Sunteți pe pagina 1din 14

The Breast 23 (2014) 489e502

Contents lists available at ScienceDirect

The Breast
journal homepage: www.elsevier.com/brst

ESO-ESMO 2nd international consensus guidelines for advanced


breast cancer (ABC2)*
F. Cardoso a, *, A. Costa b, c, L. Norton d, E. Senkus e, M. Aapro f, F. Andre  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. Falloweld 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. Nordstro m 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. vant 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, Portugal
b
European School of Oncology, Milan, Italy
c
European School of Oncology, Bellinzona, Switzerland
d
Breast Cancer Program, Memorial Sloan-Kettering Cancer Centre, New York, USA
e
Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland
f
Division of Oncology, Institut Multidisciplinaire d'Oncologie, Genolier, Switzerland
g
Department of Medical Oncology, Gustave-Roussy Institute, Villejuif, France
h
Department of Medicine, PUCRS School of Medicine, Porto Alegre, Brazil
i
Department of Oncology/Radiumhemmet, Karolinska Institutet & Cancer Center Karolinska and Karolinska University Hospital, Stockholm, Sweden
j
Department of Medical Oncology, Sandro Pitigliani Oncology Centre, Prato, Italy
k
Breast Cancer Clinical Program, Duke Cancer Institute, Durham, USA
l
Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal
m
University Clinic Golnik, Medical Faculty Ljubljana, Ljubljana, Slovenia
n
NK Basile Cancer Institute Breast Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon
o
Brighton & Sussex Medical School, University of Sussex, Falmer, UK
p
Breast Care Support Group, Europa Donna Malta, Mtarfa, Malta
q
Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
r
BC Cancer Agency, Vancouver, Canada
s
Departments of Health Services Research and Breast Medical Oncology, UT MD Anderson Cancer Center, Houston, USA
t
APHP Tenon, IUC-UPMC, Francilian Breast Intergroup, Arome, Paris, France
u
Program of Breast Health, European Institute of Oncology, Milan, Italy
v
Brustzentrum der Universita t Mnchen, Munich, DE, USA
w
Screening and Test Evaluation Program, School of Public Health, Sydney Medical School, University of Sydney, Sydney, Australia
x
Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, USA
y
Sheba Medical Center, Tel Hashomer, Israel
z
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
aa
Europa Donna Cyprus, Nicosa, Cyprus
ab
Advanced BC.org, New York, USA
ac
University of Michigan Medical School and School of Public Health, Ann Arbor, USA
ad
Europa Donna Sweden & Bro stcancerfo
reningarnas Riksorganisation, BRO, Sundbyberg, Sweden
ae
Oncology Institute of Southern Switzerland and Breast Unit of Southern Switzerland, Bellinzona, Switzerland
af
Department Medical Oncology, Division of Women's Cancers, Dana-Farber Cancer Institute, Boston, USA
ag
Jean Perrin Centre, Comprehensive Cancer Centre, Clermont Ferrand, France
ah
Department of Medicine, Institut Jules Bordet, Brussels, Belgium
ai
Department of Medicine, Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA
aj
Indiana University Medical CTR, Indianapolis, USA
ak
Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle an der Saale, DE, Germany
al
Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA
am
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 Braslia, s/n, 1400-048 Lisbon, Portugal. Tel.: 351 (210) 480 002; fax: 351 (210) 480
298.
E-mail address: fatimacardoso@fundacaochampalimaud.pt (F. Cardoso).

http://dx.doi.org/10.1016/j.breast.2014.08.009
0960-9776/ 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/).
490 F. Cardoso et al. / The Breast 23 (2014) 489e502

an
Department of Radiotherapy, Clinique des Grangettes, Geneva, Switzerland
ao
Nursing Division, Health Board, Cardiff and Vale University, Cardiff, UK
ap
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: November 7e9, 2013. The conference brought together about 1100
Received 5 August 2014 participants from 71 countries, including health professionals, pa-
Available online 20 September 2014 tient advocates and journalists. A series of guidelines were dis-
cussed and agreed upon, based on the most up-to-date evidence
and can be used to guide treatment decision-making in diverse
health care settings globally. These guidelines are developed as a
joint effort from ESO and ESMO (European Society of Medical
Oncology), are endorsed by EUSOMA (European Society of Breast
Introduction
Cancer Specialists), SIS (Senologic International Society) and Flam
(Federacion Latino Americana de Mastologia), and organized under
Advanced Breast Cancer (ABC) is a treatable but still generally
the auspices of UICC (Union Internationale Contre Le Cancer), OECI
incurable disease. The goals of care are to optimize both length and
(Organization of European Cancer Institutes) and the BCRF (Breast
quality of life. Due to continuous research, several advances have
Cancer Research Foundation).
been made, particularly for the HER-2-positive and for Luminal-like
The present manuscript summarizes the guidelines developed
subtypes. Notwithstanding these advances, median overall survival
at ABC2. The guidelines include the level of evidence, the per-
of patients with ABC is still only 2e3 years, although the range is
centage of panel members who agreed with the consensus state-
wide [1e5], and survival may be longer for patients treated in
ments, and the supporting references for each recommendation.
specialized institutions [6]. Implementation of current knowledge
Importantly, the ABC guidelines are developed as clinical man-
is highly variable among countries and within each country.
agement recommendations potentially applicable worldwide,
The use of treatment guidelines has been associated with a
albeit with the necessary adjustments for each country, depending
signicant improvement in survival [7e9]. This has been achieved
on access to therapies. The guidelines are based on the underlying
mainly in early breast cancer. For ABC, and particularly metastatic
principles of modern oncology, emphasizing the crucial role of a
breast cancer (MBC), less level 1 evidence exists and only recently
multidisciplinary and individualized approach that respects the
have international consensus guidelines been developed (ABC1 e
specicities of the advanced setting and the preferences of each
[10]. The ABC Consensus Conference was created by the European
patient. The manuscript also clearly highlights areas where
School of Oncology (ESO) with the ambitious goal of improving
research efforts are urgently needed.
outcomes for all patients with advanced breast cancer. Backed by
strong political advocacy, ABC guidelines are seeking to improve
standards of care, to raise awareness about how to best meet to the Methodology
needs of this underserved group of patients, and to identify
research priorities so that clinical research is focused on the most Prior to the ABC2 Conference, a set of preliminary recommen-
important areas of unmet need. dation statements on the treatment of ABC were prepared, based
Following the work of the ESO-ABC Task Force [11e14], created on available published data and following the ESMO guidelines
in 2005, and the successful undertaking of the 1st International methodology. These recommendations were circulated to all 43
Consensus Guidelines Conference on ABC (ABC1), held in panel members by email for comments and corrections on content
November 2011, the 2nd International Consensus Conference for and wording. A nal set of recommendations was presented, dis-
Advanced Breast Cancer (ABC2) took place in Lisbon, Portugal, on cussed and voted upon during the consensus session of ABC2. All

Table 1
Levels of evidence grading system [15].

Grade of recommendation/ Benet vs. risk and burdens Methodological quality of supporting evidence Implications
description

1 A/Strong recommendation, Benets clearly outweigh risk RCTs without important limitations or Strong recommendation, can apply to
high quality evidence and burdens, or vice versa overwhelming evidence from observational most patients in most circumstances
studies without reservation
1 B/Strong recommendation, Benets clearly outweigh risk RCTs with important limitations (inconsistent Strong recommendation, can apply to
moderate quality evidence and burdens, or vice versa results, methodological aws, indirect, or most patients in most circumstances
imprecise) or exceptionally strong evidence without reservation
from observational studies
1 C/Strong recommendation, Benets clearly outweigh risk Observational studies or case series Strong recommendation, but may
low quality evidence and burdens, or vice versa change when higher quality evidence
becomes available
2A/Weak recommendation, Benets closely balanced with RCTs without important limitations or Weak recommendation, best action
high quality evidence risks and burden overwhelming evidence from observational may differ depending on circumstances
studies or patients' or societal values
2 B/Weak recommendation, Benets closely balanced with RCTs with important limitations (inconsistent Weak recommendation, best action
moderate quality evidence risks and burden results, methodological aws, indirect, or may differ depending on circumstances
imprecise) or exceptionally strong evidence or patients' or societal values
from observational studies
2 C/Weak recommendation, Benets closely balanced with Observational studies or case series Very weak recommendation, other
low quality evidence risks and burden alternatives may be equally reasonable
F. Cardoso et al. / The Breast 23 (2014) 489e502 491

panel members were instructed to vote on all questions, with nurse, who should be part of the multidisciplinary team managing
members with a potential conict of interest or who did not feel ABC patients. In some countries however, this role may be played
comfortable answering the question (e.g. because it is not their area by a physician assistant or another trained and specialized health
of expertise) instructed to abstain from voting. Additional care practitioner. It is also recognized that in many centres it is not
changes in the wording of statements were made during the ses- yet possible for each patient to have a navigator due to lack of
sion. The statement on Everolimus was updated after the presen- human resources.
tation of the overall survival results of the BOLERO-2 trial and re- There is an implicit assumption that the recording of adverse
voted by email by all panel members. events by clinicians reliably documents patients' side effects and
Supplementary Table 1 lists all members of the ABC2 consensus symptoms. However, there is an accumulating body of evidence
panel and their disclosure of any relationships that could be suggesting that the frequency and severity of many symptoms that
perceived as a potential conict of interest. impact upon an individual patient's quality of life go under-reported,
Table 1 describes the grading system used [15]. under-recognised and consequently under-treated [21]. Since qual-
Three main issues were discussed at ABC2: inoperable locally ity of life is one of the main aims of ABC treatment, this poses an
advanced breast cancer (LABC) both inammatory and nonin- important problem. It is also potentially dangerous from a drug
ammatory; MBC; and specic denitions for which a consensus safety point of view. The inability of traditional methods for
was deemed important. capturing adverse events has led to renewed interest in incorpo-
For clarication, ABC comprises both inoperable LABC and MBC rating Patient Reported Outcomes (PROs/PROMs) with Common
or stage IV. Some of the ABC guidelines apply to both LABC and Terminology Criteria for Adverse Events (CTC-AEs) in clinical trials,
MBC, while others are specic to each of the settings. as well as utilising PROs outside a clinical trial setting to reect and
monitor more accurately the harms and benets of patient experi-
General guidelines ence. This may be particularly important for drugs approved based
solely on progression-free survival (PFS) benets or only modest
overall survival (OS) benets, for which the balance between efcacy
Guideline statement LoE Consensus
and toxicity may be more difcult to accurately determine. Many
All ABC patients should be offered IB 97.2% (36) Yes standardised, well-validated instruments or PRO measures are
comprehensive, culturally sensitive, up-to- 0% (0) Abstain available with translations into most languages. The most frequently
date and easy to understand information (37 voters)
about their disease and its management.
used are the generic EORTC-QLQ-C3 (http://groups.eortc.be/qol/
Specialized oncology nurses (if possible Expert 92.1% (35) Yes eortc-qlq-c30) and the FACT (http://www.facit.org/FACITOrg/
specialized breast nurses) should be part of opinion 7.8% (3) Abstain Questionnaires). Both have breast cancer specic modules/sub-
the multidisciplinary team managing ABC (38 voters) scales (EORTC QLQ-BR23 and FACT-B) and the FACT in particular has
pts. In some countries, this role may be
several other specic subscales covering, for example, treatment
played by a physician assistant or other
trained and specialized health care with EGFR inhibitors, taxanes, anti-angiogenesis drugs, endocrine
practitioner. agents and monoclonal antibodies. Recently the FDA and EMA have
Strong consideration should be given to the use IC 89.4% (34) Yes published guidance for industry on how to utilise PROs in applica-
of validated instruments for patients to 5.2% (2) Abstain tions for drug labelling claims. There has also been an important
report the symptoms of disease and side (38 voters)
effects of treatment they experience as a
initiative, funded by the NCI, to produce a Patient-Reported Out-
regular part of their clinical care. These PRO comes version of the Common Terminology Criteria for Adverse
(patient-reported outcomes) instruments Events (PRO-CTCAE), which is suggested for use in NCI sponsored
should be simple and user-friendly to trials (http://outcomes.cancer.gov/tools/pro-ctcae.html).
facilitate their use in clinical practice. This
Although age is an important factor to consider in decision-
systematic monitoring will serve to facilitate
communication between patients and their making for ABC, it must not be the sole factor to determine the in-
treatment teams, allow optimal quality of tensity and type of treatment. There is a tendency to withhold
life, and may better characterize the therapy in some elderly patients because of fear of toxicity or
toxicities of all anticancer therapies. concern about co-morbidity. In some cases, however, such therapies
The age of the patient should not be the sole IB 100% (38) Yes
may be highly effective and could improve both survival and quality
reason to withhold effective therapy (in 0% (0) Abstain
elderly patients) nor to overtreat (in young (38 voters) of life. At the same time, younger patients are often overtreated or
patients). Age alone should not determine treated somewhat inappropriately. Age may inuence breast cancer
the type and intensity of treatment. treatment, but it should not be the guiding force [10,22e24].
LoE: Available level of evidence; Consensus: Percentage of panel members in
agreement with the statement. Survivorship in ABC

