Cardoso 2014

special article Annals of Oncology 25: 1871–1888, 2014
doi:10.1093/annonc/mdu385
Published online 18 September 2014
ESO-ESMO 2nd international consensus guidelines

for advanced breast cancer (ABC2)†
F. Cardoso1*, A. Costa2,3, L. Norton4, E. Senkus5, M. Aapro6, F. André7, C. H. Barrios8, J. Bergh9,
L. Biganzoli10, K. L. Blackwell11, M. J. Cardoso12, T. Cufer13, N. El Saghir14, L. Fallowfield15,
D. Fenech16, P. Francis17, K. Gelmon18, S. H. Giordano19, J. Gligorov20, A. Goldhirsch21,
N. Harbeck22, N. Houssami23, C. Hudis24, B. Kaufman25, I. Krop26, S. Kyriakides27, U. N. Lin26,
M. Mayer28, S. D. Merjaver29, E. B. Nordström30, O. Pagani31, A. Partridge32, F. Penault-Llorca33,
Downloaded from http://annonc.oxfordjournals.org/ at Oxford Brookes University on December 24, 2014

M. J. Piccart34, H. Rugo35, G. Sledge36, C. Thomssen37, L. van’t Veer38, D. Vorobiof39, C. Vrieling40,
N. West41, B. Xu42 & E. Winer26
1
European School of Oncology & Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal; 2European School of Oncology, Milan, Italy; 3European School of Oncology,
Bellinzona, Switzerland; 4Breast Cancer Program, Memorial Sloan-Kettering Cancer Centre, New York, USA; 5Department of Oncology and Radiotherapy, Medical
University of Gdansk, Gdansk, Poland; 6Division of Oncology, Institut Multidisciplinaire d’Oncologie, Genolier, Switzerland; 7Department of Medical Oncology, Gustave-
Roussy Institute, Villejuif, France; 8Department of Medicine, PUCRS School of Medicine, Porto Alegre, Brazil; 9Department of Oncology/Radiumhemmet, Karolinska
Institutet & Cancer Center Karolinska and Karolinska University Hospital, Stockholm, Sweden; 10Department of Medical Oncology, Sandro Pitigliani Oncology Centre, Prato,
Italy; 11Breast Cancer Clinical Program, Duke Cancer Institute, Durham, USA; 12Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal; 13University Clinic Golnik,
Medical Faculty Ljubljana, Ljubljana, Slovenia; 14NK Basile Cancer Institute Breast Center of Excellence, American University of Beirut Medical Center, Beirut, Lebanon;
15
Brighton & Sussex Medical School, University of Sussex, Falmer, UK; 16Breast Care Support Group, Europa Donna Malta, Mtarfa, Malta; 17Division of Cancer Medicine,
Peter MacCallum Cancer Centre, Melbourne, Australia; 18BC Cancer Agency, Vancouver, Canada; 19Departments of Health Services Research and Breast Medical
Oncology, UT MD Anderson Cancer Center, Houston, USA; 20APHP Tenon, IUC-UPMC, Francilian Breast Intergroup, AROME, Paris, France; 21Program of Breast Health,
special article
European Institute of Oncology, Milan, Italy; 22Brustzentrum der Universität München, Munich, Denmark; 23Screening and Test Evaluation Program, School of Public Health,
Sydney Medical School, University of Sydney, Sydney, Australia; 24Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, USA; 25Sheba
Medical Center, Tel Hashomer, Israel; 26Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 27Europa Donna Cyprus, Nicosa, Cyprus;
28
AdvancedBC.org, New York; 29University of Michigan Medical School and School of Public Health, Ann Arbor, USA; 30Europa Donna Sweden &
Bröstcancerföreningarnas Riksorganisation, BRO, Sundbyberg, Sweden; 31Oncology Institute of Southern Switzerland and Breast Unit of Southern Switzerland, Bellinzona,
Switzerland; 32Department Medical Oncology, Division of Women’s Cancers, Dana-Farber Cancer Institute, Boston, USA; 33Jean Perrin Centre, Comprehensive Cancer
Centre, Clermont Ferrand, France; 34Department of Medicine, Institut Jules Bordet, Brussels, Belgium; 35Department of Medicine, Breast Oncology Program, UCSF Helen
Diller Family Comprehensive Cancer Center, San Francisco; 36Indiana University Medical CTR, Indianapolis, USA; 37Department of Gynaecology, Martin-Luther-University
Halle-Wittenberg, Halle an der Saale, Germany; 38Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA; 39Sandton
Oncology Centre, Johannesburg, South Africa; 40Department of Radiotherapy, Clinique des Grangettes, Geneva, Switzerland; 41Nursing Division, Health Board, Cardiff and
Vale University, Cardiff, UK; 42Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Received 5 August 2014; accepted 11 August 2014
introduction specialized institutions [6]. Implementation of current knowl-

edge is highly variable among countries and within each
Advanced breast cancer (ABC) is a treatable but still generally
country.
incurable disease. The goals of care are to optimize both length
The use of treatment guidelines has been associated with a
and quality of life. Due to continuous research, several advances
significant improvement in survival [7–9]. This has been
have been made, particularly for the human epidermal growth
achieved mainly in early breast cancer. For ABC, and particu-
factor receptor 2 (HER-2)-positive and for luminal-like sub-
larly metastatic breast cancer (MBC), less level 1 evidence
types. Notwithstanding these advances, median overall survival
exists and only recently has international consensus guidelines
of patients with ABC is still only 2–3 years, although the range
been developed (ABC1) [10]. The ABC Consensus Conference
is wide [1–5], and survival may be longer for patients treated in
was created by the European School of Oncology (ESO) with
the ambitious goal of improving outcomes for all patients
*Correspondence to: Dr Fatima Cardoso, Champalimaud Cancer Center, Av. De Brasília,
s/n, 1400-048 Lisbon, Portugal. Fax: +351-210-480-298; E-mail: fatimacardoso@
with ABC. Backed by strong political advocacy, ABC guide-
fundacaochampalimaud.pt lines are seeking to improve standards of care, to raise aware-
†
ness about how to best meet to the needs of this underserved
Important note: These Guidelines were developed by ESO and ESMO and are pub-
group of patients, and to identify research priorities, so that
lished 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: 1871–1888) and both must clinical research is focused on the most important areas of
be cited. unmet need.
© The Authors 2014. Published by Oxford University Press.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/
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special article Annals of Oncology
Following the work of the ESO-ABC Task Force [11–14],

created in 2005, and the successful undertaking of the 1st
Strong recommendation, but may change when higher
Very weak recommendation, other alternatives may be

Strong recommendation, can apply to most patients in
Strong recommendation, can apply to most patients in
depending on circumstances or patients’ or societal
depending on circumstances or patients’ or societal

International Consensus Guidelines Conference on ABC
(ABC1), held in November 2011, the 2nd International
Weak recommendation, best action may differ
Weak recommendation, best action may differ

Consensus Conference for Advanced Breast Cancer (ABC2)
most circumstances without reservation
most circumstances without reservation

took place in Lisbon, Portugal, on 7–9 November 2013. The
quality evidence becomes available

conference brought together about 1100 participants from 71
countries, including health professionals, patient advocates,
and journalists. A series of guidelines were discussed 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
equally reasonable
globally. These guidelines are developed as a joint effort from
ESO and ESMO (European Society of Medical Oncology), are
Implications
endorsed by EUSOMA (European Society of Breast Cancer
values
values
Specialists), SIS (Senologic International Society), and Flam

(Federación Latino Americana de Mastologia), and organized
under the auspices of UICC (Union Internationale Contre
RCTs with important limitations (inconsistent results, methodological flaws,
RCTs with important limitations (inconsistent results, methodological flaws,

