncologist 2003;8:521e30.

[33] Yamauchi H, Woodward WA, Valero V, Alvarez RH, Lucci A, Buchholz TA,et al. Inflammatory breast cancer: what we know and what we need to learn.Oncologist 2012;17(7):891e9.

[34] Brennan ME, Houssami N. Evaluation of the evidence on staging imaging fordetection of asymptomatic distant metastases in newly diagnosed breastcancer. Breast 2012;21:112e23.

[35] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Useof chemotherapy plus a monoclonal antibody against HER2 for metastaticbreast cancer that overexpresses HER2. N Engl J Med 2001 Mar 15;344(11):783e92.

[36] Buzdar AU, Suman V, Bernstam F. ACOSOG Z1041 (Alliance): definitiveanalysis of randomized neoadjuvant trial comparing FEC followed by pacli-taxel plus trastuzumab (FEC / PþT) with paclitaxel plus trastuzumab fol-lowed by FEC plus trastuzumab (PþT / FECþT) in HER2þ operable breastcancer. J Clin Oncol 2013;31. suppl; abstr 502.

[37] Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, et al. Randomized phase IIneoadjuvant comparison between letrozole, anastrozole, and exemestane forpostmenopausal women with estrogen receptor-rich stage 2 to 3 breastcancer: clinical and biomarker outcomes and predictive value of the baselinePAM50-based intrinsic subtypeeACOSOG Z1031. J Clin Oncol 2011;29(17):2342e9.

[38] Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, et al.Comparison of anastrozole versus tamoxifen as preoperative therapy inpostmenopausal women with hormone receptor-positive breast cancer: thePre-Operative “Arimidex” Compared to Tamoxifen (PROACT) trial. Cancer2006;106(10):2095e103.

[39] Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. BreastCancer Res Treat 2007;105(Suppl. 1):33e43.

[40] Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, et al. Neo-adjuvant treatment of postmenopausal breast cancer with anastrozole,tamoxifen, or both in combination: the Immediate Preoperative Anastrozole,Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blindrandomized trial. J Clin Oncol 2005;23(22):5108e16.

[41] Loibl S, Volz C, Mau C, Blohmer JU, Costa SD, Eidtmann H, et al. Response andprognosis after neoadjuvant chemotherapy in 1,051 patients with infiltratinglobular breast carcinoma. Breast Cancer Res Treat 2014;144(1):153e62.

[42] Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, et al.Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin forpremenopausal breast cancer (STAGE): a double-blind, randomised phase 3trial. Lancet Oncol 2012;13(4):345e52.

[43] Sinacki M, Badzio A, Wełnicka-Ja�skiewicz M, Bogaerts J, Piccart MJ,Therasse P, et al. Pattern of care in locally advanced breast cancer: focus onlocal therapy. Breast 2011 Apr;20(2):145e50.

[44] Dawood S, Merajver SD, Viens P, Vermeulen PB, Swain SM, Buchholz TA,et al. International expert panel on inflammatory breast cancer: consensusstatement for standardized diagnosis and treatment. Ann Oncol 2011;22(3):515e23.

[45] Cox C, Holloway CM, Shaheta A, Nofech-Mozes S, Wright FC. What is theburden of axillary disease after neoadjuvant therapy in women with locallyadvanced breast cancer? Curr Oncol 2013;20(2):111e7.

[46] Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al.Pathologic complete response rates in young women with BRCA1-positivebreast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010;28(3):375e9.

[47] Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, et al. Responseto neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer pa-tients. Breast Cancer Res Treat 2009;115(2):359e63.

[48] Byrski T, Foszczynska-Kloda M, Huzarski T, Dent R, Gronwald J, Cybulski C,et al. Cisplatin chemotherapy in the treatment of BRCA1-positive metastaticbreast cancer (MBC). J Clin Oncol 2009;27(15S). ASCO Annual Meeting Pro-ceedings (Post-Meeting Edition). (May 20 Supplement), 2009: 1099.