The complex needs of patients living with ABC, at times for


ABC1 Guidelines had already emphasised the importance of many years, as well as their caregivers, should be addressed not
including the patient in all steps of the decision-making process only in terms of supportive and palliative care but also regarding
[10]. For active and informed participation, patients must have survivorship concerns. The multidisciplinary approach of ABC
access to comprehensive, culturally sensitive, up-to-date and easy should encompass early in the history of the disease not only
to understand information about their disease and its physical but also functional, social, psychological and spiritual do-
management. mains [25e27].
A patient navigator can help the patient going through all It is important to clearly dene the disease context with patients
phases of the cancer journey [16e20]. This is particularly relevant and families, addressing the concept of uncertainty and tailoring
for advanced cancer patients who are often overwhelmed with the treatment strategy according to individual priorities and dis-
difcult decisions to make, through complex information and ease status [28]. Specic psychosocial needs of young and elderly
available treatment options, and are frequently co-managed by the patients should also be recognized and supported, i.e. social secu-
breast cancer and the palliative care teams. This role is best taken rity, job exibility, rehabilitation, body image (including sexuality),
by a specialized breast nurse, or at least a specialized oncology home and child care.
492 F. Cardoso et al. / The Breast 23 (2014) 489e502

Important ABC-related denitions (continued )

Guideline statement LoE Consensus

A combined treatment modality based on a 100% (39) Yes


Guideline statement LoE Consensus multidisciplinary approach (systemic 0% (0) Abstain
therapy, surgery and radiotherapy) is (39 voters)
VISCERAL CRISIS is dened as severe organ Expert 95.0% (38) Yes
strongly indicated in the vast majority of
dysfunction as assessed by signs and opinion 5.0% (2)
cases.
symptoms, laboratory studies, and rapid Abstain
For TRIPLE NEGATIVE LABC, anthracycline- and- IA 85.3% (35) Yes
progression of disease. Visceral crisis is not (40 voters)
taxane-based chemotherapy is 9.7% (4) Abstain
the mere presence of visceral metastases, but
recommended as initial treatment. (41 voters)
implies important visceral compromise
For HER-2-POSITIVE LABC, concurrent taxane IA 91.8% (34) Yes
leading to a clinical indication for a more
and anti-HER-2 therapy is recommended 5.4% (2) Abstain
rapidly efcacious therapy, particularly since
since it increases the rate of pathological (37 voters)
another treatment option at progression will
complete response (pCR).
probably not be possible.
For HER-2-POSITIVE LABC, anthracycline-based IA 71.7% (28) Yes
PRIMARY ENDOCRINE RESISTANCE is dened Expert 66.6% (22) Yes
chemotherapy should be incorporated in the 12.8% (5) Abstain
as: relapse while on the rst 2 years of opinion 21.2% (7)
treatment regimen. (39 voters)
adjuvant ET, or PD within rst 6 months of Abstain
In HER-2-POSITIVE LABC, when an IA 86.8% (33) Yes
1st line ET for MBC, while on ET (33 voters)
anthracycline is given, it should be 10.5% (4) Abstain
SECONDARY (ACQUIRED) ENDOCRINE
administered sequentially with the anti- (38 voters)
RESISTANCE is dened as: relapse while on
HER-2 therapy.
adjuvant ET but after the rst 2 years, or
Options for HORMONAL RECEPTOR POSITIVE IA 85.3% (35) Yes
relapse within 12 months of completing
LABC include an anthracycline- and taxane- 9.7% (4) Abstain
adjuvant ET, or PD  6 months after initiating
based chemotherapy regimen, or endocrine (41 voters)
ET for MBC, while on ET.
therapy.
LoE: Available level of evidence; Consensus: Percentage of panel members in The choice of chemotherapy vs. endocrine
agreement with the statement; ET: endocrine therapy; PD: progressive disease; therapy, as initial treatment, will depend on
MBC: metastatic breast cancer. tumour (grade, biomarker expression) and
patient (menopausal status, performance
status, comorbidities, preference)
Current terminology uses several ill-dened terms that often have considerations.
Following effective neoadjuvant systemic II B 97.5% (39) Yes
different meanings, leading to confusion and difculty in adapting
therapy with or without radiotherapy, 0% Abstain
clinical trial ndings to current practice populations. surgery will be possible in many patients. (40 voters)
The ABC2 Panel tried to dene two of these important terms, This will consist of mastectomy with axillary
aiming at standardization of their use. dissection in the vast majority of cases, but in
Regarding endocrine resistance, an attempt was made to be selected patients with a good response,
breast conserving surgery may be possible.
consistent with a denition reached by a number of investigators
involved in breast cancer clinical trials, at a meeting sponsored by LABC: locally advanced breast cancer; LoE: Available level of evidence; Consensus:
Percentage of panel members in agreement with the statement; ER: oestrogen re-
NCI held in May 2012 and later approved by the North American
ceptor; PR: progesterone receptor.
Breast Cancer Groups (NABCG).
It is also important to note that endocrine resistance is a con-
tinuum and that strict denitions are mainly helpful for the clinical Inoperable locally advanced, inammatory, breast cancer
trials setting and not necessarily for routine clinical practice.

Inoperable locally advanced, non-inammatory, breast cancer


Guideline statement LoE Consensus

For inammatory LABC, overall treatment IB 92.6% (38) Yes


recommendations are similar to those for 4.8% (2) Abstain
non-inammatory LABC, with systemic (41 voters)
Guideline statement LoE Consensus therapy as rst treatment.
Mastectomy with axillary dissection is IB 95.1% (39) Yes
Before starting any therapy, a core biopsy IB 97.2% (36) Yes
recommended in almost all cases, even when 4.8% (2) Abstain
providing histology and biomarker (ER, PR, 2.7% (1) Abstain
there is good response to primary systemic (41 voters)
HER-2, proliferation/grade) expression is (37 voters)
therapy.
indispensable to guide treatment decisions.
Immediate reconstruction is generally not Expert 94.7% (36) Yes
Since LABC patients have a signicant risk of IB 100% (37) Yes
recommended in patients with inammatory opinion 2.6% (1) Abstain
metastatic disease, a full staging workup, 0% (0) Abstain
LABC. (38 voters)
including a complete history, physical (37 voters)
Loco-regional radiotherapy (chest wall and IB 97.5% (39) Yes
examination, lab tests and imaging of chest
lymph nodes) is required, even when a pCR is 2.5% (1) Abstain
and abdomen (preferably CT scans) and bone,
achieved with systemic therapy. (40 voters)
prior to initiation of systemic therapy is
highly recommended. MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-
PET-CT, if available, may be used (instead of and II B 100% (37) Yes centage of panel members in agreement with the statement; pCR: pathological
not on top of CT scans and bone scan). 0% (0) Abstain complete remission.
(37 voters)
Systemic therapy (not surgery or radiotherapy) Expert 100% (40) Yes
should be the initial treatment. If LABC opinion 0% (0) Abstain
remains inoperable after systemic therapy (40 voters)
and eventual radiation, palliative LABC occurs at rst presentation in about one fth of breast
mastectomy should not be done, unless the cancer patients worldwide, with lower incidence in countries with
surgery is likely to result in an overall established screening programs but as high as 60% in some other
improvement in quality of life.
countries [29]. Usually, the denition of LABC includes large oper-
IA
able primary breast tumours (stage IIB, IIIA) and/or those involving
F. Cardoso et al. / The Breast 23 (2014) 489e502 493