Le Cancer), OECI (Organization of European Cancer Insti-
tutes), and the BCRF (Breast Cancer Research Foundation).
The present study summarizes the guidelines developed at
RCTs without important limitations or overwhelming evidence from

randomized clinical trials (RCTs) without important limitations or
ABC2. The guidelines include the level of evidence, the per-
indirect, or imprecise) or exceptionally strong evidence from
indirect, or imprecise) or exceptionally strong evidence from

centage of panel members who agreed with the consensus
statements, and the supporting references for each recom-
mendation. Importantly, the ABC guidelines are developed as
overwhelming evidence from observational studies

clinical management recommendations potentially applicable
worldwide, albeit with the necessary adjustments for each country, Methodological quality of supporting evidence
depending on access to therapies. The guidelines are based on the
underlying principles of modern oncology, emphasizing the
crucial role of a multidisciplinary and individualized approach
Observational studies or case series
Observational studies or case series

that respects the specificities of the advanced setting and the pre-
ferences of each patient. The manuscript also clearly highlights
areas where research efforts are urgently needed. observational studies
observational studies
observational studies
methodology
Prior to the ABC2 Conference, a set of preliminary recommendation state-
ments on the treatment of ABC were prepared, based on available
published data and following the ESMO guidelines methodology. These
recommendations were circulated to all 43 panel members by email for
Benefits clearly outweigh risk

and burdens, or vice versa
comments and corrections on content and wording. A final set of recom-

Benefits closely balanced

with risks and burden

mendations was presented, discussed, and voted upon during the consen-
Benefit versus risk and
sus session of ABC2. All panel members were instructed to vote on all
questions, with members with a potential conflict of interest or who did
not feel comfortable answering the question (e.g. because it is not their
Table 1. Levels of evidence grading system [15]
area of expertise) instructed to ‘abstain’ from voting. Additional changes

burdens
in the wording of statements were made during the session. The state-
ment on everolimus was updated after the presentation of the overall sur-
vival results of the BOLERO-2 trial and re-voted by email by all panel
1C/strong recommendation, low-
2A/weak recommendation, high-
members.
2C/weak recommendation, low-
Supplementary Table S1, available at Annals of Oncology online, lists all

moderate-quality evidence
moderate-quality evidence
1A/strong recommendation,
1B/strong recommendation,
Grade of recommendation/
2B/weak recommendation,
members of the ABC2 consensus panel and their disclosure of any relation-
high-quality evidence
ships that could be perceived as a potential conflict of interest.

quality evidence
quality evidence
quality evidence
Table 1 describes the grading system used [15].

Three main issues were discussed at ABC2: inoperable locally advanced
breast cancer (LABC), both inflammatory and non-inflammatory; MBC; and
description
specific definitions for which a consensus was deemed important.

For clarification, ABC comprises both LABC and MBC or stage IV. Some
of the ABC guidelines apply to both LABC and MBC, while others are spe-
cific to each of the settings.
 | Cardoso et al. Volume 25 | No. 10 | October 2014

Annals of Oncology special article
I. general guidelines A ‘patient navigator’ can help the patient going through all
phases of the cancer journey [16–20]. This is particularly rele-
vant for advanced cancer patients who are often overwhelmed
with difficult decisions to make, through complex information
Guideline statement LoE Consensus and available treatment options, and are frequently co-
managed by the breast cancer and the palliative care teams.
All ABC patients should be IB 97.2% (36) yes
This role is best taken by a specialized breast nurse, or at least a
offered comprehensive, 0% (0) abstain
specialized oncology nurse, who should be part of the multi-
culturally sensitive, up-to- (37 voters)
disciplinary team managing ABC patients. In some countries,
date, and easy to understand
however, this role may be played by a physician assistant or
information about their
disease and its management.
another trained and specialized health-care practitioner. It is also
Specialized oncology nurses (if Expert opinion 92.1% (35) yes
recognized that, in many centres, it is not yet possible for each
possible specialized breast 7.8% (3) abstain patient to have a navigator due to the lack of human resources.
nurses) should be part of the (38 voters) There is an implicit assumption that the recording of adverse
multidisciplinary team events by clinicians reliably documents patients’ side-effects and

managing ABC patients. In symptoms. However, there is an accumulating body of evidence
some countries, this role suggesting that the frequency and severity of many symptoms
may be played by a that impact on an individual patient’s quality of life go under-
physician assistant or other reported, under-recognized, and consequently under-treated
trained and specialized [21]. Since quality of life is one of the main aims of ABC treat-
health-care practitioner. ment, this poses an important problem. It is also potentially
Strong consideration should be IC 89.4% (34) yes dangerous from a drug safety point of view. The inability of
given to the use of validated 5.2% (2) abstain traditional methods for capturing adverse events has led to
instruments for patients to (38 voters) renewed interest in incorporating patient-reported outcomes
report the symptoms of (PROs/PROMs) with Common Terminology Criteria for
disease and side-effects of Adverse Events (CTC-AEs) in clinical trials, as well as utilizing
treatment they experience as PROs outside a clinical trial setting to reflect and monitor more
a regular part of their accurately the harms and benefits of patient experience. This
clinical care. These patient-
may be particularly important for drugs approved based solely
reported outcome (PRO)
on progression-free survival (PFS) benefits or only modest
instruments should be
overall survival (OS) benefits, for which the balance between ef-
simple and user-friendly to
ficacy and toxicity may be more difficult to accurately determine.
facilitate their use in clinical
Many standardized, well-validated instruments or PRO mea-
practice. This systematic
monitoring will serve to
sures are available with translations into most languages. The
facilitate communication most frequently used are the generic EORTC-QLQ-C3 (http://
between patients and their groups.eortc.be/qol/eortc-qlq-c30) and the FACT (http://www.
treatment teams, allow facit.org/FACITOrg/Questionnaires). Both have breast cancer-
optimal quality of life, and specific modules/subscales (EORTC QLQ-BR23 and FACT-B)
may better characterize the and the FACT, in particular, has several other specific subscales
toxicities of all anticancer covering, for example, treatment with epidermal growth factor
therapies. receptor (EGFR) inhibitors, taxanes, anti-angiogenesis drugs,
The age of the patient should IB 100% (38) yes endocrine agents, and monoclonal antibodies. Recently, the
not be the sole reason to 0% (0) abstain FDA and EMA have published guidance for industry on how
withhold effective therapy (38 voters) to utilize PROs in applications for drug labelling claims. There
(in elderly patients) nor to has also been an important initiative, funded by the NCI, to
overtreat (in young produce a PRO version of the Common Terminology Criteria
patients). Age alone should for Adverse Events (PRO-CTCAE), which is suggested for use
not determine the type and in NCI-sponsored trials (http://outcomes.cancer.gov/tools/pro-
intensity of treatment. ctcae.html).
Although age is an important factor to consider in decision-
LoE: available level of evidence; consensus: percentage of panel
making for ABC, it must not be the sole factor to determine the
members in agreement with the statement.
intensity and type of treatment. There is a tendency to withhold
therapy in some elderly patients because of fear of toxicity or
concern about co-morbidity. In some cases, however, such ther-
ABC1 guidelines had already emphasized the importance of in- apies may be highly effective and could improve both survival
cluding the patient in all steps of the decision-making process [10]. and quality of life. At the same time, younger patients are often
For active and informed participation, patients must have access to overtreated or treated somewhat inappropriately. Age may influ-
comprehensive, culturally sensitive, up-to-date, and easy to under- ence breast cancer treatment, but it should not be the guiding
stand information about their disease and its management. force [10, 22–24].
Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