[49] Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatinand/or bevacizumab to neoadjuvant weekly paclitaxel followeed by dose-dense AC on pathologic complete response in triple-negative breast cancer(TNBC): CALGB 40603 (Alliance). Abstr. 2013 San Antonio breast Cancersymposium, S5eS01.

[50] von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al.Neoadjuvant carboplatin in patients with triple-negative and HER2-positiveearly breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. LancetOncol 2014;15(7):747e56.

[51] Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, et al. Thevalue of platinum agents as neoadjuvant chemotherapy in triple-negativebreast cancers: a systematic review and meta-analysis. Breast Cancer ResTreat 2014;144(2):223e32.

[52] Alba E, Chacon J, Lluch A, Anton A, Estevez L, Cirauqui B, et al. A randomizedphase II trial of platinum salts in basal-like breast cancer patients in theneoadjuvant setting. Results from the GEICAM/2006-03, multicenter study.Breast Cancer Res Treat 2012;136(2):487e93.

[53] Koshy N, Quispe D, Shi R, Mansour R, Burton GV. Cisplatin-gemcitabinetherapy in metastatic breast cancer: improved outcome in triple negativebreast cancer patients compared to non-triple negative patients. Breast 2010Jun;19(3):246e8.

[54] Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC. Plasma pre-cursors of oestrogen. II. Correlation of the extent of conversion of plasmaandrostenedione to estrone with age. J Clin Endocrinol Metab 1974;38:476e9.

[55] Handesman D. Androgen actions and pharmacologic uses, Endocrinology.Philadelphia: WB Saunders; 2001. p. 2232e42.

[56] Sousa B, Moser E, Cardoso F. An update on male breast cancer and futuredirections for research and treatment. Eur J Pharmacol 2013;717:71e83.

[57] Nordman IC, Dalley DN. Breast cancer in mendshould aromatase inhibitorsbecome first-line hormonal treatment? Breast J 2008;4:562e9.

[58] Faneyte IF, Turgers EJ, Zoetmulder FA. Chest wall resection in the treatmentof locally recurrent breast carcinoma: indications and outcome for 44 pa-tients. Cancer 1997;80(5):886.



































http://refhub.elsevier.com/S0960-9776(14)00158-1/sref2s














http://dx.doi.org/10.1056/NEJMp0911494













http://refhub.elsevier.com/S0960-9776(14)00158-1/sref3d














http://dx.doi.org/10.1136/bmjspcare-2014-000654.159

http://dx.doi.org/10.1136/bmjspcare-2014-000654.159





http://refhub.elsevier.com/S0960-9776(14)00158-1/sref4g











http://refhub.elsevier.com/S0960-9776(14)00158-1/sref5h
























http://refhub.elsevier.com/S0960-9776(14)00158-1/sref6j








http://refhub.elsevier.com/S0960-9776(14)00158-1/sref7y









http://refhub.elsevier.com/S0960-9776(14)00158-1/sref8w






http://refhub.elsevier.com/S0960-9776(14)00158-1/sref9e




http://refhub.elsevier.com/S0960-9776(14)00158-1/sref10t





































http://refhub.elsevier.com/S0960-9776(14)00158-1/sref18u


































[59] Schwaibold F, Fowble BL, Solin LJ, Schultz DJ, Goodman RL. The results ofradiation therapy for isolated local regional recurrence after mastectomy. IntJ Radiat Oncol Biol Phys 1991;21(2):299e310.

[60] Skinner HD, Strom EA, Motwani SB, Woodward WA, Green MC, Babiera G,et al. Radiation dose escalation for loco-regional recurrence of breast cancerafter mastectomy. Radiat Oncol 2013;8:13.

[61] Müller AC, Eckert F, Heinrich V, Bamberg M, Brucker S, Hehr T. Re-surgeryand chest wall re-irradiation for recurrent breast cancer: a second curativeapproach. BMC Cancer 2011;11:197.

