Abc3 Esmo

Download as pdf or txt
Download as pdf or txt
You are on page 1of 18

Annals of Oncology 28: 16–33, 2017

doi:10.1093/annonc/mdw544
Published online 5 December 2016

SPECIAL ARTICLE

3rd ESO–ESMO International Consensus Guidelines


for Advanced Breast Cancer (ABC 3)

F. Cardoso1*, A. Costa2, E. Senkus3, M. Aapro4, F. André5, C. H. Barrios6, J. Bergh7, G. Bhattacharyya8,


L. Biganzoli9, M. J. Cardoso10, L. Carey11, D. Corneliussen-James12, G. Curigliano13, V. Dieras14,
N. El Saghir15, A. Eniu16, L. Fallowfield17, D. Fenech18, P. Francis19, K. Gelmon20, A. Gennari21,
N. Harbeck22, C. Hudis23, B. Kaufman24, I. Krop25, M. Mayer26, H. Meijer27, S. Mertz28, S. Ohno29,
O. Pagani30, E. Papadopoulos31, F. Peccatori32, F. Penault-Llorca33, M. J. Piccart34, J. Y. Pierga35,
H. Rugo36, L. Shockney37, G. Sledge38, S. Swain39, C. Thomssen40, A. Tutt41, D. Vorobiof42, B. Xu43,
L. Norton44 & E. Winer45
1
European School of Oncology & Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal; 2European School of Oncology, Milan, Italy and European School of
Oncology, Bellinzona, Switzerland; 3Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; 4Breast Center, Genolier Cancer
Center, Genolier, Switzerland; 5Department of Medical Oncology, Gustave Roussy Institute, Villejuif, France; 6Department of Medicine, PUCRS School of Medicine,
Porto Alegre, Brazil; 7Department of Oncology/Radiumhemmet, Karolinska Institutet & Cancer Center Karolinska and Karolinska University Hospital, Stockholm,
Sweden; 8Department of Medical Oncology, Fortis Hospital, Kolkata, India; 9Medical Oncology Department, Hospital of Prato, Prato, Italy; 10Breast Unit,
Champalimaud Clinical Center, Lisbon, Portugal; 11Department of Hematology and Oncology, UNC Lineberger Comprehensive Cancer Center; 12METAvivor
Research and Support, Annapolis, USA; 13Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy; 14Department of Medical Oncology,
Institut Curie, Paris, France; 15NK Basile Cancer Institute Breast Center of Excellence, American University of Beirut, Beirut, Lebanon; 16Department of Breast
Tumors, Cancer Institute ‘I. Chiricuta’, Cluj-Napoca, Romania; 17Brighton & Sussex Medical School, University of Sussex, Falmer, UK; 18Breast Care Support Group,
Europa Donna Malta, Mtarfa, Malta; 19Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia; 20BC Cancer Agency, Vancouver Cancer
Centre, Vancouver, Canada; 21Department of Medical Oncology, Galliera Hospital, Genoa, Italy; 22Brustzentrum der Universitat München, Munich, Germany;
23
Breast Medicine Service, Memorial Sloan-Kettering Cancer Centre, New York, USA; 24Sheba Medical Center, Tel Hashomer, Israel; 25Department of Medical
Oncology, Dana-Farber Cancer Institute, Boston; 26Advanced Breast Cancer.org, New York, USA; 27Department of Radiation Oncology, Radvoud University Medical
Center, Nijmegen, The Netherlands; 28Metastatic Breast Cancer Network US, Inversness, USA; 29Breast Oncology Centre, Cancer Institute Hospital, Tokyo, Japan;
30
Oncology Institute of Southern Switzerland and Breast Unit of Southern Switzerland, Bellinzona, Switzerland; 31Europa Donna, Nicosia, Cyprus; 32European
School of Oncology, Milan, Italy and Bellinzona, Switzerland; 33Jean Perrin Centre, Comprehensive Cancer Centre, Clermont Ferrand, France; 34Department of
Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; 35Department of Medical Oncology, Institut Curie-Université Paris Descartes, Paris,
France; 36Department of Medicine, Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco; 37Department of Surgery
and Oncology, Johns Hopkins Breast Center, Baltimore; 38Indiana University Medical CTR, Indianapolis; 39Lombardi Comprehensive Cancer Center, Georgetown
University, Washington, USA; 40Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle an der Saale, Germany; 41Breakthrough Breast
Cancer Research Unit, King’s College London and Guy’s and St Thomas’s NHS Foundation Trust, London, UK; 42Sandton Oncology Centre, Johannesburg, South
Africa; 43Department of Medical Oncology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; 44Breast Cancer Program,
Memorial Sloan-Kettering Cancer Centre, New York; 45Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA

*Correspondence to: Fatima Cardoso, Dr Breast Unit, Champalimaud Clinical Center, Av. De Brasılia s/n, 1400-038 Lisbon, Portugal. Tel: þ351-210-480-004; E-mail:
fatimacardoso@fundacaochampalimaud.pt
Note: These Guidelines were developed by ESO and ESMO and are published simultaneously in Annals of Oncology (2016; doi:10.1093/annonc/mdw544) and
The Breast and should both be cited.