the skin or chest wall and/or those with extensive lymphadenop- (continued )
athies (stage IIIB, IIIC) [30]. For the purpose of ABC guidelines we Guideline statement LoE Consensus
dene LABC as inoperable locally advanced disease that has not yet
For MALE PATIENTS WITH ABC who need to Expert 86.1% (31) Yes
spread to distant sites. receive an aromatase inhibitor, a opinion 11.1% (4) Abstain
Inoperable LABC is a heterogeneous designation encompassing concomitant LHRH agonist or orchiectomy is (36 voters)
a range of clinical situations from neglected low-grade ER-positive the preferred option. Aromatase inhibitor
breast cancers to rapidly progressing usually ER-negative disease monotherapy may also be considered, with
close monitoring of response.
[30e33].
Clinical trials are needed in this patient
A more homogenous form of LABC is inammatory breast can- population.
cer (IBC), a distinct clinic-pathologic entity. IBC has a greater as-
MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-
sociation with younger age at diagnosis, higher tumour grade, and centage of panel members in agreement with the statement.
negative oestrogen receptor (ER) status.
The rst steps in the management of this disease are a core
biopsy to provide histology and biomarker assessment
(including ER, PR, HER-2, proliferation/grade), and a full staging As predicted by their DNA-damaging mechanism of action,
workup. Due to a relatively high risk of distant metastases [34], platinum compounds are expected to be particularly active in tu-
thoracic and abdominal CT scans are preferred to thorax X-ray mours decient of mechanisms responsible for DNA damage repair,
and liver ultrasound, and a PET-CT is also an acceptable option e.g. those without active BRCA1/2 proteins. Due to rarity of such
[34]. patients, little evidence exists on the clinical activity of these drugs
A multimodality approach is key for loco-regional control and in BRCA1/2 mutation carriers in the metastatic setting. However,
survival, including systemic therapies, surgery and radiation. available data suggest their promising activity mostly in the neo-
The type of systemic therapy is similar to the one used in the adjuvant setting [46,47], and to a lesser degree in advanced disease
(neo)adjuvant setting, with anthracycline and taxanes as the [48].
backbone of the chemotherapy regimes. For HER-2-positive LABC, In triple-negative breast cancer (TNBC), another putatively
anthracyclines should not be administered concurrently with BRCA-decient population, a relatively large amount of data
trastuzumab since this approach does not increase the pCR rate, from prospective studies, recently summarized in a meta-
and it could increase the risk of cardiac toxicity, based largely on analysis, demonstrated improved pCR rates in patients whose
studies in the metastatic setting [35,36]. neoadjuvant treatment included a platinum compound
For luminal-like LABC, initial treatment options include [49e51]. However, which patients denitely benet is not yet
chemotherapy (with sequential anthracyclines and taxanes) and clear since there is also one negative GEICAM study adding
endocrine therapy, depending on tumour (grade, biomarker carboplatin to EC-Docetaxel in basal-like breast cancer [52].
expression) and patient characteristics (menopausal status, Fewer data exist for inclusion of platinum in the treatment of
performance status, comorbidities) and preferences. A number metastatic disease, although the benet in the TNBC popula-
of studies have demonstrated signicant activity of endocrine tion seems to be larger than in other breast cancer patients
therapy, particularly in luminal A-like disease [37e40]. Data [53].
presented after ABC2 strongly suggest that this subset of breast Taking available evidence into account, most of the ABC2
cancer, especially lobular histology, is less sensitive to chemo- panel supported the inclusion of platinum-containing regimens
therapy (at least in terms of pCR rate) [41]. Very few data exist in the treatment of BRCA1/2 mutant patients pretreated with
on primary endocrine therapy in premenopausal women [42] anthracyclines and taxanes and demonstrated to be endocrine-
and, therefore, it cannot be recommended outside of clinical resistant.
trials. ABC1 issued several recommendations for the treatment of
Primary systemic therapy in inoperable LABC allows breast male patients with ABC [10] that still remain valid for ABC2 (see
conserving surgery in variable percentages depending on tumour/ Table 2). One additional recommendation is added at this point,
patient characteristics [43]. Mastectomy remains the only option related to the use of aromatase inhibitors in this patient
before or after radiotherapy for those patients not amenable to population.
breast conservation and for all patients with IBC [44]. For the time There are concerns about the efcacy of these agents when used
being, axillary dissection is still standard of care in inoperable LABC in monotherapy in male patients, due to the hypothalamic-
[45]. pituitary negative feedback.
As for all other stages of breast cancer, decision-making at a Important differences exist in the physiology of oestrogen
multidisciplinary tumour board is highly recommended. production between men and women. In men, 80% of circu-
lating oestrogens result from the peripheral aromatization of
Specic ABC populations androgens, 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. So
peripheral conversion results in less than 5% of all testos-
Guideline statement LoE Consensus terone, 80% of all dihydrotestosterone and oestradiol, and
nearly all of estrone (98%) [56,57]. Additionally, oestradiol
In patients with BRCAeASSOCIATED TRIPLE IC 82.5% (33) Yes
NEGATIVE OR ENDOCRINEeRESISTANT 12.5% (5) Abstain levels are 3e4 times higher in older males than in post-
MBC previously treated with an (40 voters) menopausal females.
anthracycline and a taxane (in the adjuvant For these reasons, and despite the lack of prospective and ran-
or metastatic setting), a platinum regimen domized data, the majority of panel members recommend that
may be considered, if the patient is not
included in a clinical trial.
when an aromatase inhibitor needs to be used in male ABC pa-
All other treatment recommendations are tients, a concomitant LHRH agonist or orchiectomy should be added
similar to sporadic MBC. to further down-regulate testicular function.
494 F. Cardoso et al. / The Breast 23 (2014) 489e502

Specic sites of metastases Due to the lack of prospective randomized data for the man-
agement of liver metastases from breast cancer, and the existence
of several loco-regional techniques, local therapy of liver metasta-
ses should only be considered in highly selected patients. Each case
Guideline statement LoE Consensus should be discussed with a multidisciplinary tumour board, before
a decision is made. Inclusion in a clinical trial, when available, is
Prospective randomized clinical trials of local Expert 83.3% (25) Yes
therapy for breast cancer LIVER opinion 16.6% (5) considered the best option.
METASTASES are urgently needed, since (30 voters) When breast cancer recurs only on the chest wall after mastec-
available evidence comes only from series tomy, the use of intensive local-regional therapy should be consid-
in highly selected patients. Since there are ered. Therapy can include surgical excision alone, surgical excision
no randomized data supporting the effect
of local therapy on survival, every patient
followed by radiation therapy, radiation therapy alone (when sur-
must be informed of this when discussing a gical excision is not feasible) or concurrent chemotherapy and ra-
potential local therapy technique. Local diation. Complete surgical resection reduces the total required dose
therapy should only be proposed in very of radiation therapy and also maximizes the likelihood of long-term
selected cases of good performance status,
disease control. Complete excision alone can lead to a 5-year disease
with limited liver involvement, no extra-
hepatic lesions, after adequate systemic free survival rate of 35% [58]. Complete resection followed by loco-
therapy has demonstrated control of the regional radiotherapy results in a 5-year local regional control
disease. Currently, there are no data to ranging from 60 to 77% [59,60]. Long-term predictors of disease free
select the best technique for the individual survival after a local regional recurrence include a disease-free in-
patient (surgery, stereotactic RT, intra-
hepatic CT or other).
terval greater than 24 months and a complete excision [59].
With modern radiotherapy techniques it is often possible to re-
MALIGNANT PLEURAL EFFUSIONS require II B 86.4% (32) Yes
irradiate with full dose without too many side effects [61]. The rst
systemic treatment with/without local 10.8% (4) Abstain
management. Thoracentesis for diagnosis (37 voters) results of retreatment with stereotactic body radiotherapy (SBRT)
should be performed if it is likely that this techniques have been published recently, describing promising
will change clinical management. False local control rates [62].
negative results are common. Drainage is Concurrent chemoradiation has both preclinical rationale and
recommended in patients with
clinical efcacy in many solid tumour types. Potential mechanisms
symptomatic, clinically signicant pleural
effusion. Use of an intrapleural catheter or of chemotherapy and radiotherapy interactions include increasing
intrapleural administration of talc or drugs radiation damage, inhibition of DNA repair processes, enhanced
(e.g. bleomycin, biological response activity against hypoxic and radioresistant cells, and prevention of
modiers) can be helpful.
regrowth of tumour after radiation [63]. In patients who have
Clinical trials evaluating the best technique
are needed.
received prior radiation, chemoradiation can be considered, as the
residual tumour should be considered radioresistant unless com-
Chest wall and regional (nodal) recurrences
bined with a potentiating agent, provided that the patient is judged
Due to the high risk of concomitant distant Expert 100% (38) Yes
metastases, patients with chest wall or opinion 0% (0) Abstain a candidate and can tolerate additional radiation therapy. Agents
regional (nodal) recurrence should (38 voters) having shown potential synergy with radiation include platinum
undergo full restaging, including analogs [64], antimetabolites [65e67], and taxanes [68]. Several
assessment of chest, abdomen and bone. novel therapeutics are also being studied in the trial setting in
Chest wall and regional recurrences should be IB 97.3% (37) Yes
treated with surgical excision when 2.6% (1) Abstain
combination with radiation, including EGFR inhibitors [69], HER-2
feasible with limited risk of morbidity. (38 voters) inhibitors [70], and PARP inhibitors [71]. Patients who have resid-
Locoregional radiotherapy is indicated for IB 97.3% (37) Yes ual isolated local-regional recurrence after attempted resection, or
patients not previously irradiated. 2.6% (1) Abstain minimal systemic disease, might derive benet from consideration
(38 voters)
of this multi-modality approach.
For patients previously irradiated, re- Expert 97.3% (37) Yes
irradiation of all or part of the chest wall opinion 2.6% (1) Abstain Hyperthermia has a proven benet for the treatment of super-
may be considered in selected cases. (38 voters) cial malignancies, acting as a radiosensitizer. Trials evaluating the
In addition to local therapy (surgery and/or IB 94.8% (37) Yes role of hyperthermia in combination with radiotherapy in patients
RT), in the absence of distant metastases, 5.1% (2) Abstain with chest wall recurrences have shown a signicant improvement
the use of systemic therapy (CT, ET and/or (39 voters)
anti-HER-2 therapy) should be considered.
in complete response rates with the addition of hyperthermia,
CT after rst local or regional recurrence especially in previously irradiated patients (e.g. CR: 24%e31% in the
improves long-term outcomes primarily in no-hyperthermia arm vs. 57%e68% in the hyperthermia arm)
ER negative disease. [72,73]. However, there was no difference in survival between the
ET in this setting improves long-term
two treatment arms. Recent studies have analysed the combination
outcomes for ER positive disease.
The choice of systemic treatment depends on of radiotherapy, hyperthermia and concurrent chemotherapy in
tumour biology, previous treatments, this patient population [74].
length of disease free interval, and patient- Finally, systemic therapy (both endocrine and chemotherapy)
related factors (co-morbidities, has been shown to benet patients after complete resection of a
preferences, etc).
In patients with disease not amenable to Expert 97.3% (37) Yes
rst locoregional isolated recurrence [75,76]. The CALOR study [76],
radical local treatment, the choice of opinion 2.6% (1) Abstain a randomized Phase 3 study, allocated 162 patients to either phy-
palliative systemic therapy should be made (38 voters) sician's choice chemotherapy or no chemotherapy. The use of
according to principles previously dened chemotherapy after surgery resulted in a signicant reduction in
for metastatic BC. These patients may still
systemic recurrence (HR 0.59; p 0.046). In the subgroup of
be considered for palliative local therapy.
patients with ER-negative tumours, there was also a signicant
MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per- improvement in survival. This study provides important data in
centage of panel members in agreement with the statement; CT: chemotherapy; RT:
radiotherapy; ET: endocrine therapy.
support of use of systemic chemotherapy after surgical resection of
isolated locoregional recurrence of ER-negative breast cancer.
F. Cardoso et al. / The Breast 23 (2014) 489e502 495