‘Survivorship’ in ABC Current terminology uses several ill-defined terms that often
The complex needs of patients living with ABC, at times for have different meanings, leading to confusion and difficulty in
many years, as well as their caregivers, should be addressed not adapting clinical trial findings to current practice populations.
only in terms of supportive and palliative care but also regarding The ABC2 panel tried to define two of these important terms,
‘survivorship’ concerns. The multidisciplinary approach of ABC aiming at standardization of their use.
should encompass early in the history of the disease not only Regarding endocrine resistance, an attempt was made to be
physical, but also functional, social, psychological, and spiritual, consistent with a definition reached by a number of investigators
domains [25–27]. involved in breast cancer clinical trials, at a meeting sponsored
It is important to clearly define the disease context with by NCI held in May 2012 and later approved by the North
patients and families, addressing the concept of uncertainty and American Breast Cancer Groups (NABCGs).
tailoring the treatment strategy according to individual priorities It is also important to note that endocrine resistance is a con-
and disease status [28]. Specific psychosocial needs of young tinuum, and that strict definitions are mainly helpful for the clin-
and elderly patients should also be recognized and supported, ical trial setting and not necessarily for routine clinical practice.
i.e. social security, job flexibility, rehabilitation, body image
(including sexuality), home, and child care. III. inoperable locally advanced,

non-inflammatory, breast cancer
II. important ABC-related definitions
Guideline statements LoE Consensus
Guideline statements LoE Consensus Before starting any therapy, a IB 97.2% (36) yes
core biopsy providing 2.7% (1) abstain
Visceral crisis is defined as Expert opinion 95.0% (38) yes
histology and biomarker (ER, (37 voters)
severe organ dysfunction as 5.0% (2) abstain
PR, HER-2, and
assessed by signs and (40 voters)
proliferation/grade)
symptoms, laboratory
expression is indispensable
studies, and rapid
to guide treatment decisions.
progression of disease.
Since LABC patients have a IB 100% (37) yes
Visceral crisis is not the
significant risk of metastatic 0% (0) abstain
mere presence of visceral
disease, a full staging (37 voters)
metastases, but implies
workup, including a
important visceral
complete history, physical
compromise leading to a
examination, laboratory tests,
clinical indication for a
and imaging of chest and
more rapidly efficacious
abdomen (preferably CT
therapy, particularly since
scans) and bone, prior to
another treatment option
initiation of systemic
at progression will probably
therapy, is highly
not be possible.
recommended.
Primary endocrine resistance Expert opinion 66.6% (22) Yes
PET–CT, if available, may be IIB 100% (37) yes
is defined as: a relapse 21.2% (7) abstain
used (instead of and not on 0% (0) abstain
while on the first 2 years of (33 voters)
top of CT scans and bone (37 voters)
adjuvant ET, or PD within
scan).
first 6 months of first-line
Systemic therapy (not surgery Expert 100% (40) yes
ET for MBC, while on ET
or radiotherapy) should be opinion 0% (0) abstain
Secondary (acquired)
the initial treatment. If LABC (40 voters)
endocrine resistance is
remains inoperable after
defined as: a relapse while
systemic therapy and
on adjuvant ET but after
eventual radiation, ‘palliative’
the first 2 years, or a relapse
mastectomy should not be
within 12 months of
done, unless the surgery is
completing adjuvant ET, or
likely to result in an overall
PD ≥6 months after
improvement in quality of
initiating ET for MBC,
life.
while on ET.
A combined treatment IA 100% (39) yes
modality based on a 0% (0) abstain
multidisciplinary approach (39 voters)
members in agreement with the statement; ET: endocrine therapy;
(systemic therapy, surgery,
PD: progressive disease; MBC: metastatic breast cancer.
and radiotherapy) is strongly
Continued
 | Cardoso et al. Volume 25 | No. 10 | October 2014

Continued IV. inoperable, locally advanced
inflammatory, breast cancer
indicated in the vast majority
of cases.
For triple-negative LABC, IA 85.3% (35) yes Guideline statements LoE Consensus
anthracycline- and taxane- 9.7% (4) abstain
based chemotherapy is (41 voters) For inflammatory LABC, IB 92.6% (38) yes
recommended as an initial overall treatment 4.8% (2) abstain
treatment. recommendations are (41 voters)
For HER-2-positive LABC, IA 91.8% (34) yes similar to those for non-
concurrent taxane and anti- 5.4% (2) abstain inflammatory LABC, with
HER-2 therapy is (37 voters) systemic therapy as a first
recommended since it treatment.
increases the rate of Mastectomy with axillary IB 95.1% (39) yes
pathological complete dissection is recommended 4.8% (2) abstain

response (pCR). in almost all cases, even (41 voters)
For HER-2-positive LABC, IA 71.7% (28) yes when there is a good
anthracycline-based 12.8% (5) response to primary
chemotherapy should be abstain systemic therapy.
incorporated into the (39 voters) Immediate reconstruction is Expert opinion 94.7% (36) yes
treatment regimen. generally not recommended 2.6% (1) abstain
In HER-2-positive LABC, when IA 86.8% (33) yes in patients with (38 voters)
an anthracycline is given, it 10.5% (4) inflammatory LABC.
should be administered abstain Locoregional radiotherapy IB 97.5% (39) yes
sequentially with the anti- (38 voters) (chest wall and lymph 2.5% (1) abstain
HER-2 therapy. nodes) is required, even (40 voters)
Options for hormonal receptor- IA 85.3% (35) yes when a pCR is achieved with
positive LABC include an 9.7% (4) abstain systemic therapy.
anthracycline- and taxane- (41 voters)
based chemotherapy MBC: metastatic breast cancer; LoE: available level of evidence;
regimen, or endocrine consensus: percentage of panel members in agreement with the
therapy. statement; pCR: pathological complete remission.
The choice of chemotherapy
versus endocrine therapy, as
an initial treatment, will
depend on tumour (grade,
biomarker expression) and
LABC occurs at first presentation in about one-fifth of breast
patient (menopausal status, cancer patients worldwide, with lower incidence in countries
performance status, with established screening programmes but as high as 60% in
comorbidities, preference) some other countries [29]. Usually, the definition of LABC
considerations. includes large operable primary breast tumours (stage IIB, IIIA)
Following effective neoadjuvant IIB 97.5% (39) yes and/or those involving the skin or chest wall and/or those with
systemic therapy with or 0% abstain extensive lymphadenopathies (stage IIIB, IIIC) [30]. For the
without radiotherapy, surgery (40 voters) purpose of ABC guidelines, we define LABC as inoperable
will be possible in many locally advanced disease that has not yet spread to distant sites.
patients. This will consist of Inoperable LABC is a heterogeneous designation encompass-
mastectomy with axillary ing a range of clinical situations from neglected low-grade ER-
dissection in the vast majority positive breast cancers to rapidly progressing usually ER-nega-
of cases, but in selected tive disease [30–33].
patients with a good response, A more homogenous form of LABC is inflammatory breast
breast-conserving surgery may cancer (IBC), a distinct clinic–pathologic entity. IBC has a greater
be possible. association with younger age at diagnosis, higher tumour grade,
and negative estrogen receptor (ER) status.
LABC: locally advanced breast cancer; LoE: available level of
The first steps in the management of this disease are a core
evidence; consensus: percentage of panel members in agreement
biopsy to provide histology and biomarker assessment (includ-
with the statement; ER: estrogen receptor; PR: progesterone receptor;
ing ER, PR, HER-2, and proliferation/grade), and a full staging
CT: chemotherapy.
workup. Due to a relatively high risk of distant metastases [34],
thoracic and abdominal CT scans are preferred to thorax X-ray
Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