Introduction improved outcomes, quality of life, awareness and information


Advanced Breast Cancer (ABC) comprises both locally advanced regarding ABC.
(LABC) and metastatic breast cancer (MBC) [1]. Although treat- The level of evidence used to base many recommendations re-
able, MBC remains an incurable disease with a median overall mains low, and more and better designed trials are needed to ad-
survival of 2–3 years and a 5-year survival of only 25% [2–4]. dress clinically important questions. An improved understanding
Some more recent series seem to indicate an improvement in me- of the biology of ABC, its heterogeneity, and of the mechanisms
dian overall survival [5, 6]. of resistance to the different types of therapies is being acquired
A recent comprehensive report [2] of the advances in this field and it is anticipated that the application of new technologies,
in the last decade shows that progress has been slow in terms of such as next generation sequencing, patient xenographs, systems

C The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-
commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please
contact journals.permissions@oup.com
Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
Table 1. Grading system [7]

Grade of recommendation/ Benefit versus risk and burdens Methodological quality of sup- Implications
description porting evidence

1A/Strong recommendation, high Benefits clearly outweigh risk and RCTs without important limitations Strong recommendation, can
quality evidence burdens, or vice versa or overwhelming evidence from apply to most patients in most
observational studies circumstances without
reservation
1B/Strong recommendation, mod- Benefits clearly outweigh risk and RCTs with important limitations (in- Strong recommendation, can
erate quality evidence burdens, or vice versa consistent results, methodological apply to most patients in most
flaws, indirect, or imprecise) or ex- circumstances without
ceptionally strong evidence from reservation
observational studies
1C/Strong recommendation, low Benefits clearly outweigh risk and Observational studies or case series Strong recommendation, but may
quality evidence burdens, or vice versa change when higher quality evi-
dence becomes available
2A/Weak recommendation, high Benefits closely balanced with risks RCTs without important limitations Weak recommendation, best ac-
quality evidence and burden or overwhelming evidence from tion may differ depending on
observational studies circumstances or patients’ or so-
cietal values
2B/Weak recommendation, mod- Benefits closely balanced with risks RCTs with important limitations (in- Weak recommendation, best ac-
erate quality evidence and burden consistent results, methodological tion may differ depending on
flaws, indirect, or imprecise) or ex- circumstances or patients’ or so-
ceptionally strong evidence from cietal values
observational studies
2C/Weak recommendation, low Benefits closely balanced with risks Observational studies or case series Very weak recommendation, other
quality evidence and burden alternatives may be equally
reasonable

SECTION I. GENERAL RECOMMENDATIONS

GUIDELINE STATEMENT LoE Consensus

The ABC community strongly calls for clinical trials addressing important unanswered clinical questions in this set- Expert opinion Voters: 43
ting, and not just for regulatory purposes. Clinical trials should continue to be performed, even after approval Yes: 100%
of a new treatment, providing real world performance of the therapy.
Every advanced breast cancer patient must have access to optimal cancer treatment and supportive care accord- Expert opinion Voters: 44
ing to the highest standards of patient centered care, as defined by: Yes: 100%
 Open communication between patients and their cancer care teams as a primary goal.
 Educating patients about treatment options and supportive care, through development and dissemination of
evidence-based information in a clear, culturally appropriate form.
 Encouraging patients to be proactive in their care and to share decision-making with their health care
providers.
 Empowering patients to develop the capability of improving their own quality of life within their cancer
experience.
 Always taking into account patient preferences, values and needs as essential to optimal cancer care.
We strongly recommend the use of objective scales, such as the ESMO Magnitude of Clinical Benefit Scale or the Expert opinion Voters: 40
ASCO Value Framework, to evaluate the real magnitude of benefit provided by a new treatment and help pri- Yes: 87.5% (35)
oritize funding, particularly in countries with limited resources. Abstain: 5% (2)
The use of telemedicine oncology to help management of patients with ABC living in remote places, is an import- Expert opinion Voters: 42
ant option to consider when geographic distances are a problem and provided that issues of connectivity are Yes: 92.8% (39)
solved. Abstain: 4.7% (2)

Continued

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 17


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
SECTION I Continued
GUIDELINE STATEMENT LoE Consensus