Update on ER positive/HER-2 negative ABC Update on Her-2-Positive ABC

Guideline statement LoE Consensus


Guideline statement LoE Consensus
The preferred 1st line ET for postmenopausal IA 83.3% (30) Yes
patients is an aromatase inhibitor or tamoxifen, 16.6% (6) Abstain In the 1st line setting, for HER-2 MBC previously IA 84.6% (33) Yes
depending on type and duration of adjuvant ET. (36 voters) treated (in the adjuvant setting) or untreated 10.2% (4) Abstain
Fulvestrant HD is also an option. IB 83.3% (30) Yes with trastuzumab, combinations of (39 voters)
16.6% (6) Abstain CT trastuzumab are superior to combinations
(36 voters) of CT lapatinib in terms of PFS and OS.
The addition of everolimus to an aromatase IB 100% Yes In 1st line therapy, the combination of IA 89.7% (35) Yes
inhibitor is a valid option for some post- (30 voters) CT trastuzumab and pertuzumab is superior to 10.2% (4) Abstain
menopausal patients with disease progression CT trastuzumab, primarily for previously (39 voters)
after a non-steroidal aromatase inhibitor, since it untreated HER-2 MBC, making it the preferred
signicantly prolongs PFS by a median interval of treatment option since it is associated with OS
5 months. There is a survival prolongation of benet.
similar magnitude (4.4 months) although this It is currently unknown how this treatment
difference is not statistically signicant. The compares to other anti-HER-2 options such as T-
decision to treat must take into account the DM1.
relevant toxicities associated with this There are currently no data supporting the use of 85.0% (34) Yes
combination and should be made on a case by dual blockade with trastuzumab pertuzumab 12.5% (5) Abstain
case basis. associated with CT beyond 1st line, after (40 voters)
At present, no predictive biomarker exists to treatment with trastuzumab pertuzumab CT
identify those patients who will benet from this in 1st line (i.e. continuing dual blockade beyond
approach. progression) and therefore this 3 drug regimen
should not be given beyond 1st line outside
LoE: Available level of evidence; Consensus: Percentage of panel members in clinical trials.
agreement with the statement; ET: endocrine therapy; PFS: progression-free In a HER-2 MBC patient previously untreated with II C 43.7% (14) Yes
survival. pertuzumab, it is acceptable to use pertuzumab 21.8% (7) Abstain
beyond 1st line. (32 voters)
After 1st line trastuzumab-based therapy, T-DM1 IA 89.7% (35) Yes
ABC2 reinforces the ABC1 recommendations for ER-positive/ provides superior efcacy relative to other HER- 10.2% (4) Abstain
HER-2-negative advanced breast cancer regarding the preferential 2-based therapies in the 2nd line (vs. (39 voters)
lapatinib capecitabine) and beyond (vs.
use of endocrine therapy, even in the presence of visceral metas-
treatment of physician's choice).
tases. Chemotherapy should be reserved for cases of rapidly pro- T-DM1 should be preferred in patients who have
gressive disease or proven endocrine-resistance. Most ABC1 progressed through at least 1 line of
recommendations remain unchanged (see Table 2). The two trastuzumab-based therapy, since it provides an
changes refer to the preferred 1st line endocrine therapy for OS benet.
All patients with HER-2 MBC who relapse after IB 87.5% (35) Yes
postmenopausal women and the use of everolimus.
adjuvant anti-HER-2 therapy should be 12.5% (5) Abstain
The preferred 1st line endocrine therapy for postmenopausal considered for further anti-HER-2 therapy, (40 voters)
women depends on the type and duration of adjuvant endocrine except in the presence of contraindications.
therapy. Available data supports the use of an aromatase inhibitor, The choice of the anti-HER-2 agent will depend on
country-specic availability, the specic anti-
tamoxifen or fulvestrant HD (i.e. 500 mg, every 4 weeks)
HER-2 therapy previously administered, and the
[31,77e88]. Fulvestrant HD is well tolerated and numerically relapse free interval.
associated with a 4.1-month difference in median OS compared The optimal sequence of all available anti-HER-2
with fulvestrant 250 mg [80]. Only the lower, less efcacious dose, therapies is currently unknown.
was compared to aromatase inhibitors and found to have similar Because patients with HER-2-positive MBC and IC 89.1% (33) Yes
brain metastases can live for several years, 10.8% (4) Abstain
efcacy; so far, no data directly comparing fulvestrant HD with an
consideration of long-term toxicity is important (37 voters)
aromatase inhibitor exist. and less toxic local therapy options (e.g.
Endocrine resistance is a common and important clinical stereotactic RT) should be preferred to whole
problem. It may be primary or secondary (see above ABC deni- brain RT, when available and appropriate (e.g. in
the setting of a limited number of brain
tions). The main identied mechanisms of endocrine resistance are
metastases).
related to ESR alterations (mutations, amplications or trans-
locations), and upregulation of alternative pathways, such as the MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-
centage of panel members in agreement with the statement; CT: chemotherapy, RT:
HER growth factor pathways and the PI3K/Akt/mTOR pathway.
radiotherapy; T-DM1: Trastuzumab Emtansine.
The mTOR inhibitor everolimus when added to exemestane, in
patients progressing on non-steroidal aromatase inhibitor, pro-
vided a signicant PFS prolongation of about 5 months [89,90]. The In the last two years, several trials in HER-2-positive ABC have
overall survival data, presented after ABC2, demonstrated a non- been reported, which led to an update on several ABC1 recom-
signicant 4-month increase in median survival (HR 0.89) [91]. mendations regarding this specic subtype.
Overall survival prolongation was also observed, in an exploratory Evidence from three trials, two in advanced and one in early
analysis of the randomized phase II TAMRAD study comparing breast cancer, support the recommendation that combinations of
combination of tamoxifen and everolimus to tamoxifen alone in AI- chemotherapy with trastuzumab are superior to chemotherapy and
resistant patients [92]. These benets must be weighed against lapatinib.
relevant toxicities associated with this compound, particularly The MA.31 trial [93] randomly compared taxanes plus trastu-
stomatitis, pneumonitis and hyperglycemia. Decisions on ever- zumab (weekly paclitaxel or three weekly docetaxel) or the same
olimus use must thus be made on a case-by-case basis, after dis- taxane plus lapatinib, as rst line treatment of 636 HER-2 positive
cussion with a well-informed patient, and administered by MBC patients, a substantial percentage of whom had de novo MBC.
physicians experienced in managing adverse effects of this With a median follow-up of 13.6 months, the taxane-lapatinib arm
compound. had inferior PFS compared to the taxane-trastuzumab (8.8 vs. 11.4
496 F. Cardoso et al. / The Breast 23 (2014) 489e502

months). There was no difference in OS and toxicity was signi- (continued )


cantly higher in the lapatinib arm. Guideline statement LoE Consensus
The CEREBEL trial [94], compared lapatinib plus capecitabine to
Additional choices include gemcitabine, platinum
trastuzumab plus capecitabine, as 1st line therapy for HER-2- agents, taxanes, and liposomal anthracyclines.
positive MBC with no evidence of CNS disease. The primary The decision should be individualized and take into
endpoint was incidence of CNS metastases as rst site of relapse. account different toxicity proles, previous
With a planned population of 475 patients, the study was termi- exposure, patient preferences, and country
availability.
nated at the time of the interim analysis due to a low number of
CNS events (3% and 5% respectively). PFS, a secondary endpoint, LoE: Available level of evidence; Consensus: Percentage of panel members in
agreement with the statement; CT: chemotherapy.
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 a Regarding the use of chemotherapy, the main recommendation
non-inferiority comparison to trastuzumab, and patients offered remains unchanged and relates to the sequential use of single
cross-over to receive trastuzumab [95]. agents, with combination chemotherapy reserved for situations of
The CLEOPATRA trial [96,97]; showed superior results, in terms of visceral crisis, rapidly progressive or highly symptomatic disease.
PFS (18.5 vs. 12.4 months) and 1-year survival (23.6% vs. 17.2), of the Available literature has been previously reviewed [12] and a recent
triplet trastuzumab pertuzumab docetaxel compared to Cochrane meta-analysis [102] conrms and provides level 1 evi-
trastuzumab docetaxel as 1st line therapy. Importantly, the majority dence for this recommendation.
(z90%) of the patients were trastuzumab-naive; if previously treated Although taxanes can be used as rst line therapy, they have not
with trastuzumab, a 12 months disease-free interval was required. shown superior benet to anthracyclines in a meta-analysis per-
Therefore, this trial did not address, and therefore cannot support, the formed in a mostly taxane-naive, anthracycline-pretreated patient
use of this combination in patients with truly trastuzumab-resistant population [103]. Considerations regarding toxicity and patient
tumours. There are also no data supporting the use of the dual preferences (namely wish to avoid alopecia) should be taken into
blockade with trastuzumab pertuzumab with CT beyond 1st line, consideration in the choice of cytotoxic agent.
after treatment with trastuzumab pertuzumab CT in 1st line (i.e. Capecitabine has shown consistent results as rst and second
continuing dual blockade beyond progression) and therefore this line therapy [104e112].
regimen should not be given beyond 1st line outside clinical trials. Vinorelbine yielded equal or superior results to both paclitaxel
The panel could not reach a consensus regarding the possible and docetaxel, when combined with trastuzumab in the HER-2
use of pertuzumab beyond 1st line in patients previously untreated positive ABC in the HERNATA [113] and TRAVIOTA trials [114].
with this drug (14 votes yes, 11 no, 7 abstain). The only Eribulin has provided an OS benet in heavily pretreated pa-
available data regarding this issue come from a phase II single arm tients (up to 5 lines of treatment) [115] and similar PFS and OS
study [98]. This phase II also showed that pertuzumab does not results to capecitabine after prior treatment with an anthracycline
work by itself but needs to be combined with trastuzumab. and taxane [116].
T-DM1 (Trastuzumab Emtansine) has shown consistent and
substantial benets in terms of PFS and OS, both in the 2nd line (vs.
Update on surgery of the primary tumour in stage IV at
lapatinib capecitabine, in the EMILIA trial) [99,100]; and beyond
diagnosis
(vs. treatment of physician's choice, in the TH3RESA trial) [101].
These results make T-DM1 the preferred choice for patients with
disease progression after treatment with at least one line of
Guideline statement LoE Consensus
trastuzumab-based therapy.
There are almost no data regarding the treatment of patients with The true value of the removal of the primary II B 100% (29) Yes
HER-2-positive ABC who relapse on or shortly after adjuvant tras- tumour in patients with de novo stage IV 0% (0) Abstain
breast cancer is currently unknown. (29 voters)
tuzumab and urgent trials are needed for this poor prognosis pop- However, it can be considered in selected
ulation. In the EMILIA trial, the overall survival advantage (hazard patients. Of note, some studies suggest that
ratio) for T-DM1 vs. lapatinib plus capecitabine in the subset of 118 surgery is only valuable if performed with
patients who were randomized in the rst-line setting, having the same attention to detail (e.g. attaining
clear margins and addressing disease in the
relapsed on or within 6 months of adjuvant trastuzumab, appeared
axilla) as in patients with early stage disease.
similar to the effect seen in the overall trial [100].
Several ABC1 recommendations for HER-2-positive ABC remain LoE: Available level of evidence; Consensus: Percentage of panel members in
agreement with the statement.
unchanged and are listed in Table 2.

Update on HER-2-negative ABC


Available data regarding the value of removal of the primary
tumour in patients with stage IV at diagnosis were extensively
reviewed and published in one of the ESO ABC Task Force manu-
Guideline statement LoE Consensus scripts [13]. All but one study published after this 2010 paper
Sequential monotherapy is the preferred choice for IA 96% (25) Yes support the surgical removal of the primary tumour in patients
MBC. Combination CT should be reserved for 4% (1) Abstain with stage IV disease, reinforcing the importance of the ongoing
patients with rapid clinical progression, life- (26 voters) prospective trials evaluating this approach since existing data come
threatening visceral metastases, or need for rapid almost exclusively from retrospective studies [117e121,124]. In the
symptom and/or disease control.
beginning of 2012, the British Columbia large retrospective series
In patients pre-treated (in the adjuvant or IB 77.1% (27) Yes
metastatic setting) with an anthracycline and a 20.0% (7) Abstain reinforced the importance of treating the primary with the most
taxane, and who do not need combination (35 voters) favourable survival rates observed in subsets of patients with young
chemotherapy, single agent capecitabine, age, good performance status, ER-positive disease, distant disease
vinorelbine or eribulin are the preferred choices.
limited to one site, bone-only involvement, or fewer than ve
F. Cardoso et al. / The Breast 23 (2014) 489e502 497

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

Guideline statement LoE Consensus

The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including Expert 100% (29) Yes
but not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gynaecologists, psycho-oncologists, opinion 0% (0) Abstain
social workers, nurses and palliative care specialists), is crucial. (29 voters)

From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care, supportive care, and symptom-related Expert 100% (30) Yes
interventions as a routine part of their care. The approach must be personalized to meet the needs of the individual patient. opinion 0% (0) Abstain
(30 voters)

Following a thorough assessment and conrmation of MBC, the potential treatment goals of care should be discussed. Patients Expert 97% (29) Yes
should be told that MBC is incurable but treatable, and that some patients can live with MBC for extended periods of time (many opinion 3% (1) Abstain
years in some circumstances). (30 voters)
This conversation should be conducted in accessible language, respecting patient privacy and cultural differences, and whenever
possible, written information should be provided.