[62] Kilburn JM, Kuremsky JG, Blackstock AW, Munley MT, Kearns WT,Hinson WH, et al. Thoracic re-irradiation using stereotactic body radio-therapy (SBRT) techniques as first or second course of treatment. RadiotherOncol 2014;110(3):505e10.

[63] Seiwer TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm-general principles. Nat Clin Pract 2007;4(2):86.

[64] Wilson GD, Bentzen SM, Harari PM. Biologic basis for combining drugs withradiation. Semin Radiat Oncol 2006;16(1):2e9.

[65] Lawrence TS, Tepper JE, Blackstock AW. Fluoropyrimidine-Radiation In-teractions in Cells and Tumors. Semin Radiat Oncol 1997;7(4):260e6.

[66] Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H. X-ray irradiationinduces thymidine phosphorylase and enhances the efficacy of capecitabine(Xeloda) in human cancer xenografts. Clin Cancer Res 1999;5(10):2948e53.

[67] Crane CH, Abbruzzese JL, Evans DB, Wolff RA, Ballo MT, Delclos M, et al. Is thetherapeutic index better with gemcitabine-based chemoradiation than with5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?Int J Radiat Oncol Biol Phys 2002;52(5):1293e302.

[68] Liebmann J, Cook JA, Fisher J, Teague D, Mitchell JB. In vitro studies of Taxolas a radiation sensitizer in human tumor cells. J Natl Cancer Inst 1994;86(6):441e6.

[69] Gonz�alez JE, Barquinero JF, Lee M, García O, Casaco A. Radiosensitizationinduced by the anti-epidermal growth factor receptor monoclonal anti-bodies cetuximab and nimotuzumab in A431 cells. Cancer Biol Ther2012;13(2):71e6.

[70] Horton JK, Halle J, Ferraro M, Carey L, Moore DT, Ollila D, et al. Radio-sensitization of chemotherapy-refractory, locally advanced or locally recur-rent breast cancer with trastuzumab: a phase II trial. Int J Radiat Oncol BiolPhys 2010;76(4):998e1004.

[71] L€oser DA, Shibata A, Shibata AK, Woodbine LJ, Jeggo PA, Chalmers AJ.Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand breakrepair. Mol Cancer Ther 2010;9(6):1775e87.

[72] Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, et al.Randomized trial of hyperthermia and radiation for superficial tumors. J ClinOncol 2005;23:3079e85.

[73] Vernon CC, Hand JW, Field SB, Machin D, Whaley JB, van der Zee J, et al.Radiotherapy with or without hyperthermia in the treatment of superficiallocalized breast cancer: results from five randomized controlled trials. Int JRadiat Oncol Biol Phys 1996;35:731e44.

[74] Zagar TM, Higgins KA, Miles EF, Vujaskovic Z, Dewhirst MW, Clough RW,et al. Durable palliation of breast cancer chest wall recurrence with radiationtherapy, hyperthermia, and chemotherapy. Radiother Oncol 2010;97:535e40.

[75] Borner M, Bacchi M, Goldhirsch A, Greiner R, Harder F, Castiglione M, et al.First isolated locoregional recurrence following mastectomy for breast can-cer: results of a phase III multicenter study comparing systemic treatmentwith observation after excision and radiation. Swiss Group for Clinical CancerResearch. J Clin Oncol 1994;12(10):2071e7.

[76] Aebi S, Gelber S, Anderson SJ, L�ang I, Robidoux A, Martín M. Chemotherapyfor isolated locoregional recurrence of breast cancer (CALOR): a randomisedtrial. Lancet Oncol 2014;15(2):156e63.

[77] Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, et al. Ful-vestrant versus anastrozole for the treatment of advanced breast carcinomain postmenopausal women: a prospective combined analysis of two multi-center trials. Cancer 2003 Jul 15;98(2):229e38.