Strong consideration should be given to the use of validated PROMs (patient-reported outcome measures) for pa- 1C Voters: 39
tients to record the symptoms of disease and side effects of treatment experienced as a regular part of clinical Yes: 87.1% (34)
care. These PROMs should be simple, and user-friendly to facilitate their use in clinical practice, and thought Abstain: 5.1% (2)
needs to be given to the easiest collection platform, e.g. tablets or smartphones. Systematic monitoring would
facilitate communication between patients and their treatment teams by better characterizing the toxicities of
all anticancer therapies. This would permit early intervention of supportive care services enhancing quality of
life
As survival is improving in many patients with ABC, consideration of survivorship issues should be part of the rou- Expert opinion Voters: 40
tine care of these patients. Health professionals should therefore be ready to change and adapt treatment strat- Yes: 95% (38)
egies to disease status, treatment adverse effects and quality of life, patients’ priorities and life plans. Abstain: 5% (2)
Attention to chronic needs for home and family care, job and social requirements, should be incorporated in the
treatment planning and periodically updated.
ABC patients who desire to work or need to work for financial reasons should have the opportunity to do so, with Expert opinion Voters: 42
needed and reasonable flexibility in their working schedules to accommodate continuous treatment and hos- Yes: 100%
pital visits.
ABC patients with stable disease, being treated as a ‘chronic condition’, should have the option to undergo breast Expert opinion Voters: 39
reconstruction. Yes: 82% (32)
Abstain: 7.6% (3)
In ABC patients with long-standing stable disease, screening breast imaging should be an option. Expert opinion Voters: 40
Yes: 52.5% (21)
N: 47.5% (19)
Breast imaging should also be performed when there is a suspicion of loco-regional progression. Expert opinion Voters: 40
Yes: 100%
A biopsy (preferably providing histology) of a metastatic lesion should be performed, if easily accessible, to con- 1B Voters: 43
firm diagnosis particularly when metastasis is diagnosed for the first time. Yes: 98% (42)
Biological markers (especially HR and HER-2) should be reassessed at least once in the metastatic setting, if clinic- 1B Voters: 44
ally feasible. Depending on the metastatic site (e.g. bone tissue), technical considerations need to be discussed Yes: 98% (43)
with the pathologist.
If the results of tumour biology in the metastatic lesion differ from the primary tumor, it is currently unknown Expert Opinion 87%
which result should be used for treatment-decision 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 therapy) when re-
ceptors are positive in at least one biopsy, regardless of timing.
To date, the removal of the primary tumor in patients with de novo stage IV breast cancer has not been associated 2B Voters: 44
with prolongation of survival, with the possible exception of the subset of patients with bone only disease. Yes: 70.4% (31)
However, it can be considered in selected patients, particularly to improve quality of life, always taking into ac-
count the patient’s preferences. Of note, some studies suggest that surgery is only valuable if performed with the
same attention to detail (e.g. complete removal of the disease) as in patients with early stage disease.
Additional prospective clinical trials evaluating the value of this approach, the best candidates and best timing are
currently ongoing
A small but very important subset of patients with ABC, for example those with oligo-metastatic disease or low vol- Expert opinion Voters: 43
ume metastatic disease that is highly sensitive to systemic therapy, can achieve complete remission and a long Yes: 91% (39)
survival.
A multimodal approach, including local-regional treatments with curative intent, should be considered for these
selected patients.

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement.

biology, and computer modelling, among others, will accelerate The ABC guidelines are developed as a joint effort from ESO
advances. (European School of Oncology) and ESMO (European Society of
Aiming at providing clinically oriented guidelines on how to Medical Oncology), and are endorsed by EUSOMA (European
best manage ABC, the 3rd International Consensus Conference Society of Breast Cancer Specialists), ESTRO (European Society
for Advanced Breast Cancer (ABC 3) took place in Lisbon, of Radiation Oncology), UICC (Union for International Cancer
Portugal on November 5th–7th, 2015, bringing together over Control), SIS (Senologic International Society) and FLAM
1100 participants from 84 countries, including health profes- (Federation LatinoAmericana de Mastologia). There was also of-
sionals, patient advocates and journalists. ficial representation of ASCO (American Society of Clinical

18 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
Table 2. Other ABC1 [10] and ABC2 [1] statements with only minor updates or with no updates