Patients (and their families, caregivers or support network, if the patient agrees) should be invited to participate in the decision- Expert 100% (30) Yes
making process at all times. When possible, patients should be encouraged to be accompanied by persons who can support them opinion 0% (0) Abstain
and share treatment decisions (e.g. family members, caregivers, support network). (30 voters)

There are few proven standards of care in ABC management. After appropriate informed consent, inclusion of patients in well- Expert 100% (30) Yes
designed, prospective, randomized independent trials must be a priority whenever such trials are available and the patient is opinion 0% (0) Abstain
willing to participate. (30 voters)

The medical community is aware of the problems raised by the cost of ABC treatment. Balanced decisions should be made in all Expert 100% (32) Yes
instances; patients' well being, length of life and preferences should always guide decisions. opinion 0% (0) Abstain
(32 voters)
Assessment guidelines
Minimal staging workup for MBC includes a history and physical examination, haematology and biochemistry tests, and imaging of 2C 67% (20) Yes
chest, abdomen and bone. 3% (1) Abstain
(30 voters)
Brain imaging should not be routinely performed in asymptomatic patients. This approach is applicable to all patients with MBC Expert 94% (30) Yes
including those patients with HER-2 and/or triple negative MBC. opinion 0% Abstain
(32 voters)
The clinical value of tumour markers is not well established for diagnosis or follow-up after adjuvant therapy, but their use is 2C 89% (24) Yes
reasonable (if elevated) as an aid to evaluate response to treatment, particularly in patients with non-measurable metastatic 4% (1) Abstain
disease. A change in tumour markers alone should not be used to initiate a change in treatment. (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 the Expert 81% (25) Yes
dynamics of the disease, the location and extent of metastatic involvement, and type of treatment. opinion 10% (3) Abstain
Imaging of a target lesion may be sufcient in many patients. In certain patients, such as those with indolent disease, less frequent (31 voters)
monitoring is acceptable.
Additional testing should be performed in a timely manner, irrespective of the planned intervals, if PD is suspected or new
symptoms appear. Thorough history and physical examination must always be performed.

A biopsy (preferably providing histology) of a metastatic lesion should be performed, if easily accessible, to conrm diagnosis 1 C* 96% (27) Yes
particularly when metastasis is diagnosed for the rst time. 0% (0) Abstain
(28 voters)
Biological markers (especially HR and HER-2) should be reassessed at least once in the metastatic setting, if clinically feasible. 2C 90% (26) Yes
7% (2) Abstain
(29 voters)
If the results of tumour biology in the metastatic lesion differ from the primary tumour, it is currently unknown which result should Expert 87% (27) Yes
be used for treatment-decision making. Since a clinical trial addressing this issue is difcult to undertake, we recommend opinion 3% (1) Abstain
considering the use of targeted therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at least one biopsy, (31 voters)
regardless of timing.

Treatment general guidelines


Treatment choice should take into account at least these factors: HR and HER-2 status, previous therapies and toxicities, disease-free Expert 100% (30) Yes
interval, tumour burden (dened as number and site of metastases), biological age, performance status, co-morbidities (including opinion 0% (0) Abstain
organ dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychological (30 voters)
factors, available therapies in the patient's country and patient preference.

A small but very important subset of patients with MBC, for example those with oligo-metastatic disease, can achieve complete Expert 96% (25) Yes
remission and a long survival. A multimodal approach should be considered for these selected patients. opinion 0% Abstain
A prospective clinical trial addressing this specic situation is needed. (26 voters)

ER /HER-2 negative ABC


Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless IA 100% (29) Yes
there is concern or proof of endocrine resistance, or there is disease needing a fast response. 0% (0) Abstain
(29 voters)
For pre-menopausal women, ovarian suppression/ablation combined with additional endocrine therapy is the rst choice. IA 97% (29) Yes
0% (0) Abstain
(30 voters)
The additional endocrine agent should be tamoxifen unless tamoxifen resistance is proven. IB 97% (29) Yes
An aromatase inhibitor is also a viable option, but absolutely mandates the use of ovarian suppression/ablation. 0% (0) Abstain
Fulvestrant has not been adequately studied in premenopausal women. (30 voters)
Optimal post-aromatase inhibitor treatment is uncertain. Available options include, but are not limited to, tamoxifen, another IA 97% (30) Yes
aromatase inhibitor (with a different mechanism of action), fulvestrant HD, megestrol acetate and everolimus aromatase 3% (1) Abstain
inhibitor. (31 voters)
(continued on next page)
498 F. Cardoso et al. / The Breast 23 (2014) 489e502

Table 2 (continued )

Guideline statement LoE Consensus

Endocrine treatment after CT (maintenance ET) to maintain benet is a reasonable option, although this approach has not been IC 88% (28) Yes
assessed in randomized trials. 9% (3) Abstain
(32 voters)
Concomitant CT ET has not shown a survival benet and should not be administered outside of a clinical trial. IB 100% (30) Yes
0% (0) Abstain
(30 voters)
HER-2-positive ABC
Anti-HER-2 therapy should be offered early to all patients with HER-2 MBC, except in the presence of contra-indications to the use IA 91% (30) Yes
of such therapy. 3% (1) Abstain
(33 voters)
For patients with ER/HER-2 MBC for whom ET was chosen over CT, anti-HER-2 therapy ET should be considered with the IA 90% (27) Yes
initiation of endocrine therapy (provided that further anti-HER-2 therapy is available) since anti-HER-2 therapy (either 10% (3) Abstain
trastuzumab or lapatinib) in combination with ET has shown substantial PFS benet (i.e. time without CT) compared to ET alone. (30 voters)
The addition of anti-HER-2 therapy in this setting has not led to a survival benet.

Patients whose tumours progress on an anti-HER-2 therapy combined with a cytotoxic or endocrine agent should be offered IB 97% (29) Yes
additional anti-HER-2 therapy with subsequent treatment since it is benecial to continue suppression of the HER-2 pathway. 0% (0) Abstain
The optimal duration of anti-HER-2 therapy for MBC (i.e. when to stop these agents) is currently unknown. (30 voters)

Patients who have received any type of (neo)adjuvant anti-HER-2 therapy should not be excluded from clinical trials for HER-2 IB 100% (23) Yes
MBC. 0% (0) Abstain
(27 voters)
In case of progression on trastuzumab, the combination of trastuzumab lapatinib is also a reasonable treatment option in the IB 83% (24) Yes
course of the disease. 10% (3) Abstain
(29 voters)
Chemotherapy and biological therapy
In the absence of medical contraindications or patient concerns, anthracycline or taxane based regimens, preferably as single agents, IA 71% (17) Yes
would usually be considered as rst line CT for HER-2 negative MBC, in those patients who have not received these regimens as 4% (1) Abstain
adjuvant treatment and for whom chemotherapy is appropriate. Other options are, however, available and effective, such as (24 voters)
capecitabine 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) who IA 59% (14) Yes
are being considered for further CT, taxane-based therapy, preferably as single agents, would usually be considered as treatment 8% (2) Abstain
of choice. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding (24 voters)
alopecia 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 of IA 92% (22) Yes
disease-free survival. 8% (2) Abstain
(24 voters)
Duration of each regimen and the number of regimens should be tailored to each individual patient. Expert 96% (26) Yes
opinion 0% (0) Abstain
(27 voters)
Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity. IB 72% (21) Yes
What is considered unacceptable should be dened together with the patient. 7% (2) Abstain
(29 voters)
Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides only a moderate benet in PFS and no IA 74% (17) Yes
benet in OS. The absence of known predictive factors for bevacizumab efcacy renders recommendations on its use difcult. 17% (4) Abstain
Bevacizumab can only therefore be considered as an option in selected cases in these settings and is not recommended after 1st/ (23 voters)
2nd line.

Specic sites of metastases: bone and brain


A bone modifying agent (bisphosphonate or denosumab) should be routinely used in combination with other systemic therapy in IA 96% (26) Yes
patients with MBC and bone metastases. 4% (1) Abstain
(27 voters)
Radiological assessments are required in patients with persistent and localized pain due to bone metastases to determine whether IA 96% (23) Yes
there are impending or actual pathological fractures. If a fracture of a long bone is likely or has occurred, an orthopaedic 4% (1) Abstain
assessment is required as the treatment of choice may be surgical stabilization, which is generally followed by RT. In the absence (24 voters)
of 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 of IB 100% (24) Yes
urgency. This requires a full radiological assessment of potentially affected area as well as adjacent areas of the spine. MRI is the 0% (0) Abstain
method of choice. An emergency surgical opinion (neurosurgical or orthopaedic) may be required for surgical decompression. If (24 voters)
no decompression/stabilization is feasible, emergency radiotherapy is the treatment of choice and vertebroplasty is also an
option.

Patients with a single or small number of potentially resectable brain metastases should be treated with surgery or radiosurgery. IB 92% (22) Yes
Radiosurgery is an option for some unresectable brain metastases. 4% (1) Abstain
(24 voters)
If surgery/radiosurgery is performed it may be followed by whole brain radiotherapy but this should be discussed in detail with the IB 72% (18) Yes
patient, balancing the longer duration of intracranial disease control against the risk of neurocognitive effects. 16% (4) Abstain
(25 voters)

Supportive and palliative care


Supportive care allowing safer and more tolerable delivery of appropriate treatments should always be part of the treatment plan. IA 100% (26) Yes
0% (0) Abstain
(26 voters)
Early introduction of expert palliative care, including effective control of pain and other symptoms, should be a priority. IA 100% (26) Yes
0% (0) Abstain
(26 voters)
F. Cardoso et al. / The Breast 23 (2014) 489e502 499

Table 2 (continued )

Guideline statement LoE Consensus

Access to effective pain treatment (including morphine, which is inexpensive) is necessary for all patients in need of pain relief. IA 100% (27) Yes
0% (0) Abstain
(27 voters)
Optimally, discussions about patient preferences at the end of life should begin early in the course of metastatic disease. However, Expert 96% (25) Yes
when active treatment no longer is able to control widespread and life-threatening disease, and the toxicities of remaining opinion 0% (0) Abstain
options outweigh benets, physicians and other members of the healthcare team should initiate discussions with the patient (and (26 voters)
family members/friends, if the patient agrees) about end-of-life care.
Metastatic male breast cancer
For ER Male MBC, which represents the majority of cases, ET is the preferred option, unless there is concern or proof of endocrine Expert 100% (25) Yes
resistance or rapidly progressive disease needing a fast response. opinion 0% (0) Abstain
(25 voters)
For ER Male MBC, tamoxifen is the preferred option. Expert 83% (15) Yes
opinion 6% (1) Abstain
(18 voters)