and liver ultrasound, and a PET–CT is also an acceptable Continued

option [34].
A multimodality approach is key for locoregional control and Guideline statements LoE Consensus
survival, including systemic therapies, surgery, and radiation. the preferred option.
The type of systemic therapy is similar to the one used in the Aromatase inhibitor
(neo)adjuvant setting, with anthracycline and taxanes as the monotherapy may also be
backbone of the chemotherapy regimes. For HER-2-positive considered, with close
LABC, anthracyclines should not be administered concurrently monitoring of response.
with trastuzumab since this approach does not increase the pCR Clinical trials are needed in
rate, and it could increase the risk of cardiac toxicity, based this patient population.
largely on studies in the metastatic setting [35, 36].
For luminal-like LABC, initial treatment options include MBC: metastatic breast cancer; LHRH: luteinizing-hormone–
chemotherapy (with sequential anthracyclines and taxanes) and releasing hormone; LoE: available level of evidence; consensus:
endocrine therapy, depending on tumour (grade, biomarker ex- percentage of panel members in agreement with the statement.
pression) and patient characteristics (menopausal status, per-

formance status, comorbidities) and preferences. A number of
studies have demonstrated significant activity of endocrine As predicted by their DNA-damaging mechanism of action,
therapy, particularly in luminal A-like disease [37–40]. Data pre- platinum compounds are expected to be particularly active in
sented after ABC2 strongly suggest that this subset of breast tumours deficient of mechanisms responsible for DNA damage
cancer, especially lobular histology, is less sensitive to chemo- repair, e.g. those without active BRCA1/2 proteins. Due to rarity
therapy (at least in terms of pCR rate) [41]. Very few data exist of such patients, little evidence exists on the clinical activity of
on primary endocrine therapy in premenopausal women [42] these drugs in BRCA1/2 mutation carriers in the metastatic
and, therefore, it cannot be recommended outside of clinical setting. However, available data suggest their promising activity
trials. mostly in the neoadjuvant setting [46, 47], and to a lesser degree
Primary systemic therapy in inoperable LABC allows breast- in advanced disease [48].
conserving surgery in variable percentages depending on In triple-negative breast cancer (TNBC), another putatively
tumour/patient characteristics [43]. Mastectomy remains the BRCA-deficient population, a relatively large amount of data
only option before or after radiotherapy for those patients not from prospective studies, recently summarized in a meta-analysis,
amenable to breast conservation and for all patients with IBC demonstrated improved pCR rates in patients whose neoadjuvant
[44]. For the time being, axillary dissection is still standard of treatment included a platinum compound [49–51]. However,
care in inoperable LABC [45]. which patients definitely benefit is not yet clear since there is also
As for all other stages of breast cancer, decision-making at a one negative GEICAM study adding carboplatin to epidoxorubicin–
multidisciplinary tumour board is highly recommended. cyclophosphamide-docetaxel in basal-like breast cancer [52].
Fewer data exist for inclusion of platinum in the treatment of
metastatic disease, although the benefit in the TNBC population
V. specific ABC populations seems to be larger than in other breast cancer patients [53].
Taking available evidence into account, most of the ABC2 panel
supported the inclusion of platinum-containing regimens in the
Guideline statements LoE Consensus treatment of BRCA1/2 mutant patients pre-treated with anthracy-
In patients with BRCA- IC 82.5% (33) yes clines and taxanes and demonstrated to be endocrine-resistant.
associated triple-negative 12.5% (5) abstain ABC1-issued several recommendations for the treatment of
or endocrine-resistant (40 voters) male patients with ABC [10] that still remain valid for ABC2
MBC previously treated (Table 2). One additional recommendation is added at this point,
with an anthracycline and a related to the use of aromatase inhibitors in this patient population.
taxane (in the adjuvant or There are concerns about the efficacy of these agents when
metastatic setting), a used in monotherapy in male patients, due to the hypothalamic–
platinum regimen may be pituitary negative feedback.
considered, if the patient is Important differences exist in the physiology of estrogen pro-
not included in a clinical duction between men and women. In men, 80% of circulating
trial. estrogens result from the peripheral aromatization of androgens,
All other treatment whereas 20% are directly secreted in the testicles [54–56].
recommendations are Adrenals secrete <1% of circulating sex steroids, but precursors
similar to sporadic MBC.
can undergo peripheral aromatization. So, peripheral conversion
For male patients with ABC Expert opinion 86.1% (31) yes
results in <5% of all testosterone, 80% of all dihydrotestosterone
who need to receive an 11.1% (4) abstain
and estradiol, and nearly all of estrone (98%) [56, 57].
aromatase inhibitor, a (36 voters)
Additionally, estradiol levels are 3–4 times higher in older males
concomitant LHRH
than in postmenopausal females.
agonist or orchiectomy is
For these reasons, and despite the lack of prospective and ran-
Continued domized data, the majority of panel members recommend that
 | Cardoso et al. Volume 25 | No. 10 | October 2014

when an aromatase inhibitor needs to be used in male ABC Continued
patients, a concomitant luteinizing-hormone–releasing hormone
agonist or orchiectomy should be added to further down-regulate Guideline statements LoE Consensus
testicular function. restaging, including assessment
of chest, abdomen, and bone.
Chest wall and regional recurrences IB 97.3% (37) yes
VI. specific sites of metastases should be treated with surgical 2.6% (1)
excision when feasible with a abstain
limited risk of morbidity. (38 voters)
Locoregional radiotherapy is IB 97.3% (37) Yes
Guideline statements LoE Consensus indicated for patients not 2.6% (1)
Prospective randomized clinical Expert 83.3% (25) yes previously irradiated. abstain
trials of local therapy for breast opinion 16.6% (5) (38 voters)
cancer liver metastases are (30 voters) For patients previously irradiated, Expert 97.3% (37) yes
urgently needed, since available re-irradiation of all or part of the opinion 2.6% (1)
chest wall may be considered in abstain

evidence comes only from series
in highly selected patients. Since selected cases. (38 voters)
there are no randomized data In addition to local therapy (surgery IB 94.8% (37) yes
supporting the effect of local and/or RT), in the absence of 5.1% (2)
therapy on survival, every patient distant metastases, the use of abstain
must be informed of this when systemic therapy (CT, ET, and/or (39 voters)
discussing a potential local anti-HER-2 therapy) should be
therapy technique. Local therapy considered.
should only be proposed in very CT after first local or regional
selected cases of good recurrence improves long-term
performance status, with limited outcomes primarily in ER-
liver involvement, no extra- negative disease.
hepatic lesions, after adequate ET in this setting improves long-
systemic therapy has term outcomes for ER-positive
demonstrated control of the disease.
disease. Currently, there are no The choice of systemic treatment
data to select the best technique depends on tumour biology,
for the individual patient previous treatments, length of
(surgery, stereotactic RT, intra- disease-free interval, and patient-
hepatic CT, or other). related factors (co-morbidities,
preferences, etc.).
Malignant pleural effusions IIB 86.4% (32) yes In patients with disease not Expert 97.3% (37) yes
require systemic treatment with/ 10.8% (4) amenable to radical local opinion 2.6% (1)
without local management. abstain treatment, the choice of palliative abstain
Thoracentesis for diagnosis (37 voters) systemic therapy should be made (38 voters)
should be performed if it is likely according to principles
that this will change clinical previously defined for metastatic
management. False negative BC. These patients may still be
results are common. Drainage is considered for palliative local
recommended in patients with therapy.
symptomatic, clinically
significant pleural effusion. The MBC: metastatic breast cancer; LoE: available level of evidence;
use of an intrapleural catheter or consensus: percentage of panel members in agreement with the
intrapleural administration of talc statement; CT: chemotherapy; RT: radiotherapy; ET: endocrine therapy.
or drugs (e.g. bleomycin, biological
response modifiers) can be helpful.
Clinical trials evaluating the best
technique are needed. Due to the lack of prospective randomized data for the man-
agement of liver metastases from breast cancer, and the exist-
Chest wall and regional (nodal)
ence of several locoregional techniques, local therapy of liver
recurrences
metastases should only be considered in highly selected patients.
Due to the high risk of concomitant Expert 100% (38) yes
Each case should be discussed with a multidisciplinary tumour
distant metastases, patients with opinion 0% (0)
board, before a decision is made. Inclusion in a clinical trial,
chest wall or regional (nodal) abstain
when available, is considered the best option.
recurrence should undergo full (38 voters)
When breast cancer recurs only on the chest wall after mastec-
Continued tomy, the use of intensive local–regional therapy should be
Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