Recommendations LoE % Consensus

ABC IMPORTANT DEFINITIONS


VISCERAL CRISIS is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies, Expert opinion 95
and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies import-
ant visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since an-
other treatment option at progression will probably not be possible.
PRIMARY ENDOCRINE RESISTANCE is defined as: Relapse while on the first 2 years of adjuvant ET, or PD within Expert opinion 67
first 6 months of 1st line ET for MBC, while on ET.
SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as: Relapse while on adjuvant ET but after the first
2 years, or Relapse within 12 months of completing adjuvant ET, or PD  6 months after initiating ET for MBC, while
on ET.
Note: resistance is a continuum and these definitions help mainly clinical trials and not necessarily clinical practice
GENERAL STATEMENTS
The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary Expert opinion 100
team (including but not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gyne-
cologists, psycho-oncologists, social workers, nurses and palliative care specialists), is crucial.
From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care, supportive care, and Expert opinion 100
symptom-related interventions as a routine part of their care. The approach must be personalized to meet the
needs of the individual patient.
Following a thorough assessment and confirmation of MBC, the potential treatment goals of care should be dis- Expert opinion 97
cussed. Patients should be told that MBC is incurable but treatable, and that some patients can live with MBC for ex-
tended periods of time (many years in some circumstances).
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 Expert opinion 100
the decision-making process at all times. When possible, patients should be encouraged to be accompanied by
persons who can support them and share treatment decisions (e.g. family members, caregivers, support network).
There are few proven standards of care in ABC management. After appropriate informed consent, inclusion of pa- Expert opinion 100
tients in well-designed, prospective, independent trials must be a priority whenever such trials are available and
the patient is willing to participate.
The medical community is aware of the problems raised by the cost of ABC treatment. Balanced decisions should Expert opinion 100
be made in all instances; patients’ well-being, length of life and preferences should always guide decisions.
Specialized oncology nurses (if possible specialized breast nurses) should be part of the multidisciplinary team Expert opinion 92
managing ABC pts. In some countries this role may be played by a physician assistant or another trained and speci-
alized health care practitioner.
All ABC patients should be offered comprehensive, culturally sensitive, up-to-date and easy to understand informa- 1B 97
tion about their disease and its management.
The age of the patient should not be the sole reason to withhold effective therapy (in elderly patients) nor to over- 1B 100
treat (in young patients). Age alone should not determine the intensity of treatment.
ASSESSMENT GUIDELINES
Minimal staging workup for MBC includes a history and physical examination, hematology and biochemistry tests, 2C 67
and imaging of chest, abdomen and bone.
Brain imaging should not be routinely performed in asymptomatic patients. This approach is applicable to all pa- Expert opinion 94
tients with MBC including those patients with HER-2þ and/or TNBC MBC.
The clinical value of tumor markers is not well established for diagnosis or follow-up after adjuvant therapy, but 2C 89
their use is reasonable (if elevated) as an aid to evaluate response to treatment, particularly in patients with non-
measurable metastatic disease. A change in tumor markers alone should not be used to initiate a change in
treatment.
Evaluation of response to therapy should generally occur every 2–4 months for ET or after two to four cycles for CT, Expert opinion 81
depending on the dynamics of the disease, the location and extent of metastatic involvement, and type of
treatment.
Imaging of target lesions may be sufficient in many patients. In certain patients, such as those with indolent disease,
less frequent 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.

Continued

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 19


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
Table 2 Continued
Recommendations LoE % Consensus

TREATMENT GENERAL GUIDELINES


Treatment choice should take into account at least these factors: HR and HER-2 status, previous therapies and tox- Expert opinion 100
icities, disease-free interval, tumour burden (defined as number and site of metastases), biological age, perform-
ance status, co-morbidities (including organ dysfunctions), menopausal status (for ET), need for a rapid disease/
symptom control, socio-economic and psychological factors, available therapies in the patient’s country and pa-
tient preference.
ER 1/HER-2 NEGATIVE ABC
Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable option, although this approach 1C 88
has not been assessed in randomized trials.
Concomitant CTþET has not shown a survival benefit and should not be performed outside of a clinical trial. 1B 100
CHEMOTHERAPY AND BIOLOGICAL THERAPY
Both combination and sequential single agent CT are reasonable options. Based on the available data, we recom- 1B 96
mend sequential monotherapy as the preferred choice for MBC. Combination CT should be reserved for patients
with rapid clinical progression, life-threatening visceral metastases, or need for rapid symptom and/or disease
control
In the absence of medical contraindications or patient concerns, anthracycline or taxane based regimens, prefer- 1A 71
ably as single agents, would usually be considered as first line CT for HER-2 negative MBC, in those patients who
have not received these regimens as (neo)adjuvant treatment and for whom chemotherapy is appropriate. Other
options are, however, available and effective, such as 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 maximum cumulative dose or 1A 59
toxicity (i.e. cardiac) who are being considered for further CT, taxane-based therapy, preferably as single agents,
would usually be considered as treatment of choice. Other options are, however, available and effective, such as
capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient.
In patients pre-treated (in the adjuvant and/or metastatic setting) with an anthracycline and a taxane, and who do 1B 77
not need combination CT, single agent capecitabine, vinorelbine or eribulin are the preferred choices. Additional
choices include gemcitabine, platinum agents, taxanes, and liposomal anthracyclines. The decision should be indi-
vidualized and take into account different toxicity profiles, previous exposure, patient preferences, and country
availability.
If given in the adjuvant setting, a taxane can be re-used as 1st line therapy, particularly if there has been at least 1A 92
1 year of disease-free survival.
Duration of each regimen and the number of regimens should be tailored to each individual patient. Expert opinion 96
Usually each regimen (except anthracyclines) should be given until progression of disease or unacceptable toxicity. 1B 72
What is considered unacceptable should be defined together with the patient.
OTHER AGENTS
Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides only a moderate benefit 1A 74
in PFS and no benefit in OS. The absence of known predictive factors for bevacizumab efficacy renders recommen-
dations on its use difficult. Bevacizumab can only therefore be considered as an option in selected cases in these
settings and is not recommended after 1st/2nd line.
SPECIFIC POPULATIONS: TREATMENT OF METASTATIC MALE MBC
For ERþ Male MBC, which represents the majority of the cases, ET is the preferred option, unless there is concern Expert opinion 100
or proof of endocrine resistance or rapidly progressive disease needing a fast response.
For ERþ Male MBC tamoxifen is the preferred option. Expert opinion 83
For male patients with MBC who need to receive an AI, a concomitant LHRH agonist or orchidectomy is the pre- Expert opinion 86
ferred option. AI monotherapy may also be considered, with close monitoring of response.
Clinical trials are needed in this patient population.
SPECIFIC SITES OF METASTASES
BONE METASTASES
Radiological assessments are required in patients with persistent and localized pain due to bone metastases to de- 1A 96
termine whether there are impending or actual 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 stabilization, which is
generally followed by RT. In the absence 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 1B 100
as a matter of urgency. This requires a full radiological assessment of potentially affected area as well as adjacent
areas of the spine. MRI is the method of choice. An emergency surgical opinion (neurosurgical or orthopaedic) may
be required for surgical decompression. If no decompression/stabilization is feasible, emergency radiotherapy is
the treatment of choice and vertebroplasty is also an option.