[78] Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, et al. Ful-vestrant versus anastrozole for the treatment of advanced breast carcinoma:a prospectively planned combined survival analysis of two multicenter trials.Cancer 2005 Jul 15;104(2):236e9.

[79] Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al.Double-blind, randomized placebo controlled trial of fulvestrantcompared with exemestane after prior nonsteroidal aromatase inhibitortherapy in postmenopausal women with hormone receptor-positive,advanced breast cancer: results from EFECT. J Clin Oncol 2008;26(10):1664e70.

[80] Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R,et al. Results of the confirm phase III trial comparing fulvestrant 250 mgwith fulvestrant 500 mg in postmenopausal women with estrogenreceptor-positive advanced breast cancer. J Clin Oncol 2010;28(30):4594e600.

[81] Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, ,et alSoFEA Investigators. Fulvestrant plus anastrozole or placebo versusexemestane alone after progression on non-steroidal aromatase inhibitors inpostmenopausal patients with hormone-receptor-positive locally advancedor metastatic breast cancer (SoFEA): a composite, multicentre, phase 3randomised trial. Lancet Oncol 2013;14(10):989e98.

[82] Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for treatmentof advanced breast cancer in postmenopausal women. Cochrane DatabaseSyst Rev 2009;(4):CD003370.

[83] Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L,Koralewski P, et al. Anastrozole versus tamoxifen as first-line therapy foradvanced breast cancer in 668 postmenopausal women: results of theTamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. JClin Oncol 2000;18(22):3748e57.

[84] Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, et al.Anastrozole is superior to tamoxifen as first-line therapy for advanced breastcancer in postmenopausal women: results of a North American multicenterrandomized trial. Arimidex Study Group. J Clin Oncol 2000;18(22):3758e67.

[85] Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, et al. Anastrozoleversus tamoxifen as first-line therapy in postmenopausal patients withhormone-dependent advanced breast cancer: a prospective, randomized,phase III study. Am J Clin Oncol 2003;26(3):317e22.

[86] Paridaens R, Dirix L, Lohrisch C, et al. European Organization for the Researchand Treatment of Cancer (EORTC)- Investigational Drug Branch for BreastCancer (IDBBC). Mature results of a randomized phase II multicenter study ofexemestane versus tamoxifen as first-line hormone therapy for post-menopausal women with metastatic breast cancer. Ann Oncol 2003;14:1391e8.

[87] Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A,et al. Phase III study of letrozole versus tamoxifen as first-line therapy ofadvanced breast cancer in postmenopausal women: analysis of survival andupdate of efficacy from the International Letrozole Breast Cancer Group. JClin Oncol 2003;21(11):2101e9.

[88] Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, et al. Phase IIIstudy comparing exemestane with tamoxifen as first-line hormonal treat-ment of metastatic breast cancer in postmenopausal women: the EuropeanOrganisation for Research and Treatment of Cancer Breast Cancer Coopera-tive Group. J Clin Oncol 2008;26(30):4883e90.

[89] Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, et al.Everolimus in postmenopausal hormone-receptor-positive advanced breastcancer. N Engl J Med 2012;366(6):520e9.

[90] Yardley DA, Noguchi S, Pritchard KI, Burris 3rd HA, Baselga J, Gnant M, et al.Everolimus plus exemestane in postmenopausal patients with HR(+) breastcancer: BOLERO-2 final progression-free survival analysis. Adv Ther2013;30(10):870e84.

[91] Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Noguchi S, Rugo H, et al.Overall Survival Results From BOLERO-2. In: Presented at EBCC-9; 2014.Everolimus Plus Exemestane for Hormone Receptor-Positive (HR+), HumanEpidermal Growth Factor Receptor-2eNegative (HER2e) Advanced BreastCancer (BC) Abstract 1 LBA.