considered. Therapy can include surgical excision alone, surgical VII. update on ER-positive/
excision followed by radiation therapy, radiation therapy alone HER-2-negative ABC
(when surgical excision is not feasible), or concurrent chemother-
apy and radiation. Complete surgical resection reduces the total
required dose of radiation therapy and also maximizes the likeli- Guideline statements LoE Consensus
hood of long-term disease control. Complete excision alone can The preferred first-line ET for IA 83.3% (30) yes
lead to a 5-year disease-free survival rate of 35% [58]. Complete re- postmenopausal patients is an 16.6% (6) abstain
section followed by locoregional radiotherapy results in a 5-year aromatase inhibitor or tamoxifen, (36 voters)
local–regional control ranging from 60% to 77% [59, 60]. Long- depending on the type and duration of
term predictors of disease-free survival after a local–regional recur- adjuvant ET.
rence include a disease-free interval of >24 months and a complete Fulvestrant HD is also an option. IB 83.3% (30) yes
excision [59]. 16.6% (6) abstain
With modern radiotherapy techniques, it is often possible to (36 voters)
re-irradiate with full dose without too many side-effects [61]. The addition of everolimus to an IB 100% yes
The first results of retreatment with stereotactic body radiother- aromatase inhibitor is a valid option (30 voters)

apy techniques have been published recently, describing promis- for some postmenopausal patients
ing local control rates [62]. with disease progression after a non-
Concurrent chemoradiation has both preclinical rationale and steroidal aromatase inhibitor, since it
clinical efficacy in many solid tumour types. Potential mechan- significantly prolongs PFS by a
isms of chemotherapy and radiotherapy interactions include in- median interval of 5 months. There is
creasing radiation damage, inhibition of DNA repair processes, a survival prolongation of similar
enhanced activity against hypoxic and radioresistant cells, and magnitude (4.4 months), although this
difference is not statistically
prevention of regrowth of tumour after radiation [63]. In
significant. The decision to treat must
patients who have received prior radiation, chemoradiation can
take into account the relevant
be considered, as the residual tumour should be considered
toxicities associated with this
radioresistant unless combined with a potentiating agent, pro-
combination and should be made on a
vided that the patient is judged a candidate and can tolerate add-
case-by-case basis.
itional radiation therapy. Agents having shown potential At present, no predictive biomarker
synergy with radiation include platinum analogues [64], anti- exists to identify those patients who
metabolites, [65–67], and taxanes [68]. Several novel therapeu- will benefit from this approach.
tics are also being studied in the trial setting in combination
with radiation, including EGFR inhibitors [69], HER-2 inhibi- LoE: available level of evidence; consensus: percentage of panel
tors [70], and poly (ADP-ribose) polymerase inhibitors [71]. members in agreement with the statement; ET: endocrine therapy;
Patients who have residual isolated local–regional recurrence after PFS: progression-free survival.
attempted resection, or minimal systemic disease, might derive
benefit from consideration of this multimodality approach.
Hyperthermia has a proven benefit for the treatment of superfi-
cial malignancies, acting as a radiosensitizer. Trials evaluating the ABC2 reinforces the ABC1 recommendations for ER-posi-
role of hyperthermia in combination with radiotherapy in patients tive/HER-2-negative ABC regarding the preferential use of
with chest wall recurrences have shown a significant improvement endocrine therapy, even in the presence of visceral metastases.
in complete response rates with the addition of hyperthermia, es- Chemotherapy should be reserved for cases of rapidly progres-
pecially in previously irradiated patients (e.g. complete response: sive disease or proven endocrine resistance. Most ABC1 recom-
24%–31% in the no-hyperthermia arm versus 57%–68% in the mendations remain unchanged (see Table 2). The two changes
hyperthermia arm) [72, 73]. However, there was no difference in refer to the preferred first-line endocrine therapy for postmeno-
survival between the two treatment arms. Recent studies have ana- pausal women and the use of everolimus.
lysed the combination of radiotherapy, hyperthermia, and concur- The preferred first-line endocrine therapy for postmenopau-
rent chemotherapy in this patient population [74]. sal women depends on the type and duration of adjuvant endo-
Finally, systemic therapy (both endocrine and chemotherapy) crine therapy. Available data support the use of an aromatase
has been shown to benefit patients after complete resection of a inhibitor, tamoxifen, or fulvestrant HD (i.e. 500 mg, every
first locoregional isolated recurrence [75, 76]. The CALOR study 4 weeks) [77–88]. Fulvestrant HD is well tolerated and numeric-
[76], a randomized phase 3 study, allocated to 162 patients to ally associated with a 4.1-month difference in median OS com-
either physician’s choice chemotherapy or no chemotherapy. pared with fulvestrant 250 mg [80]. Only the lower, less-
The use of chemotherapy after surgery resulted in a significant efficacious dose was compared to aromatase inhibitors and
reduction in systemic recurrence (hazard ratio, HR 0.59; found to have similar efficacy; so far, no data directly comparing
P = 0.046). In the subgroup of patients with ER-negative fulvestrant HD with an aromatase inhibitor exist.
tumours, there was also a significant improvement in survival. Endocrine resistance is a common and important clinical
This study provides important data in support of use of systemic problem. It may be primary or secondary (see above ABC defini-
chemotherapy after surgical resection of isolated locoregional tions). The main identified mechanisms of endocrine resistance
recurrence of ER-negative breast cancer. are related to ESR alterations (mutations, amplifications, or
 | Cardoso et al. Volume 25 | No. 10 | October 2014

translocations), and upregulation of alternative pathways, such as Continued
the HER growth factor pathways and the PI3K/Akt/mammalian
target of rapamycin (mTOR) pathway. Guideline statements LoE Consensus
The mTOR inhibitor everolimus when added to exemestane, lapatinib + capecitabine) and beyond
in patients progressing on non-steroidal aromatase inhibitor, (versus treatment of physician’s choice).
provided a significant PFS prolongation of about 5 months [89, T-DM1 should be preferred in patients
90]. The overall survival data, presented after ABC2, demon- who have progressed through at least one
strated a non-significant 4-month increase in median survival line of trastuzumab-based therapy, since
(HR 0.89) [91]. Overall survival prolongation was also observed, it provides an OS benefit.
in an exploratory analysis of the randomized phase II TAMRAD All patients with HER-2 + MBC who IB 87.5% (35) yes
study comparing the combination of tamoxifen and everolimus relapse after adjuvant anti-HER-2 12.5% (5) abstain
to tamoxifen alone in aromatase inhibitor (AI)-resistant patients therapy should be considered for further (40 voters)
[92]. These benefits must be weighed against relevant toxicities anti-HER-2 therapy, except in the
associated with this compound, particularly stomatitis, pneu- presence of contraindications.
monitis, and hyperglycaemia. Decisions on everolimus use must The choice of the anti-HER-2 agent will
depend on country-specific availability,