Continued

20 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
Table 2 Continued
Recommendations LoE % Consensus

BRAIN METASTASES
Patients with a single or small number of potentially resectable brain metastases should be treated with surgery or 1B 92
radiosurgery. Radiosurgery is also an option for some unresectable brain metastases.
If surgery/radiosurgery is performed it may be followed by whole brain radiotherapy but this should be discussed 1B 72
in detail with the patient, balancing the longer duration of intracranial disease control and the risk of neurocogni-
tive effects.
Because patients with HER2þve MBC and brain metastases can live for several years, consideration of long-term 1C 89
toxicity is important and less toxic local therapy options (e.g. stereotactic RT) should be preferred to whole brain
RT, when available and appropriate (e.g. in the setting of a limited number of brain metastases).
LIVER METASTASES
Prospective randomized clinical trials of local therapy for BC liver metastases are urgently needed, since available Expert opinion 83
evidence comes only from series in highly selected patients. Since there are no randomized data supporting the ef-
fect of local therapy on survival, every patient must be informed of this when discussing a potential local therapy
technique. Local therapy should only be proposed in very selected cases of good performance status, with limited
liver involvement, no extra-hepatic lesions, after adequate systemic therapy has demonstrated control of the dis-
ease. Currently, there are no data to select the best technique for the individual patient (surgery, stereotactic RT,
intra-hepatic CT. . .).
MALIGNANT PLEURAL EFFUSIONS
Malignant pleural effusions require systemic treatment with/without local management. Thoracentesis for diagno- 2B 86
sis should be performed if it is likely that this will change clinical management. False negative results are common.
Drainage is recommended in patients with symptomatic, clinically significant pleural effusion. Use of an intrapleural
catheter or intrapleural administration of talc or drugs (e.g. bleomycin, biological response modifiers) can be help-
ful. Clinical trials evaluating the best technique are needed.
CHEST WALL AND REGIONAL (NODAL) RECURRENCES
Due to the high risk of concomitant distant metastases, patients with chest wall or regional (nodal) recurrence Expert opinion 100
should undergo full restaging, including assessment of chest, abdomen and bone.
Chest wall and regional recurrences should be treated with surgical excision when feasible with limited risk of 1B 97
morbidity.
Locoregional radiotherapy is indicated for patients not previously irradiated. 1B 97
For patients previously irradiated, re-irradiation of all or part of the chest wall may be considered in selected cases. Expert opinion 97
In addition to local therapy (surgery and/or RT), in the absence of distant metastases, the use of systemic therapy 1B 95
(CT, ET and/or anti-HER-2 therapy) should be considered.
CT after first local or regional recurrence improves long-term outcomes primarily in ER negative disease. ET in this
setting improves long-term outcomes for ER positive disease.
The choice of systemic treatment depends on tumor biology, previous treatments, length of disease free interval,
and patient-related factors (co-morbidities and preferences).
In patients with disease not amenable to radical local treatment, the choice of palliative systemic therapy should be Expert opinion 97
made according to principles previously defined for metastatic BC.
These patients may still be considered for palliative local therapy.
SUPPORTIVE AND PALLIATIVE CARE
Supportive care allowing safer and more tolerable delivery of appropriate treatments should always be part of the 1A 100
treatment plan.
Early introduction of expert palliative care, including effective control of pain and other symptoms, should be a 1A 100
priority.
Access to effective pain treatment (including morphine, which is inexpensive) is necessary for all patients in need 1A 100
of pain relief.
Optimally, discussions about patient preferences at the end of life should begin early in the course of metastatic Expert 96
disease. However, when active treatment no longer is able to control widespread and life-threatening disease, and Opinion
the toxicities of remaining options outweigh benefits, physicians and other members of the healthcare team
should initiate discussions with the patient (and family members/friends, if the patient agrees) about end-of-life
care.
ABC STATEMENTS FOR LABC (Note: For the purpose of these recommendations, LABC means inoperable, non-metastatic locally advanced
breast cancer)
Before starting any therapy, a core biopsy providing histology and biomarker (ER, PR, HER-2, proliferation/grade) ex- 1B 97
pression is indispensable to guide treatment decisions.
1B 100