[92] Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G,et al. Randomized phase II trial of everolimus in combination withtamoxifen in patients with hormone receptor-positive, human epidermalgrowth factor receptor 2-negative metastatic breast cancer with priorexposure to aromatase inhibitors: a GINECO study. J Clin Oncol2012;30(22):2718e24.

[93] Gelmon KA, Boyle F, Kaufman B, Huntsman D, Manikhas A, Di Leo A, et al.Open-label phase III randomized controlled trial comparing taxane-basedchemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line ther-apy for women with HER2+ metastatic breast cancer: Interim analysis (IA) ofNCIC CTG MA.31/GSK EGF 108919. J Clin Oncol 2012;30 [suppl; abstrLBA671].

[94] Pivot X, _Zurawski B, Allerton R, Fabi A, Ciruelos E, Parikh R, et al. CEREBEL(EGF111438): an open label randomized phase III study comparing theincidence of CNS metastases in patients (pts) with HER2+ metastatic breastcancer (MBC), treated with lapatinib plus capecitabine (LC) versus trastu-zumab plus capecitabine (TC); LBA11. Ann Oncol 2012;23:ixe1e30.

[95] Piccart-Gebhart MJ, Holmes AP, Baselga J, De Azambuja E, Dueck AC, Viale G,et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance]N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L),trastuzumab alone (T), their sequence (T/L), or their combination (T+L) inthe adjuvant treatment of HER2-positive early breast cancer (EBC). J ClinOncol 2014;32(5s). abstr LBA4.

[96] Baselga J, Cort�es J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plustrastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med2012;366(2):109e19.

[97] Swain SM, Kim SB, Cort�es J, Ro J, Semiglazov V, Campone M, et al. Pertu-zumab, trastuzumab, and docetaxel for HER2-positive metastatic breastcancer (CLEOPATRA study): overall survival results from a randomised,double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14(6):461e71.

[98] Cort�es J, Fumoleau P, Bianchi GV, Petrella TM, Gelmon K, Pivot X, et al.Pertuzumab monotherapy after trastuzumab-based treatment and subse-quent reintroduction of trastuzumab: activity and tolerability in patientswith advanced human epidermal growth factor receptor 2-positive breastcancer. J Clin Oncol 2012 May 10;30(14):1594e600.

[99] Blackwell KL, Miles D, Gianni L, Krop IE, Welslaw M, Baselga J, et al. Primaryresults from EMILIA, a phase III study of trastuzumab emtansine (T-DM1)versus capecitabine (X) and lapatinib (L) in HER2-positive locally advancedor metastatic breast cancer (MBC) previously treated with trastuzumab (T)and a taxane. J Clin Oncol 2012;30(5s). suppl; abstr LBA1.

http://refhub.elsevier.com/S0960-9776(14)00158-1/sref19p




http://refhub.elsevier.com/S0960-9776(14)00158-1/sref20z













http://refhub.elsevier.com/S0960-9776(14)00158-1/sref21c



http://refhub.elsevier.com/S0960-9776(14)00158-1/sref22b







http://refhub.elsevier.com/S0960-9776(14)00158-1/sref24q


























































































http://refhub.elsevier.com/S0960-9776(14)00158-1/sref31i





http://refhub.elsevier.com/S0960-9776(14)00158-1/sref32k






















































































http://refhub.elsevier.com/S0960-9776(14)00158-1/sref44o






[100] Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumabemtansine for HER2-positive advanced breast cancer. N Engl J Med2012;367(19):1783e91.

[101] Krop IE, Kim SB, Gonz�alez-Martín A, LoRusso PM, Ferrero JM, Smitt M, et al.Trastuzumab emtansine versus treatment of physician's choice for pre-treated HER2-positive advanced breast cancer (TH3RESA): a randomised,open-label, phase 3 trial. Lancet Oncol 2014;15(7):689e99.