thus be made on a case-by-case basis, after discussion with a
the specific anti-HER-2 therapy
well-informed patient, and administered by physicians experi-
previously administered, and the relapse-
enced in managing adverse effects of this compound.
free interval.
The optimal sequence of all available
anti-HER-2 therapies is currently
VIII. update on HER-2-positive ABC unknown.
Because patients with HER-2-positive MBC IC 89.1% (33) yes
and brain metastases can live for several 10.8% (4) abstain
Guideline statements LoE Consensus years, consideration of long-term toxicity (37 voters)
is important and less toxic local therapy
In the first-line setting, for HER-2 + MBC IA 84.6% (33) yes options (e.g. stereotactic RT) should be
previously treated (in the adjuvant 10.2% (4) abstain preferred to whole-brain RT, when
setting) or untreated with trastuzumab, (39 voters) available and appropriate (e.g. in the
combinations of CT + trastuzumab are setting of a limited number of brain
superior to combinations of metastases).
CT + lapatinib in terms of PFS and OS.
In first-line therapy, the combination of IA 89.7% (35) yes MBC: metastatic breast cancer; LoE: available level of evidence;
CT + trastuzumab and pertuzumab is 10.2% (4) abstain consensus: percentage of panel members in agreement with the
superior to CT + trastuzumab, primarily (39 voters) statement; CT: chemotherapy, RT: radiotherapy; T-DM1:
for previously untreated HER-2 + MBC, trastuzumab emtansine.
making it the preferred treatment option
since it is associated with an OS benefit.
It is currently unknown how this
treatment compares with other anti- In the last 2 years, several trials in HER-2-positive ABC have
HER-2 options such as T-DM1. been reported, which led to an update on several ABC1 recom-
There are currently no data supporting the 85.0% (34) yes mendations regarding this specific subtype.
use of dual blockade with 12.5% (5) abstain Evidence from three trials, two in advanced and one in early
trastuzumab + pertuzumab associated (40 voters) breast cancer, supports the recommendation that combinations
with CT beyond the first line, after of chemotherapy with trastuzumab are superior to chemother-
treatment with apy and lapatinib.
trastuzumab + pertuzumab + CT in the The MA.31 trial [93] randomly compared taxanes plus trastu-
first line (i.e. continuing dual blockade zumab (weekly paclitaxel or three weekly docetaxel) or the same
beyond progression) and, therefore, this taxane plus lapatinib, as the first-line treatment of 636 HER-2-
three drug regimen should not be given positive MBC patients, a substantial percentage of whom had de
beyond the first line outside clinical novo MBC. With a median follow-up of 13.6 months, the taxane–
trials. lapatinib arm had inferior PFS compared with the taxane–trastu-
In a HER-2 + MBC patient previously IIC 43.7% (14) yes zumab (8.8 versus 11.4 months). There was no difference in OS
untreated with pertuzumab, it is 21.8% (7) abstain and toxicity was significantly higher in the lapatinib arm.
acceptable to use pertuzumab beyond the (32 voters)
The CEREBEL trial [94] compared lapatinib plus capecitabine
first line.
with trastuzumab plus capecitabine, as first-line therapy for
After first-line trastuzumab-based therapy, IA 89.7% (35) yes
HER-2-positive MBC with no evidence of central nervous
T-DM1 provides superior efficacy 10.2% (4) abstain
system (CNS) disease. The primary end point was incidence of
relative to other HER-2-based therapies (39 voters)
CNS metastases as a first site of relapse. With a planned popula-
in the second line (versus
tion of 475 patients, the study was terminated at the time of the
Continued interim analysis due to a low number of CNS events (3% and
Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

special article
 | Cardoso et al.
Table 2. Advanced breast cancer (ABC)1 statements [10] with minor update or with no update
LoE Consensus
General recommendations
The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including but not restricted to medical, Expert opinion 100% (29) yes
radiation, surgical oncologists, imaging experts, pathologists, gynaecologists, psycho-oncologists, social workers, nurses, and palliative care specialists) is crucial. 0% (0) abstain
(29 voters)
From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care, supportive care, and symptom-related interventions as a routine part Expert opinion 100% (30) yes
of their care. The approach must be personalized to meet the needs of the individual patient. 0% (0) abstain
(30 voters)
Following a thorough assessment and confirmation of metastatic breast cancer (MBC), the potential treatment goals of care should be discussed. Patients should be Expert opinion 97% (29) yes
told that MBC is incurable but treatable, and that some patients can live with MBC for extended periods of time (many years in some circumstances). 3% (1) abstain
This conversation should be conducted in accessible language, respecting patient privacy and cultural differences, and whenever possible, written information (30 voters)
should be provided.
Patients (and their families, caregivers, or support network, if the patient agrees) should be invited to participate in the decision-making process at all times. When Expert opinion 100% (30) yes
possible, patients should be encouraged to be accompanied by persons who can support them and share treatment decisions (e.g. family members, caregivers, 0% (0) abstain
and support network). (30 voters)
There are few proven standards of care in ABC management. After appropriate informed consent, inclusion of patients in well-designed, prospective, randomized Expert opinion 100% (30) yes
independent trials must be a priority whenever such trials are available and the patient is willing to participate. 0% (0) abstain
(30 voters)
The medical community is aware of the problems raised by the cost of ABC treatment. Balanced decisions should be made in all instances; patients’ well-being, Expert opinion 100% (32) yes
length of life, and preferences should always guide decisions. 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 chest, abdomen, and bone. 2C 67% (20) yes
3% (1) abstain
(30 voters)
Brain imaging should not be routinely carried out in asymptomatic patients. This approach is applicable to all patients with MBC including those patients with Expert opinion 94% (30) yes
HER-2+ and/or triple-negative breast cancer MBC. 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 reasonable (if elevated) as an aid to 2C 89% (24) yes
evaluate response to treatment, particularly in patients with non-measurable metastatic disease. A change in tumour markers alone should not be used to initiate 4% (1) abstain
Volume 25 | No. 10 | October 2014
a change in treatment. (27 voters)
Evaluation of response to therapy should generally occur every 2–4 months for endocrine therapy (ET) or after two to four cycles for chemotherapy (CT), Expert opinion 81% (25) yes
depending on the dynamics of the disease, the location and extent of metastatic involvement, and type of treatment. 10% (3) abstain
Imaging of a target lesion may be sufficient in many patients. In certain patients, such as those with indolent disease, less frequent monitoring is acceptable. (31 voters)
Additional testing should be carried out in a timely manner, irrespective of the planned intervals, if progressive disease is suspected or new symptoms appear.
Annals of Oncology
Thorough history and physical examination must always be performed.
A biopsy (preferably providing histology) of a metastatic lesion should be carried out, if easily accessible, to confirm diagnosis particularly when metastasis is 1Ca 96% (27) yes
diagnosed for the first time. 0% (0) abstain
(28 voters)