*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 also advocacy groups) to develop well designed, high quality multidis-
published in 2012 reinforced the idea that surgery of the primary ciplinary (involving other issues than drug-development) trials for
tumour appeared to be an independent factor for improved survival ABC remains of critical importance. Many questions are still
in the multivariate analyses from the individual studies, with an HR unanswered, related to management strategies, optimal drug use,
of 0.69 (p < 0.00001) [123]. and individualized treatment (based on predictive markers and
Since 2011 several randomized trials have started accrual eventually new technologies aiming at better characterization of
comparing loco-regional treatment of primary vs. no treatment in the individual tumour).
stage IV patients at presentation [124,125]. Research and education are the two pillars for advances in
In 2013, very early data from 2 prospectively randomized trials oncology today. Research is indispensible for improving the man-
presented at San Antonio Breast Cancer Symposium could not agement and outcome of patients with cancer, now and in the
conrm the previous conclusions. In these two studies, only a future. Education, including implementation of carefully developed
limited subgroup of patients with solitary bone metastases seemed high quality guidelines such as the current ABC International
to prot from surgery, while patients with multiple visceral me- Consensus Guidelines, allows the appropriate application of cur-
tastases showed a worse prognosis with initial surgery. However, rent knowledge to patient care, which will substantially improve
these trials were small, had short follow-up time and included all- the long-term outcomes of current ABC patients worldwide.
comers [126,127].
More studies and better patient selection are necessary to Appendix A. Supplementary data
resolve this question, and several other prospective randomized
trials are ongoing. Until these results are available, ABC2 retains the Supplementary data related to this article can be found at http://
ABC1 recommendation, which considers that surgery of the pri- dx.doi.org/10.1016/j.breast.2014.08.009.
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.
References

[1] Cardoso F. Metastatic breast cancer patients: the forgotten heroes! Breast
Conclusions 2009;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 Oncol
Advances in survival outcomes for ABC, particularly for MBC,
2008;19:2012e9.
have been frustratingly slow. MBC remains a virtually incurable [3] Andre Fabrice, Slimane Khemaies, Bachelot Thomas, Dunant Arianne,
disease and LABC patients generally have a poor prognosis with a Namer Moise, Barrelier Alain, et al. Breast cancer with synchronous metas-
high risk of distant recurrence. tases: trends in survival during a 14-year period. J Clin Oncol 2004;22:
3302e8.
In the last few years, a deeper focus on this historically [4] Sundquist M, Eriksson Z, Tejler G, Brudin L. Trends in survival in metastatic
neglected patient population has occurred, with new and better breast cancer [abstract 453] Eur J Cancer 2010;8(3):191.
designed clinical trials, a dedicated conference and the develop- [5] Foukakis Theodoros, Fornander Tommy, Lekberg Tobias, Hellborg Henrik,
Adolfsson Jan, Bergh Jonas. Age-specic trends of survival in metastatic
ment of international consensus guidelines. Patient surveys have breast cancer: 26 years longitudinal data from a population-based cancer
shown a slight improvement in patient satisfaction about the registry in Stockholm, Sweden. Breast Cancer Res Treat 2011. http://
several steps of their care but emphasize that much remains to be 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-term
done. Implementation of guidelines is very heterogeneous between follow-up of patients with metastatic breast cancer treated by trastuzumab:
countries but also within countries, according to the environment impact of institutions. The Breast 2014;23(2):165e9.
where the patient is treated and cost of treatment. [7] Hebert-Croteau N, Brisson J, Latreille J, Rivard M, Abdelaziz N, Martin G.
Compliance with consensus recommendations for systemic therapy is
The complexity of this disease, the multiple factors that must be associated with improved survival of women with node-negative breast
taken into account, the lack of high-level evidence for several cancer. J Clin Oncol 2004;22(18):3685e93.
clinical situations, and new highly specialized techniques available [8] Griggs JJ, Culakova E, Sorbero ME, Poniewierski MS, Wolff DA, Crawford J,
et al. Social and racial differences in selection of breast cancer adjuvant
for local management of specic sites of metastases, all constitute
chemotherapy regimens. J Clin Oncol 2007;25(18):2522e7.
strong reasons for the treatment of these patients by a specialized [9] Hassett MJ, Hughes ME, Niland JC, Ottesen R, Edge SB, Bookman MA, et al.
multidisciplinary team, rather than management by an isolated Selecting high priority quality measures for breast cancer quality improve-
oncologist regardless of his/her skills or experience. ment. Med Care 2008;46(8):762e70.
[10] Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Falloweld L, et al. 1st
Our plea for a strong commitment of all involved parties international consensus guidelines for advanced breast cancer (ABC1). Breast
(academia, pharmaceutical industry, independent funding sources, 2012;21(3):242e52.
500 F. Cardoso et al. / The Breast 23 (2014) 489e502

[11] Metastatic breast cancer: recommendations proposal from the European [36] Buzdar AU, Suman V, Bernstam F. ACOSOG Z1041 (Alliance): denitive
school of oncology (ESO)eMBC task force. Breast 2007;16:9e10. analysis of randomized neoadjuvant trial comparing FEC followed by pacli-
[12] Cardoso F*, Bedard PL*, Winer EP, Pagani O, Senkus-Konefka E, Falloweld LJ, taxel plus trastuzumab (FEC / PT) with paclitaxel plus trastuzumab fol-
et al., On Behalf of the ESO-MBC Task Force. *Co-rst authors. International lowed by FEC plus trastuzumab (PT / FECT) in HER2 operable breast
guidelines for management of metastatic breast cancer: combination vs cancer. J Clin Oncol 2013;31. suppl; abstr 502.
sequential single-agent chemotherapy. J Natl Cancer Inst 2009;101: [37] Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, et al. Randomized phase II
1174e81. neoadjuvant comparison between letrozole, anastrozole, and exemestane for
[13] Pagani* Olivia, Senkus-Konefka* Elzbieta, _ Wood William, Colleoni Marco, postmenopausal women with estrogen receptor-rich stage 2 to 3 breast
Cufer Tanja, Kyri-akides Stella, et al., On Behalf of the ESO-MBC Task Force. *Co- cancer: clinical and biomarker outcomes and predictive value of the baseline
rst authors. International guidelines for management of metastatic breast PAM50-based intrinsic subtypeeACOSOG Z1031. J Clin Oncol 2011;29(17):
cancer (MBC) from the European school of oncology (ESO)eMBC task force: 2342e9.
can metastatic breast cancer be cured? J Natl Cancer Inst 2010;102:1e8. [38] Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, et al.
[14] Lin* Nancy U, Thomssen* Christoph, Cardoso Fatima, Cameron David, Comparison of anastrozole versus tamoxifen as preoperative therapy in
Cufer Tanja, Falloweld Lesley, et al., On Behalf of the ESO-MBC Task Force. postmenopausal women with hormone receptor-positive breast cancer: the
International guidelines for management of metastatic breast cancer (MBC) Pre-Operative Arimidex Compared to Tamoxifen (PROACT) trial. Cancer
from the European school of oncology (ESO)eMBC task force: surveillance, 2006;106(10):2095e103.
staging, and evaluation of patients with early-stage and metastatic breast [39] Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast
cancer. Breast 2013;22(3):203e10. Cancer Res Treat 2007;105(Suppl. 1):33e43.
[15] Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EM, [40] Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, et al. Neo-
Phillips B, et al. Grading strength of recommendations and quality of evi- adjuvant treatment of postmenopausal breast cancer with anastrozole,
dence in clinical guidelines: report from an american college of chest phy- tamoxifen, or both in combination: the Immediate Preoperative Anastrozole,
sicians task force. Chest 2006;129(1):174e81. Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind
[16] Freeman HP. Patient navigation: a community centered approach to randomized trial. J Clin Oncol 2005;23(22):5108e16.
reducing cancer mortality. J Cancer Educ 2006;21(Suppl. 1):S11e4. [41] Loibl S, Volz C, Mau C, Blohmer JU, Costa SD, Eidtmann H, et al. Response and
[17] Freund KM, Battaglia TA, Calhoun E, Dudley DJ, Fiscella K, Paskett E, et al. prognosis after neoadjuvant chemotherapy in 1,051 patients with inltrating
National Cancer Institute Patient Navigation Research Program: methods, lobular breast carcinoma. Breast Cancer Res Treat 2014;144(1):153e62.
protocol, and measures. Cancer 2008;113(12):3391e9. [42] Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, et al.
[18] Hopkins J, Mumber MD. Patient navigation through the cancer care contin- Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for
uum: an overview. J Oncol Pract 2009;5(4):150e1525. premenopausal breast cancer (STAGE): a double-blind, randomised phase 3
[19] Robinson-White S, Conroy B, Slavish KH, Rosenzweig M. Patient navigation trial. Lancet Oncol 2012;13(4):345e52.
in breast cancer: a systematic review. Cancer Nurs 2010;33(2):127e40. [43] Sinacki M, Badzio A, Wenicka-Jaskiewicz M, Bogaerts J, Piccart MJ,
[20] Ko NY, Darnell JS, Calhoun E, Freund KM, Wells KJ, Shapiro CL, et al. Can Therasse P, et al. Pattern of care in locally advanced breast cancer: focus on
patient navigation improve receipt of recommended breast cancer care? local therapy. Breast 2011 Apr;20(2):145e50.
evidence from the national patient navigation research program. J Clin Oncol [44] Dawood S, Merajver SD, Viens P, Vermeulen PB, Swain SM, Buchholz TA,
2014 Jul 28. pii: JCO.2013.53.6037. [Epub ahead of print]. et al. International expert panel on inammatory breast cancer: consensus
[21] Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med statement for standardized diagnosis and treatment. Ann Oncol 2011;22(3):
March 11 2010;362:865e9. http://dx.doi.org/10.1056/NEJMp0911494. 515e23.
[22] Biganzoli L, Wildiers H, Oakman C, Marottu L, Loibl S, reed M, et al. Man- [45] Cox C, Holloway CM, Shaheta A, Nofech-Mozes S, Wright FC. What is the
agement of elderly patients with breast cancer: updated recommendations burden of axillary disease after neoadjuvant therapy in women with locally
of the International Society of Geriatric Oncology (SIOG) and European So- advanced breast cancer? Curr Oncol 2013;20(2):111e7.
ciety of Breast Specialists (EUSOMA). Lancet Oncol 2012;13:e148e60. [46] Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al.
[23] Cardoso Fatima, Loibl Sibylle, Pagani Olivia, Graziottin Alessandra, Pathologic complete response rates in young women with BRCA1-positive
Panizza Pietro, Martincich Laura, et al. The EUSOMA recommendations for breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010;28(3):
the management of young women with breast cancer. Eur J Cancer 375e9.
2012;48(18):3355e77. [47] Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, et al. Response
[24] *Co-rst authors; #Co-last authors Partridge* Ann H, Pagani* Olivia, to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer pa-
Abulkhair Omalkhair, Aebi Stefan, Amant Fre de ric, Azim Jr Hatem A, et al. tients. Breast Cancer Res Treat 2009;115(2):359e63.
First international consensus guidelines for breast Cancer in young women [48] Byrski T, Foszczynska-Kloda M, Huzarski T, Dent R, Gronwald J, Cybulski C,
(BCY1). Breast 2014. published online, http://dx.doi.org/10.1016/j.breast. et al. Cisplatin chemotherapy in the treatment of BRCA1-positive metastatic
2014.03.011. breast cancer (MBC). J Clin Oncol 2009;27(15S). ASCO Annual Meeting Pro-
[25] Zimmermann C, Swami N, Krzyzanowska M, Hannon B, Leighl N, Oza A, et al. ceedings (Post-Meeting Edition). (May 20 Supplement), 2009: 1099.
Early palliative care for patients with advanced cancer: a cluster-randomised [49] Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin
controlled trial. Lancet 2014;383(9930):1721e30. and/or bevacizumab to neoadjuvant weekly paclitaxel followeed by dose-
[26] Ganz PA, Yip CH, Gralow JR, Distelhorst SR, Albain KS, Andersen BL, et al. dense AC on pathologic complete response in triple-negative breast cancer
Supportive care after curative treatment for breast cancer (survivorship care): (TNBC): CALGB 40603 (Alliance). Abstr. 2013 San Antonio breast Cancer
resource allocations in low- and middle-income countries. A Breast Health symposium, S5eS01.
Global Initiative 2013 consensus statement. Breast 2013;22(5):606e15. [50] von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al.
[27] Cardoso F, Bese N, Distelhorst SR, Bevilacqua JL, Ginsburg O, Grunberg SM, Neoadjuvant carboplatin in patients with triple-negative and HER2-positive
et al. Supportive care during treatment for breast cancer: resource alloca- early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet
tions in low- and middle-income countries. A Breast Health Global Initiative Oncol 2014;15(7):747e56.
2013 consensus statement. Breast 2013;22(5):593e605. [51] Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, et al. The
[28] Silverman R, Smith L, Sundar S. 'Is it my last christmas dinner?' survival of value of platinum agents as neoadjuvant chemotherapy in triple-negative
cancer patients having palliative chemotherapy during christmas period. breast cancers: a systematic review and meta-analysis. Breast Cancer Res
BMJ Support Palliat Care 2014 Mar;4(Suppl. 1):A56. http://dx.doi.org/ Treat 2014;144(2):223e32.
10.1136/bmjspcare-2014-000654.159. [52] Alba E, Chacon J, Lluch A, Anton A, Estevez L, Cirauqui B, et al. A randomized
[29] El Saghir NS, Adebamowo CA, Anderson BO, Carlson RW, Bird PA, Corbex M, et al. phase II trial of platinum salts in basal-like breast cancer patients in the
Breast cancer management in low resource countries (LRCs): consensus state- neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study.
ment from the Breast Health Global Initiative. Breast 2011;20(Suppl. 2):S3e11. Breast Cancer Res Treat 2012;136(2):487e93.
[30] Macdonald SM, Harris EE, Arthur DW, Bailey L, Bellon JR, Carey L, et al. ACR [53] Koshy N, Quispe D, Shi R, Mansour R, Burton GV. Cisplatin-gemcitabine
appropriateness criteria locally advanced breast cancer. Breast J therapy in metastatic breast cancer: improved outcome in triple negative
2011;17(6):579e85. breast cancer patients compared to non-triple negative patients. Breast 2010
[31] Chia S, Swain SM, Byrd DR, Mankoff DA. Locally advanced and inammatory Jun;19(3):246e8.
breast cancer. J Clin Oncol 2008;26:786e90. [54] Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC. Plasma pre-
[32] Giordano SH. Update on locally advanced breast cancer. Oncologist 2003;8: cursors of oestrogen. II. Correlation of the extent of conversion of plasma
521e30. androstenedione to estrone with age. J Clin Endocrinol Metab 1974;38:
[33] Yamauchi H, Woodward WA, Valero V, Alvarez RH, Lucci A, Buchholz TA, 476e9.
et al. Inammatory breast cancer: what we know and what we need to learn. [55] Handesman D. Androgen actions and pharmacologic uses, Endocrinology.
Oncologist 2012;17(7):891e9. Philadelphia: WB Saunders; 2001. p. 2232e42.
[34] Brennan ME, Houssami N. Evaluation of the evidence on staging imaging for [56] Sousa B, Moser E, Cardoso F. An update on male breast cancer and future
detection of asymptomatic distant metastases in newly diagnosed breast directions for research and treatment. Eur J Pharmacol 2013;717:71e83.
cancer. Breast 2012;21:112e23. [57] Nordman IC, Dalley DN. Breast cancer in mendshould aromatase inhibitors
[35] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use become rst-line hormonal treatment? Breast J 2008;4:562e9.
of chemotherapy plus a monoclonal antibody against HER2 for metastatic [58] Faneyte IF, Turgers EJ, Zoetmulder FA. Chest wall resection in the treatment
breast cancer that overexpresses HER2. N Engl J Med 2001 Mar 15;344(11): of locally recurrent breast carcinoma: indications and outcome for 44 pa-
783e92. tients. Cancer 1997;80(5):886.
F. Cardoso et al. / The Breast 23 (2014) 489e502 501