[102] Dear RF, McGeechan K, Jenkins MC, Barratt A, Tattersall MHN, Wilcken N.Combination versus sequential single agent chemotherapy for metastaticbreast cancer. Cochrane Database Syst Rev 2013;(12). http://dx.doi.org/10.1002/14651858.CD008792.pub2. Art. No.: CD008792.

[103] Piccart-Gebhart MJ, Burzykowski T, Buyse M, Sledge G, Carmichael J, Lück HJ,et al. Taxanes alone or in combination with anthracyclines as first-linetherapy of patients with metastatic breast cancer. J Clin Oncol 2008 Apr20;26(12):1980e6.

[104] Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, et al.Capecitabine versus classical cyclophosphamide, methotrexate, and fluoro-uracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol2011;29(34):4498e504.

[105] Blum JL, Barrios CH, Feldman N, Verma S, McKenna Lee LF, et al. Pooledanalysis of individual patient data from capecitabine monotherapy clinicaltrials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat2012;136(3):777e88.

[106] Robert NJ, Di�eras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al.RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial ofchemotherapy with or without bevacizumab for first-line treatment of hu-man epidermal growth factor receptor 2-negative, locally recurrent ormetastatic breast cancer. J Clin Oncol 2011;29(10):1252e60.

[107] Oshaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, et al.Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. areference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. AnnOncol 2001;12(9):1247e54.

[108] Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, et al. RIBBON-2:a randomized, double-blind, placebo-controlled, phase III trial evaluating theefficacy and safety of bevacizumab in combination with chemotherapy forsecond-line treatment of human epidermal growth factor receptor 2-nega-tive metastatic breast cancer. J Clin Oncol 2011;29(32):4286e93.

[109] Talbot DC, Moiseyenko V, Van Belle S, O'Reilly SM, Alba Conejo E, Ackland S,et al. Randomised, phase II trial comparing oral capecitabine (Xeloda) withpaclitaxel in patients with metastatic/advanced breast cancer pretreatedwith anthracyclines. Br J Cancer 2002;86(9):1367e72.

[110] Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, et al. Multicenterphase II study of capecitabine in paclitaxel-refractory metastatic breastcancer. J Clin Oncol 1999;17(2):485e93.

[111] Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, et al. Multi-center, Phase II study of capecitabine in taxane-pretreated metastatic breastcarcinoma patients. Cancer 2001;92(7):1759e68.

[112] Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L,et al. Randomized phase III trial of capecitabine compared with bevacizumabplus capecitabine in patients with previously treated metastatic breastcancer. J Clin Oncol 2005;23(4):792e9.

[113] Andersson Michael, Lidbrink Elisabeth, Bjerre Karsten, Wist Erik,Enevoldsen Kristin, Jensen Anders B, et al. Phase III randomized studycomparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab asfirst-line therapy of metastatic or locally advanced human epidermal growthfactor receptor 2ePositive breast Cancer: the HERNATA study. J Clin Oncol2010;29:264e71.

[114] Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK,et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbineor taxane study. Cancer 2007 Sep 1;110(5):965e72.

[115] Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al.Eribulin monotherapy versus treatment of physician's choice in patientswith metastatic breast cancer (EMBRACE): a phase 3 open-label randomisedstudy. Lancet 2011 Mar 12;377(9769):914e23.

[116] Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Wanders J, et al. A phaseIII, open-label, randomized, multicenter study of eribulin mesylate versuscapecitabine in patients with locally advanced or metastatic breast cancerpreviously treated with anthracyclines and taxanes. Cancer Res2012;72(Suppl. 24). Abstract nr S6e6.

[117] Dominici L, Najita J, Hughes M, Niland J, Marcom P, Wong YN, et al. Surgeryof the primary tumor does not improve survival in stage IV breast cancer.Breast Cancer Res Treat 2011;129(2):459e65.

[118] Ly BH, Nguyen NP, Vinh-Hung V, Rapiti E, Vlastos G. Loco-regional treatmentin metastatic breast cancer patients: is there a survival benefit? BreastCancer Res Treat 2010;119(3):537e45.