Annals of Oncology
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 be used for treatment decision- Expert opinion 87% (27) yes
making. Since a clinical trial addressing this issue is difficult to undertake, we recommend considering the use of targeted therapy (ET and/or anti-HER-2 3% (1) abstain
therapy) when receptors are positive in at least one biopsy, regardless of timing. (31 voters)
Treatment general guidelines
Treatment choice should take into account at least these factors: HR and HER-2 status, previous therapies and toxicities, disease-free interval, tumour burden Expert opinion 100% (30) yes
(defined as the number and site of metastases), biological age, performance status, co-morbidities (including organ dysfunctions), menopausal status (for ET), 0% (0) abstain
need for a rapid disease/symptom control, socioeconomic and psychological factors, available therapies in the patient’s country and patient preference. (30 voters)
A small but very important subset of patients with MBC, for example those with oligometastatic disease, can achieve complete remission and a long survival. A Expert opinion 96% (25) yes
multimodal approach should be considered for these selected patients. 0% abstain
A prospective clinical trial addressing this specific situation is needed. (26 voters)
ER+/HER-2-negative ABC
ET is the preferred option for hormone receptor-positive disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance, or IA 100% (29) yes
there is disease needing a fast response. 0% (0) abstain
(29 voters)
For premenopausal women, ovarian suppression/ablation combined with additional ET is the first choice. IA 97% (29) yes
0% (0) abstain
(30 voters)
The additional endocrine agent should be tamoxifen unless tamoxifen resistance is proved. 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 aromatase inhibitor (with a different IA 97% (30) yes
mechanism of action), fulvestrant HD, megestrol acetate, and everolimus + aromatase inhibitor. 3% (1) abstain
(31 voters)
Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable option, although this approach has not been assessed in randomized trials. IC 88% (28) yes
9% (3) abstain
(32 voters)
Concomitant CT + ET has not shown a survival benefit and should not be administered outside of a clinical trial. IB 100% (30) yes
0% (0) abstain
(30 voters)
HER-2-positive ABC
special article
Anti-HER-2 therapy should be offered early to all patients with HER-2+ MBC, except in the presence of contraindications to the use of such therapy. IA 91% (30) yes
doi:10.1093/annonc/mdu385 | 
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 initiation of ET (provided that IA 90% (27) yes
further anti-HER-2 therapy is available) since anti-HER-2 therapy (either trastuzumab or lapatinib) in combination with ET has shown substantial progression- 10% (3) abstain
free survival (PFS) benefit (i.e. ‘time without CT’) compared with ET alone. The addition of anti-HER-2 therapy in this setting has not led to a survival benefit. (30 voters)
Patients whose tumours progress on an anti-HER-2 therapy combined with a cytotoxic or endocrine agent should be offered additional anti-HER-2 therapy with IB 97% (29) yes
subsequent treatment since it is beneficial 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)
Continued

Table 2. Continued
special article
 | Cardoso et al.
LoE Consensus
Patients who have received any type of (neo)adjuvant anti-HER-2 therapy should not be excluded from clinical trials for HER-2+ MBC. IB 100% (23) yes
0% (0) abstain
(27 voters)
In the case of progression on trastuzumab, the combination of trastuzumab + lapatinib is also a reasonable treatment option in the course of the disease. IB 83% (24) yes
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 a single agent, would usually be considered IA 71% (17) yes
as first-line CT for HER-2-negative MBC, in those patients who have not received these regimens as adjuvant treatment and for whom chemotherapy is 4% (1) abstain
appropriate. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient. (24 voters)
In patients with taxane-naive and anthracycline-resistant MBC or with anthracycline cumulative dose or toxicity (i.e. cardiac) who are being considered for further IA 59% (14) yes
CT, taxane-based therapy, preferably as a single agent, would usually be considered as the treatment of choice. Other options are, however, available and effective, 8% (2) abstain
such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient. (24 voters)
If given in the adjuvant setting, a taxane can be re-used in the metastatic setting, particularly if there has been at least 1 year of disease-free survival. IA 92% (22) yes
8% (2) abstain
(24 voters)
Duration of each regimen and the number of regimens should be tailored to each individual patient. Expert opinion 96% (26) yes
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 defined together with the patient. 7% (2) abstain
(29 voters)
Bevacizumab combined with chemotherapy as first- or second-line therapy for MBC provides only a moderate benefit in PFS and no benefit in overall survival. The IA 74% (17) yes
absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult. Bevacizumab can only therefore be considered as an 17% (4) abstain
option in selected cases in these settings and is not recommended after a first/second line. (23 voters)
Specific sites of metastases: bone and brain

A bone modifying agent (bisphosphonate or denosumab) should be routinely used in combination with other systemic therapy in patients with MBC and bone IA 96% (26) yes
metastases. 4% (1) abstain
(27 voters)
Radiological assessments are required in patients with persistent and localized pain due to bone metastases to determine whether there are impending or actual IA 96% (23) yes
pathological fractures. If a fracture of a long bone is likely or has occurred, an orthopaedic assessment is required as the treatment of choice may be surgical 4% (1) abstain
stabilization, which is generally followed by radiotherapy (RT). In the absence of a clear fracture risk, RT is the treatment of choice. (24 voters)
Neurological symptoms and signs, which suggest the possibility of spinal cord compression, must be investigated as a matter of urgency. This requires a full IB 100% (24) yes
radiological assessment of potentially affected area as well as adjacent areas of the spine. MRI is the method of choice. An emergency surgical opinion 0% (0) abstain
Annals of Oncology
(neurosurgical or orthopaedic) may be required for surgical decompression. If no decompression/stabilization is feasible, emergency radiotherapy is the (24 voters)
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. Radiosurgery is an option for some IB 92% (22) yes
unresectable brain metastases. 4% (1) abstain
(24 voters)

Annals of Oncology
If surgery/radiosurgery is carried out it may be followed by whole-brain radiotherapy, but this should be discussed in detail with the patient, balancing the longer IB 72% (18) yes
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)
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, when active treatment no longer Expert opinion 96% (25) yes
is able to control widespread and life-threatening disease, and the toxicities of remaining options outweigh benefits, physicians, and other members of the 0% (0) abstain
health-care team should initiate discussions with the patient (and family members/friends, if the patient agrees) about end-of-life care. (26 voters)
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 resistance or rapidly Expert opinion 100% (25) yes
progressive disease needing a fast response. 0% (0) abstain
(25 voters)
For ER+ male MBC, tamoxifen is the preferred option. Expert opinion 83% (15) yes
6% (1) abstain
(18 voters)
special article
doi:10.1093/annonc/mdu385 | 
a
LoE changed since ABC1 from 2C to 1C based on new published data [128–130].

5%, respectively). PFS, a secondary end point, was lower in the Continued
lapatinib arm (6.6 versus 8.0 months).
Additional evidence comes from the adjuvant ALTTO trial, Guideline statements LoE Consensus
where the lapatinib-alone arm was closed early, due to futility in In patients pre-treated (in the adjuvant or IB 77.1% (27) yes
a non-inferiority comparison to trastuzumab, and patients metastatic setting) with an anthracycline 20.0% (7) abstain
offered cross-over to receive trastuzumab [95]. and a taxane, and who do not need (35 voters)
The CLEOPATRA trial [96, 97] showed superior results, in combination chemotherapy, single-agent
terms of PFS (18.5 versus 12.4 months) and 1-year survival (23.6% capecitabine, vinorelbine, or eribulin are
versus 17.2%), of the triplet trastuzumab + pertuzumab + docetaxel the preferred choices.
compared with trastuzumab + docetaxel as first-line therapy. Additional choices include gemcitabine,
Importantly, the majority (≈90%) of the patients were trastuzu- platinum agents, taxanes, and liposomal
mab-naive; if previously treated with trastuzumab, a 12-month anthracyclines.
disease-free interval was required. Therefore, this trial did not The decision should be individualized and
address, and therefore cannot support, the use of this combination take into account different toxicity
in patients with truly trastuzumab-resistant tumours. There are also profiles, previous exposure, patient
preferences, and country availability.