Continued

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 21


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
Table 2 Continued
Recommendations LoE % Consensus

Since LABC patients have a significant risk of metastatic disease, a full staging workup, including a complete history,
physical examination, lab tests and imaging of chest and abdomen (preferably CT) and bone, prior to initiation of
systemic therapy is highly recommended.
PET-CT, if available, may be used (instead of and not on top of CTs and bone scan). 2B 100
Systemic therapy (not surgery or RT) should be the initial treatment. Expert opinion 100
If LABC remains inoperable after systemic therapy and eventual radiation, ‘palliative’ mastectomy should not be
done, unless the surgery is likely to result in an overall improvement in quality of life.
A combined treatment modality based on a multidisciplinary approach (systemic therapy, surgery and radiother- 1A 100
apy) is strongly indicated in the vast majority of cases.
For Triple Negative LABC, Anthracycline- and-taxane-based chemotherapy is recommended as initial treatment. 1A 85
For HER-21 LABC, concurrent taxane and anti-HER-2 therapy is recommended since it increases the rate of pCR. 1A 92
For HER-21 LABC, anthracycline-based chemotherapy should be incorporated in the treatment regimen. 1A 72
When an anthracycline is given, it should be administered sequentially with the anti-HER-2 therapy. 1A 87
Options for HR1 LABC include an anthracycline- and taxane-based chemotherapy regimen, or endocrine therapy. 1A 85
The choice of CT versus ET, as initial treatment, will depend on tumor (grade, biomarker expression) and patient Expert 85
(menopausal status, performance status, comorbidities, preference) considerations. Opinion
Following effective neoadjuvant systemic therapy with or without radiotherapy, surgery will be possible in many 2B 98
patients. This will consist of mastectomy with axillary dissection in the vast majority of cases, but in selected pa-
tients with a good response, breast conserving surgery may be possible.
INFLAMMATORY LABC
For inflammatory LABC, overall treatment recommendations are similar to those for non-inflammatory LABC, with 1B 93
systemic therapy as first treatment.
Mastectomy with axillary dissection is recommended in almost all cases, even when there is good response to pri- IB 95
mary systemic therapy.
Immediate reconstruction is generally not recommended in patients with inflammatory LABC. Expert opinion 95
Loco-regional radiotherapy (chest wall and lymph nodes) is required, even when a pCR is achieved with systemic 1B 98
therapy.

Oncology) in the consensus panel. The ABC Conference was also section, were not voted on during the consensus session, but
organized under the auspices of OECI (Organization of discussed and unanimously agreed by email, and are con-
European Cancer Institutes), and with the support of the BCRF sidered to have 100% agreement.
(Breast Cancer Research Foundation) and the Susan G Komen Supplementary Table S1, available at Annals of Oncology on-
for the Cure. line, lists all members of the ABC 3 consensus panel and their
The present article summarizes the guidelines developed at disclosures of any relationships with the pharmaceutical indus-
ABC3 and is supported with the level of evidence, the percentage try that could be perceived as a potential conflict of interest.
of consensus reached at the Conference, and supporting Table 1 describes the grading system used [7]. ABC1 [10] and
references. ABC2 [1] statements with only minor updates or with no updates
are listed in Table 2.

Methodology
Prior to the ABC 3 Conference, a set of preliminary recom-
mendation statements on the management of ABC were pre- General recommendations
pared, based on available published data and following the The continuous increase in cancer care costs has inevitably led to
ESMO guidelines methodology. These recommendations were inequalities in access both between countries and within each
circulated to all 44 panel members by email for comments and country. Cost, value and access are now central discussion points
corrections on content and wording. A final set of recommen- and important factors in treatment-decision making. Both
dations was presented, discussed and voted upon during the ESMO and ASCO have put considerable effort into the develop-
consensus session of ABC 3. All panel members were in- ment of validated objective scales aiming at evaluating the real
structed to vote on all questions, with members with a poten- magnitude of benefit provided by each new treatment, including
tial conflict of interest or who did not feel comfortable efficacy measures (e.g. impact on DFS, OS or PFS) and toxicity/
answering the question (e.g. due to lack of expertise in a par- quality of life measures. The ESMO Magnitude of Clinical Benefit
ticular field) instructed to vote ‘abstain’. Additional changes in Scale [8] and the ASCO Value Framework [9] are user-friendly
the wording of statements were made during the session. The tools that can greatly assist decision-makers at the country and/or
statements related to management of side effects and difficult hospital level in the difficult decisions regarding approval and
symptoms, included under the Supportive and Palliative care reimbursement.