[59] Schwaibold F, Fowble BL, Solin LJ, Schultz DJ, Goodman RL. The results of [82] Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for treatment
radiation therapy for isolated local regional recurrence after mastectomy. Int of advanced breast cancer in postmenopausal women. Cochrane Database
J Radiat Oncol Biol Phys 1991;21(2):299e310. Syst Rev 2009;(4):CD003370.
[60] Skinner HD, Strom EA, Motwani SB, Woodward WA, Green MC, Babiera G, [83] Bonneterre J, Thrlimann B, Robertson JF, Krzakowski M, Mauriac L,
et al. Radiation dose escalation for loco-regional recurrence of breast cancer Koralewski P, et al. Anastrozole versus tamoxifen as rst-line therapy for
after mastectomy. Radiat Oncol 2013;8:13. advanced breast cancer in 668 postmenopausal women: results of the
[61] Mller AC, Eckert F, Heinrich V, Bamberg M, Brucker S, Hehr T. Re-surgery Tamoxifen or Arimidex Randomized Group Efcacy and Tolerability study. J
and chest wall re-irradiation for recurrent breast cancer: a second curative Clin Oncol 2000;18(22):3748e57.
approach. BMC Cancer 2011;11:197. [84] Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, et al.
[62] Kilburn JM, Kuremsky JG, Blackstock AW, Munley MT, Kearns WT, Anastrozole is superior to tamoxifen as rst-line therapy for advanced breast
Hinson WH, et al. Thoracic re-irradiation using stereotactic body radio- cancer in postmenopausal women: results of a North American multicenter
therapy (SBRT) techniques as rst or second course of treatment. Radiother randomized trial. Arimidex Study Group. J Clin Oncol 2000;18(22):3758e67.
Oncol 2014;110(3):505e10. [85] Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, et al. Anastrozole
[63] Seiwer TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm- versus tamoxifen as rst-line therapy in postmenopausal patients with
general principles. Nat Clin Pract 2007;4(2):86. hormone-dependent advanced breast cancer: a prospective, randomized,
[64] Wilson GD, Bentzen SM, Harari PM. Biologic basis for combining drugs with phase III study. Am J Clin Oncol 2003;26(3):317e22.
radiation. Semin Radiat Oncol 2006;16(1):2e9. [86] Paridaens R, Dirix L, Lohrisch C, et al. European Organization for the Research
[65] Lawrence TS, Tepper JE, Blackstock AW. Fluoropyrimidine-Radiation In- and Treatment of Cancer (EORTC)- Investigational Drug Branch for Breast
teractions in Cells and Tumors. Semin Radiat Oncol 1997;7(4):260e6. Cancer (IDBBC). Mature results of a randomized phase II multicenter study of
[66] Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H. X-ray irradiation exemestane versus tamoxifen as rst-line hormone therapy for post-
induces thymidine phosphorylase and enhances the efcacy of capecitabine menopausal women with metastatic breast cancer. Ann Oncol 2003;14:
(Xeloda) in human cancer xenografts. Clin Cancer Res 1999;5(10):2948e53. 1391e8.
[67] Crane CH, Abbruzzese JL, Evans DB, Wolff RA, Ballo MT, Delclos M, et al. Is the [87] Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A,
therapeutic index better with gemcitabine-based chemoradiation than with et al. Phase III study of letrozole versus tamoxifen as rst-line therapy of
5-uorouracil-based chemoradiation in locally advanced pancreatic cancer? advanced breast cancer in postmenopausal women: analysis of survival and
Int J Radiat Oncol Biol Phys 2002;52(5):1293e302. update of efcacy from the International Letrozole Breast Cancer Group. J
[68] Liebmann J, Cook JA, Fisher J, Teague D, Mitchell JB. In vitro studies of Taxol Clin Oncol 2003;21(11):2101e9.
as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 1994;86(6): [88] Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, et al. Phase III
441e6. study comparing exemestane with tamoxifen as rst-line hormonal treat-
[69] Gonz alez JE, Barquinero JF, Lee M, Garca O, Casaco A. Radiosensitization ment of metastatic breast cancer in postmenopausal women: the European
induced by the anti-epidermal growth factor receptor monoclonal anti- Organisation for Research and Treatment of Cancer Breast Cancer Coopera-
bodies cetuximab and nimotuzumab in A431 cells. Cancer Biol Ther tive Group. J Clin Oncol 2008;26(30):4883e90.
2012;13(2):71e6. [89] Baselga J, Campone M, Piccart M, Burris 3rd HA, Rugo HS, Sahmoud T, et al.
[70] Horton JK, Halle J, Ferraro M, Carey L, Moore DT, Ollila D, et al. Radio- Everolimus in postmenopausal hormone-receptor-positive advanced breast
sensitization of chemotherapy-refractory, locally advanced or locally recur- cancer. N Engl J Med 2012;366(6):520e9.
rent breast cancer with trastuzumab: a phase II trial. Int J Radiat Oncol Biol [90] Yardley DA, Noguchi S, Pritchard KI, Burris 3rd HA, Baselga J, Gnant M, et al.
Phys 2010;76(4):998e1004. Everolimus plus exemestane in postmenopausal patients with HR(+) breast
[71] Lo ser DA, Shibata A, Shibata AK, Woodbine LJ, Jeggo PA, Chalmers AJ. cancer: BOLERO-2 nal progression-free survival analysis. Adv Ther
Sensitization to radiation and alkylating agents by inhibitors of poly(ADP- 2013;30(10):870e84.
ribose) polymerase is enhanced in cells decient in DNA double-strand break [91] Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Noguchi S, Rugo H, et al.
repair. Mol Cancer Ther 2010;9(6):1775e87. Overall Survival Results From BOLERO-2. In: Presented at EBCC-9; 2014.
[72] Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, et al. Everolimus Plus Exemestane for Hormone Receptor-Positive (HR+), Human
Randomized trial of hyperthermia and radiation for supercial tumors. J Clin Epidermal Growth Factor Receptor-2eNegative (HER2e) Advanced Breast
Oncol 2005;23:3079e85. Cancer (BC) Abstract 1 LBA.
[73] Vernon CC, Hand JW, Field SB, Machin D, Whaley JB, van der Zee J, et al. [92] Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G,
Radiotherapy with or without hyperthermia in the treatment of supercial et al. Randomized phase II trial of everolimus in combination with
localized breast cancer: results from ve randomized controlled trials. Int J tamoxifen in patients with hormone receptor-positive, human epidermal
Radiat Oncol Biol Phys 1996;35:731e44. growth factor receptor 2-negative metastatic breast cancer with prior
[74] Zagar TM, Higgins KA, Miles EF, Vujaskovic Z, Dewhirst MW, Clough RW, exposure to aromatase inhibitors: a GINECO study. J Clin Oncol
et al. Durable palliation of breast cancer chest wall recurrence with radiation 2012;30(22):2718e24.
therapy, hyperthermia, and chemotherapy. Radiother Oncol 2010;97: [93] Gelmon KA, Boyle F, Kaufman B, Huntsman D, Manikhas A, Di Leo A, et al.
535e40. Open-label phase III randomized controlled trial comparing taxane-based
[75] Borner M, Bacchi M, Goldhirsch A, Greiner R, Harder F, Castiglione M, et al. chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as rst-line ther-
First isolated locoregional recurrence following mastectomy for breast can- apy for women with HER2+ metastatic breast cancer: Interim analysis (IA) of
cer: results of a phase III multicenter study comparing systemic treatment NCIC CTG MA.31/GSK EGF 108919. J Clin Oncol 2012;30 [suppl; abstr
with observation after excision and radiation. Swiss Group for Clinical Cancer LBA671].
Research. J Clin Oncol 1994;12(10):2071e7. _
[94] Pivot X, Zurawski B, Allerton R, Fabi A, Ciruelos E, Parikh R, et al. CEREBEL
[76] Aebi S, Gelber S, Anderson SJ, La ng I, Robidoux A, Martn M. Chemotherapy (EGF111438): an open label randomized phase III study comparing the
for isolated locoregional recurrence of breast cancer (CALOR): a randomised incidence of CNS metastases in patients (pts) with HER2+ metastatic breast
trial. Lancet Oncol 2014;15(2):156e63. cancer (MBC), treated with lapatinib plus capecitabine (LC) versus trastu-
[77] Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, et al. Ful- zumab plus capecitabine (TC); LBA11. Ann Oncol 2012;23:ixe1e30.
vestrant versus anastrozole for the treatment of advanced breast carcinoma [95] Piccart-Gebhart MJ, Holmes AP, Baselga J, De Azambuja E, Dueck AC, Viale G,
in postmenopausal women: a prospective combined analysis of two multi- et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance]
center trials. Cancer 2003 Jul 15;98(2):229e38. N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L),
[78] Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, et al. Ful- trastuzumab alone (T), their sequence (T/L), or their combination (T+L) in
vestrant versus anastrozole for the treatment of advanced breast carcinoma: the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin
a prospectively planned combined survival analysis of two multicenter trials. Oncol 2014;32(5s). abstr LBA4.
Cancer 2005 Jul 15;104(2):236e9. [96] Baselga J, Corte s J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus
[79] Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med
Double-blind, randomized placebo controlled trial of fulvestrant 2012;366(2):109e19.
compared with exemestane after prior nonsteroidal aromatase inhibitor [97] Swain SM, Kim SB, Corte s J, Ro J, Semiglazov V, Campone M, et al. Pertu-
therapy in postmenopausal women with hormone receptor-positive, zumab, trastuzumab, and docetaxel for HER2-positive metastatic breast
advanced breast cancer: results from EFECT. J Clin Oncol 2008;26(10): cancer (CLEOPATRA study): overall survival results from a randomised,
1664e70. double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14(6):
[80] Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, 461e71.
et al. Results of the conrm phase III trial comparing fulvestrant 250 mg [98] Cortes J, Fumoleau P, Bianchi GV, Petrella TM, Gelmon K, Pivot X, et al.
with fulvestrant 500 mg in postmenopausal women with estrogen Pertuzumab monotherapy after trastuzumab-based treatment and subse-
receptor-positive advanced breast cancer. J Clin Oncol 2010;28(30): quent reintroduction of trastuzumab: activity and tolerability in patients
4594e600. with advanced human epidermal growth factor receptor 2-positive breast
[81] Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, , cancer. J Clin Oncol 2012 May 10;30(14):1594e600.
et alSoFEA Investigators. Fulvestrant plus anastrozole or placebo versus [99] Blackwell KL, Miles D, Gianni L, Krop IE, Welslaw M, Baselga J, et al. Primary
exemestane alone after progression on non-steroidal aromatase inhibitors in results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1)
postmenopausal patients with hormone-receptor-positive locally advanced versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced
or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 or metastatic breast cancer (MBC) previously treated with trastuzumab (T)
randomised trial. Lancet Oncol 2013;14(10):989e98. and a taxane. J Clin Oncol 2012;30(5s). suppl; abstr LBA1.
502 F. Cardoso et al. / The Breast 23 (2014) 489e502