no data supporting the use of the dual blockade with trastuzumab
+ pertuzumab with CT beyond first line, after treatment with
trastuzumab + pertuzumab + CT in the first line (i.e. continuing a
members in agreement with the statement; CT: chemotherapy.
dual blockade beyond progression) and, therefore, this regimen
should not be given beyond first line outside clinical trials.
The panel could not reach a consensus regarding the possible
use of pertuzumab beyond first line in patients previously untreat- Regarding the use of chemotherapy, the main recommenda-
ed with this drug (14 votes ‘yes’, 11 ‘no’, and 7 ‘abstain’). The only tion remains unchanged and relates to the sequential use of
available data regarding this issue come from a phase II single arm single agents, with combination chemotherapy reserved for
study [98]. This phase II also showed that pertuzumab does not situations of visceral crisis, rapidly progressive or highly symp-
work by itself, but needs to be combined with trastuzumab. tomatic disease. Available literature has been previously
T-DM1 (trastuzumab emtansine) has shown consistent and reviewed [12] and a recent Cochrane meta-analysis [102] con-
substantial benefits in terms of PFS and OS, both in the second firms and provides level 1 evidence for this recommendation.
line (versus lapatinib + capecitabine, in the EMILIA trial) [99, Although taxanes can be used as first-line therapy, they have
100] and beyond (versus treatment of physician’s choice, in the not shown superior benefit to anthracyclines in a meta-analysis
TH3RESA trial) [101]. These results make T-DM1 the preferred carried out in a mostly taxane-naive, anthracycline-pre-treated
choice for patients with disease progression after treatment with patient population [103]. Considerations regarding toxicity and
at least one line of trastuzumab-based therapy. patient preferences (namely wish to avoid alopecia) should be
There are almost no data regarding the treatment of patients taken into consideration in the choice of cytotoxic agent.
with HER-2-positive ABC who relapse on or shortly after adjuvant Capecitabine has shown consistent results as first- and
trastuzumab and urgent trials are needed for this poor prognosis second-line therapy [104–112].
population. In the EMILIA trial, the overall survival advantage Vinorelbine yielded equal or superior results to both pacli-
(HR) for T-DM1 versus lapatinib plus capecitabine in the subset taxel and docetaxel, when combined with trastuzumab in the
of 118 patients who were randomized in the first-line setting, HER-2-positive ABC in the HERNATA [113] and TRAVIOTA
having relapsed on or within 6 months of adjuvant trastuzumab, trials [114].
appeared similar to the effect seen in the overall trial [100]. Eribulin has provided an OS benefit in heavily pre-treated
Several ABC1 recommendations for HER-2-positive ABC patients (up to five lines of treatment) [115] and similar PFS
remain unchanged and are listed in Table 2. and OS results to capecitabine after prior treatment with an
anthracycline and taxane [116].
IX. update on HER-2-negative ABC

X. update on surgery of the primary
tumour in stage IV at diagnosis
Sequential monotherapy is the preferred IA 96% (25) yes

choice for MBC. Combination CT 4% (1) abstain
should be reserved for patients with (26 voters) The true value of the removal of the primary IIB 100% (29) yes
rapid clinical progression, life- tumour in patients with de novo stage IV 0% (0) abstain
threatening visceral metastases, or need breast cancer is currently unknown. (29 voters)
for rapid symptom and/or disease However, it can be considered in selected
control. patients. Of note, some studies suggest that
Continued Continued
 | Cardoso et al. Volume 25 | No. 10 | October 2014

Continued several steps of their care, but emphasize that much remains to
be done. Implementation of guidelines is very heterogeneous
Guideline statements LoE Consensus between countries but also within countries, according to the
surgery is only valuable if carried out with environment where the patient is treated and cost of treatment.
the same attention to detail (e.g. attaining The complexity of this disease, the multiple factors that must
clear margins and addressing disease in the be taken into account, the lack of high-level evidence for several
axilla) as in patients with early stage disease. clinical situations, and new highly specialized techniques avail-
able for local management of specific sites of metastases, all con-
LoE: available level of evidence; consensus: percentage of panel stitute strong reasons for the treatment of these patients by a
members in agreement with the statement. specialized multidisciplinary team, rather than management by
an isolated oncologist regardless of his/her skills or experience.
Our plea for a strong commitment of all involved parties (aca-
Available data regarding the value of removal of the primary demia, pharmaceutical industry, independent funding sources,
tumour in patients with stage IV at diagnosis were extensively and advocacy groups) to develop well-designed, high-quality
reviewed and published in one of the ESO-ABC Task Force multidisciplinary (involving other issues than drug-development)

manuscripts [13]. All but one study published after this 2010 trials for ABC remains of critical importance. Many questions
paper support the surgical removal of the primary tumour in are still unanswered, related to management strategies, optimal
patients with stage IV disease, reinforcing the importance of the drug use, and individualized treatment (based on predictive
ongoing prospective trials evaluating this approach since existing markers and eventually new technologies aiming at better char-
data come almost exclusively from retrospective studies [117– acterization of the individual tumour).
121]. In the beginning of 2012, the British Columbia large retro- Research and education are the two pillars for advances in on-
spective series reinforced the importance of treating the primary cology today. Research is indispensible for improving the man-
with the most favourable survival rates observed in subsets of agement and outcome of patients with cancer, now and in the
patients with young age, good performance status, ER-positive future. Education, including implementation of carefully devel-
disease, distant disease limited to one site, bone-only involve- oped high-quality guidelines such as the current ABC
ment, or fewer than five metastatic lesions [122]. A meta-analysis International Consensus Guidelines, allows the appropriate
of 15 publications also published in 2012 reinforced the idea that application of current knowledge to patient care, which will sub-
surgery of the primary tumour appeared to be an independent stantially improve the long-term outcomes of current ABC
factor for improved survival in the multivariate analyses from the patients worldwide.
individual studies, with an HR of 0.69 (P < 0.00001) [123].
Since 2011 several randomized trials have started accrual
comparing locoregional treatment of primary versus no treat- disclosure
ment in stage IV patients at presentation [124, 125]. All conflict of interest details were included in the supplemen-
In 2013, very early data from two prospectively randomized tary material section.
trials presented at San Antonio Breast Cancer Symposium could
not confirm the previous conclusions. In these two studies, only
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 | Cardoso et al. Volume 25 | No. 10 | October 2014

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special article Annals of Oncology 25: 1871–1888, 2014

ESO-ESMO 2nd international consensus guidelines

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Received 5 August 2014; accepted 11 August 2014

introduction specialized institutions [6]. Implementation of current knowl-

© The Authors 2014. Published by Oxford University Press.

Following the work of the ESO-ABC Task Force [11–14],

Strong recommendation, but may change when higher

Very weak recommendation, other alternatives may be

Strong recommendation, can apply to most patients in

depending on circumstances or patients’ or societal

depending on circumstances or patients’ or societal

Weak recommendation, best action may differ

Weak recommendation, best action may differ

most circumstances without reservation

most circumstances without reservation

quality evidence becomes available

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RCTs with important limitations (inconsistent results, methodological flaws,

RCTs with important limitations (inconsistent results, methodological flaws,

RCTs without important limitations or overwhelming evidence from

indirect, or imprecise) or exceptionally strong evidence from

indirect, or imprecise) or exceptionally strong evidence from

overwhelming evidence from observational studies

Observational studies or case series

Observational studies or case series

Benefits clearly outweigh risk

Benefits clearly outweigh risk

and burdens, or vice versa

and burdens, or vice versa

comments and corrections on content and wording. A ﬁnal set of recom-

Benefits closely balanced

Benefits closely balanced

with risks and burden

with risks and burden

area of expertise) instructed to ‘abstain’ from voting. Additional changes

2A/weak recommendation, high-

Supplementary Table S1, available at Annals of Oncology online, lists all

ships that could be perceived as a potential conﬂict of interest.

Table 1 describes the grading system used [15].

speciﬁc deﬁnitions for which a consensus was deemed important.

 | Cardoso et al. Volume 25 | No. 10 | October 2014

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Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

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 | Cardoso et al. Volume 25 | No. 10 | October 2014

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Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

and liver ultrasound, and a PET–CT is also an acceptable Continued

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 | Cardoso et al. Volume 25 | No. 10 | October 2014

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Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

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 | Cardoso et al. Volume 25 | No. 10 | October 2014

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Volume 25 | No. 10 | October 2014 doi:10.1093/annonc/mdu385 | 

a change in treatment. (27 voters)

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