22 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
SECTION 2. ABC IMPORTANT DEFINITIONS

GUIDELINE STATEMENT LoE Consensus

OLIGO-METASTATIC DISEASE is defined as low volume metastatic disease with limited number and size of Expert opinion Voters: 36
metastatic lesions (up to five and not necessarily in the same organ), potentially amenable for local treat- Yes: 78% (28)
ment, aimed at achieving a complete remission status. Abstain: 6% (2)
PATIENTS WITH MULTIPLE CHRONIC CONDITIONS are defined as patients with additional comorbidities Expert opinion Voters: 42
(e.g. cardiovascular, impaired renal or liver function, autoimmune disease) making it difficult to account for Yes:100%
all of the possible extrapolations to develop specific recommendations for care.

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement.

The ABC3 experts also emphasize the responsibility of the aca- imaging should be performed in case of suspicion of disease pro-
demic and medical communities to advance the knowledge on gression in the breast.
breast cancer and other relevant unanswered issues, by involve- Regarding the need to biopsy metastatic disease and re-evaluate
ment in clinical research aimed at addressing important clinical the common biomarkers, the ABC recommendations had only
questions, and not only in studies conducted for regulatory minor changes. There are situations where the need for a biopsy in
purposes. the metastatic setting is very clear, such as single lesions, history of
The importance of providing patients with full information two or more malignancies, suspicion of benign histology or doubt
in appropriate, understandable and culturally sensitive way, as between progression or post-treatment necrosis. There is also con-
well as involving them in sharing the decision-making regard- sensus regarding the importance of such biopsy in situations where
ing all aspects of their management has been repeatedly stressed when a change in biomarkers would impact the treatment choice,
in all ABC guidelines [1, 10]. A high standard of patient centred which would mainly occur when biomarkers were negative in the
care includes the following elements: appropriate information, primary tumor. There is some controversy about the benefits of a
good communication with health professionals, patient educa- biopsy in situations where there is no doubt about the nature of
tion, proactive advocacy, sensitivity to the patient’s prefer- the lesion(s) and where all receptors were positive in the primary
ences, values and needs, and providing patients with the tumor, since the clinical implementation of new technologies such
capabilities to improve their own quality of life [11]. as next generation sequencing for management decision-making s
Although the overall survival of ABC has remained stable, for not yet validated. However, the exact nature of a lesion is hard to
some subtypes, and in particular HER-2-positive metastatic ascertain without the confirmation by a biopsy as shown in some
breast cancer, prolonged survival, well beyond the median 2– retrospective and prospective studies [13–15]. There is also an
3 years, has become a frequent reality. For these long-term sur- undisputable importance of collection of material for research
vivors, survivorship issues which are specific for advanced cancer purposes, both ongoing and future.
patients, have emerged and need appropriate attention, research Technical issues should be discussed with the breast patholo-
and management. Work-related issues are central and solutions gist, in particular in case of bone biopsies with the inherent decal-
not easy to implement. A recently published survey [12], found cification problems, which may interfere with the biomarker
that approximately half of the women in employment had to analysis [16, 17], as experienced in Safir01/UNICANCER trial
change their work situation due to ABC and that 37% of them [18]. For that reason, decalcification using EDTA is recom-
had to give up work temporarily or permanently. Due to these in- mended for bone biopsies, when it is the only metastatic site [17].
come problems and those related to the cost of care, the same sur- Adding to the complexity of this issue is the fact that negative bio-
vey found that 56% of ABC patients experienced a decline in marker results may limit the eligibility for reimbursement of
household income as a result of their disease. The ABC commu- therapies dedicated to specific subtypes, in some countries.
nity strongly advocates for the right of ABC patients to return or A number of prospective randomized trials have assessed or are
maintain their work, since a substantial proportion of these pa- assessing the role of removing the primary tumor in patients with
tients are in their most productive years. Furthermore, in some de novo metastatic disease. So far only two small studies have been
countries, health coverage is dependent on being employed. For published/presented [19, 20]. A subgroup analysis of the Turkish
that to occur, we need flexibility of working schedules, new com- study suggested a potential benefit in patients with ER/PgRþ,
munication technologies and home-based work which the ABC HER-2 negative, solitary bone metastasis, who are younger than 55
community supports. In many countries this may imply a change years of age, while patients with multiple pulmonary and liver me-
in the current labour-related laws. tastasis did worse with an overall 3-year survival of 31% in the sur-
Survivorship issues also include the potential discussion of gery group versus 67% for the systemic therapy group [20]. In the
breast reconstruction, in those cases where the metastatic disease Indian trial, a decrease in distant progression-free survival was
is either in complete remission or in a durable stable situation. observed in patients allocated to surgery. Results of larger, pro-
No consensus could be reached regarding the use of breast imag- spective studies are awaited. Until then, the recommendation is to
ing to follow-up the unaffected breast, but the experts agreed that discuss surgery on a case-by-case basis and importantly, only