[100] Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab [115] Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al.
emtansine for HER2-positive advanced breast cancer. N Engl J Med Eribulin monotherapy versus treatment of physician's choice in patients
2012;367(19):1783e91. with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised
[101] Krop IE, Kim SB, Gonza lez-Martn A, LoRusso PM, Ferrero JM, Smitt M, et al. study. Lancet 2011 Mar 12;377(9769):914e23.
Trastuzumab emtansine versus treatment of physician's choice for pre- [116] Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Wanders J, et al. A phase
treated HER2-positive advanced breast cancer (TH3RESA): a randomised, III, open-label, randomized, multicenter study of eribulin mesylate versus
open-label, phase 3 trial. Lancet Oncol 2014;15(7):689e99. capecitabine in patients with locally advanced or metastatic breast cancer
[102] Dear RF, McGeechan K, Jenkins MC, Barratt A, Tattersall MHN, Wilcken N. previously treated with anthracyclines and taxanes. Cancer Res
Combination versus sequential single agent chemotherapy for metastatic 2012;72(Suppl. 24). Abstract nr S6e6.
breast cancer. Cochrane Database Syst Rev 2013;(12). http://dx.doi.org/ [117] Dominici L, Najita J, Hughes M, Niland J, Marcom P, Wong YN, et al. Surgery
10.1002/14651858.CD008792.pub2. Art. No.: CD008792. of the primary tumor does not improve survival in stage IV breast cancer.
[103] Piccart-Gebhart MJ, Burzykowski T, Buyse M, Sledge G, Carmichael J, Lck HJ, Breast Cancer Res Treat 2011;129(2):459e65.
et al. Taxanes alone or in combination with anthracyclines as rst-line [118] Ly BH, Nguyen NP, Vinh-Hung V, Rapiti E, Vlastos G. Loco-regional treatment
therapy of patients with metastatic breast cancer. J Clin Oncol 2008 Apr in metastatic breast cancer patients: is there a survival benet? Breast
20;26(12):1980e6. Cancer Res Treat 2010;119(3):537e45.
[104] Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, et al. [119] Neuman HB, Morrogh M, Gonen M, Van Zee KJ, Morrow M, King TA. Stage IV
Capecitabine versus classical cyclophosphamide, methotrexate, and uoro- breast cancer in the era of targeted therapy: does surgery of the primary
uracil as rst-line chemotherapy for advanced breast cancer. J Clin Oncol tumor matter? Cancer 2010;116(5):1226e33.
2011;29(34):4498e504. [120] Rashaan ZM, Bastiaannet E, Portielje JE, van de Water W, van der Velde S,
[105] Blum JL, Barrios CH, Feldman N, Verma S, McKenna Lee LF, et al. Pooled Ernst MF, et al. Surgery in metastatic breast cancer: patients with a favorable
analysis of individual patient data from capecitabine monotherapy clinical prole seem to have the most benet from surgery. Eur J Surg Oncol
trials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2012;38(1):52e6.
2012;136(3):777e88. [121] Ruiterkamp J, Ernst MF. The role of surgery in metastatic breast cancer. Eur J
[106] Robert NJ, Die ras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. Cancer 2011;47(Suppl. 3):S6e22.
RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of [122] Nguyen DH, Truong PT, Alexander C, Walter CV, Hayashi E, Christie J, et al.
chemotherapy with or without bevacizumab for rst-line treatment of hu- Can locoregional treatment of the primary tumor improve outcomes for
man epidermal growth factor receptor 2-negative, locally recurrent or women with stage IV breast cancer at diagnosis? Int J Radiat Oncol Biol Phys
metastatic breast cancer. J Clin Oncol 2011;29(10):1252e60. 2012;84(1):39e45.
[107] Oshaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, et al. [123] Petrelli F, Barni S. Surgery of primary tumors in stage IV breast cancer: an
Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a updated meta-analysis of published studies with meta-regression. Med
reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5- Oncol 2012;29:3282e90.
uorouracil) as rst-line therapy for advanced/metastatic breast cancer. Ann [124] Ruiterkamp J, Voogd AC, Tjan-Heijnen VC, Bosscha K, van der Linden YM,
Oncol 2001;12(9):1247e54. Rutgers EJ, et al. SUBMIT: Systemic therapy with or without up front surgery
[108] Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, et al. RIBBON-2: of the primary tumor in breast cancer patients with distant metastases at
a randomized, double-blind, placebo-controlled, phase III trial evaluating the initial presentation. BMC Surg 2012 Apr 2;12:5.
efcacy and safety of bevacizumab in combination with chemotherapy for [125] Shien T, Nakamura K, Shibata T, Kinoshita T, Aogi K, Fujisawa T, et al. A
second-line treatment of human epidermal growth factor receptor 2-nega- randomized controlled trial comparing primary tumour resection plus sys-
tive metastatic breast cancer. J Clin Oncol 2011;29(32):4286e93. temic therapy with systemic therapy alone in metastatic breast cancer
[109] Talbot DC, Moiseyenko V, Van Belle S, O'Reilly SM, Alba Conejo E, Ackland S, (PRIM-BC): Japan Clinical Oncology Group Study JCOG1017. Jpn J Clin Oncol
et al. Randomised, phase II trial comparing oral capecitabine (Xeloda) with 2012;42(10):970e3.
paclitaxel in patients with metastatic/advanced breast cancer pretreated [126] Badwe R, Parmar V, Hawaldar R, Nair N, Kaushik R, Siddique S, et al. Surgical
with anthracyclines. Br J Cancer 2002;86(9):1367e72. removal of primary tumor and axillary lymph nodes in women with meta-
[110] Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, et al. Multicenter static breast cancer at rst presentation: a randomized controlled trial.
phase II study of capecitabine in paclitaxel-refractory metastatic breast Cancer Res 2013;73(Suppl. 24). S2eS02.
cancer. J Clin Oncol 1999;17(2):485e93. [127] Soran Atilla, Ozmen Vahit, Ozbas Serdar, Karanlk Hasan,
[111] Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, et al. Multi- Muslumanoglu Mahmut, Igci Abdullah, et al. Early follow up of a randomized
center, Phase II study of capecitabine in taxane-pretreated metastatic breast trial evaluating resection of the primary breast tumor in women presenting
carcinoma patients. Cancer 2001;92(7):1759e68. with de novo stage IV breast cancer: Turkish Study (Protocol MF07e01).
[112] Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Cancer Res 2013;73(Suppl. 24). S2-02.
et al. Randomized phase III trial of capecitabine compared with bevacizumab [128] Thompson AM, Jordan LB, Quinlan P, Anderson E, Skene A, Dewar JA, et al.
plus capecitabine in patients with previously treated metastatic breast Prospective comparison of switches in biomarker status between primary
cancer. J Clin Oncol 2005;23(4):792e9. and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS).
[113] Andersson Michael, Lidbrink Elisabeth, Bjerre Karsten, Wist Erik, Breast Cancer Res 2010;12(6):R92.
Enevoldsen Kristin, Jensen Anders B, et al. Phase III randomized study [129] Amir E, Clemons M, Purdie CA, Miller N, Quinlan P, Geddie W, et al. Tissue
comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as conrmation of disease recurrence in breast cancer patients: pooled analysis
rst-line therapy of metastatic or locally advanced human epidermal growth of multi-centre, multi-disciplinary prospective studies. Cancer Treat Rev
factor receptor 2ePositive breast Cancer: the HERNATA study. J Clin Oncol 2012;38(6):708e14.
2010;29:264e71. [130] Foukakis T, stro m G, Lindstro
m L, Hatschek T, Bergh J. When to order a
[114] Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, biopsy to characterise a metastatic relapse in breast cancer. Ann Oncol
et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2- 2012;23(Suppl. 10):x349e53.
overexpressing metastatic breast cancer: the trastuzumab and vinorelbine
or taxane study. Cancer 2007 Sep 1;110(5):965e72.

S-ar putea să vă placă și