[119] Neuman HB, Morrogh M, Gonen M, Van Zee KJ, Morrow M, King TA. Stage IVbreast cancer in the era of targeted therapy: does surgery of the primarytumor matter? Cancer 2010;116(5):1226e33.

[120] Rashaan ZM, Bastiaannet E, Portielje JE, van de Water W, van der Velde S,Ernst MF, et al. Surgery in metastatic breast cancer: patients with a favorableprofile seem to have the most benefit from surgery. Eur J Surg Oncol2012;38(1):52e6.

[121] Ruiterkamp J, Ernst MF. The role of surgery in metastatic breast cancer. Eur JCancer 2011;47(Suppl. 3):S6e22.

[122] Nguyen DH, Truong PT, Alexander C, Walter CV, Hayashi E, Christie J, et al.Can locoregional treatment of the primary tumor improve outcomes forwomen with stage IV breast cancer at diagnosis? Int J Radiat Oncol Biol Phys2012;84(1):39e45.

[123] Petrelli F, Barni S. Surgery of primary tumors in stage IV breast cancer: anupdated meta-analysis of published studies with meta-regression. MedOncol 2012;29:3282e90.

[124] Ruiterkamp J, Voogd AC, Tjan-Heijnen VC, Bosscha K, van der Linden YM,Rutgers EJ, et al. SUBMIT: Systemic therapy with or without up front surgeryof the primary tumor in breast cancer patients with distant metastases atinitial presentation. BMC Surg 2012 Apr 2;12:5.

[125] Shien T, Nakamura K, Shibata T, Kinoshita T, Aogi K, Fujisawa T, et al. Arandomized controlled trial comparing primary tumour resection plus sys-temic therapy with systemic therapy alone in metastatic breast cancer(PRIM-BC): Japan Clinical Oncology Group Study JCOG1017. Jpn J Clin Oncol2012;42(10):970e3.

[126] Badwe R, Parmar V, Hawaldar R, Nair N, Kaushik R, Siddique S, et al. Surgicalremoval of primary tumor and axillary lymph nodes in women with meta-static breast cancer at first presentation: a randomized controlled trial.Cancer Res 2013;73(Suppl. 24). S2eS02.

[127] Soran Atilla, Ozmen Vahit, Ozbas Serdar, Karanlık Hasan,Muslumanoglu Mahmut, Igci Abdullah, et al. Early follow up of a randomizedtrial evaluating resection of the primary breast tumor in women presentingwith de novo stage IV breast cancer: Turkish Study (Protocol MF07e01).Cancer Res 2013;73(Suppl. 24). S2-02.

[128] Thompson AM, Jordan LB, Quinlan P, Anderson E, Skene A, Dewar JA, et al.Prospective comparison of switches in biomarker status between primaryand recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS).Breast Cancer Res 2010;12(6):R92.

[129] Amir E, Clemons M, Purdie CA, Miller N, Quinlan P, Geddie W, et al. Tissueconfirmation of disease recurrence in breast cancer patients: pooled analysisof multi-centre, multi-disciplinary prospective studies. Cancer Treat Rev2012;38(6):708e14.

[130] Foukakis T, Åstr€om G, Lindstr€om L, Hatschek T, Bergh J. When to order abiopsy to characterise a metastatic relapse in breast cancer. Ann Oncol2012;23(Suppl. 10):x349e53.











http://dx.doi.org/10.1002/14651858.CD008792.pub2

http://dx.doi.org/10.1002/14651858.CD008792.pub2





























http://refhub.elsevier.com/S0960-9776(14)00158-1/sref50r




































































http://refhub.elsevier.com/S0960-9776(14)00158-1/sref59v














































eso-esmo 2nd international consensus guidelines for ... · eso-esmo 2nd international consensus...

Documents