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 23


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
SECTION 3. HER-2 POSITIVE ABC

GUIDELINE STATEMENT LoE Consensus

Anti-HER-2 therapy should be offered early (as 1st line) to all patients with HER-2þ ABC, except in the pres- 1A Voters: 43
ence of contra-indications to the use of such therapy Yes: 98% (42)
For highly selected patients* with ERþ/HER-2þ MBC, for whom ET is chosen over CT, ET should be given in 1A Voters: 43
combination with anti-HER-2 therapy (either trastuzumab or lapatinib) since the combination provides PFS Yes: 72% (31)
benefit (i.e. ‘time without CT’) compared to ET alone. The addition of anti-HER-2 therapy to ET in the 1st line Abstain: 9% (4)
setting has not led to a survival benefit but long-term follow-up was not collected in the available trials. In
addition, this strategy is currently being directly compared with CTþanti-HER2 therapy. (*see definition in
text)
For patients with ERþ/HER-2þ MBC, for whom CTþanti-HER2 therapy was chosen as 1st line therapy and pro- 1C Voters: 39
vided a benefit, it is reasonable to use ETþanti-HER2 therapy as maintenance therapy, after stopping CT, al- Yes: 79% (31)
though this strategy has not been studied in randomized trials. Abstain: 10% (4)
Patients progressing on an anti-HER-2 therapy combined with a cytotoxic or endocrine agent should be 1B Voters: 43
offered additional anti-HER-2 therapy with subsequent treatment since it is beneficial to continue suppres- Yes: 91% (39)
sion of the HER-2 pathway. The optimal duration of anti-HER-2 therapy for MBC (i.e. when to stop these Abstain: 7% (3)
agents) is currently unknown.
In patients achieving a complete remission, the optimal duration of maintenance anti-HER2 therapy is un- Expert Opinion Voters: 42
known and needs to be balanced against treatment toxicity, logistical burden and cost. Stopping anti-HER2 Yes: 93% (39)
therapy after several years of sustained complete remission may be considered in some patients, particu- No: 7% (3)
larly if treatment re-challenge is available in case of progression.
Patients who have received any type of (neo)adjuvant anti-HER-2 therapy should not be excluded from clinical 1B Voters: 40
trials for HER-2þ MBC. These patients remain candidates for anti-HER-2 therapies. Yes: 100%
In the 1st line setting, for HER-2þ MBC previously treated (in the adjuvant setting with DFI >12 months) or un- 1A Voters: 44
treated with trastuzumab, combinations of CTþtrastuzumab are superior to combinations of CTþlapatinib Yes: 95% (42)
in terms of PFS and OS. Abstain: 5% (2)
The standard 1st line therapy for patients previously untreated with anti-HER-2 therapy is the combination of 1A Voters: 42
CTþtrastuzumab and pertuzumab, because it has proven to be superior to CTþtrastuzumab in terms of OS Yes: 86% (36)
in this population. Abstain: 12% (5)
For patients previously treated (in the (neo)adjuvant setting) with anti-HER-2 therapy, the combination of 1A Voters: 41
CTþtrastuzumab and pertuzumab is an important option for 1st line therapy. Few (88) of these patients Yes: 76% (31)
were treated in the Cleopatra trial and all with trastuzumab-free interval >12 months. Abstain: 22% (9)
There are currently no data supporting the use of dual blockade with trastuzumabþpertuzumab and CT be- 1 A (against its use) Voters: 43
yond progression (i.e. continuing dual blockade beyond progression) and therefore this 3 drug regimen Yes: 86% (37)
should not be given beyond progression outside clinical trials. Abstain: 9% (4)
In a HER-2þ MBC patient, previously untreated with the combination of CTþtrastuzumabþpertuzumab, it is Expert Opinion Voters: 37
acceptable to use this treatment after 1st line. Yes: 76% (28)
Abstain: 16% (6)
After 1st line trastuzumab-based therapy, T-DM1 provides superior efficacy relative to other HER-2-based thera- 1A Voters: 42
pies in the 2nd line (versus lapatinibþcapecitabine) and beyond (versus treatment of physician’s choice). Yes: 88% (37)
T-DM1 should be preferred in patients who have progressed through at least 1 line of trastuzumab-based ther- Abstain: 129% (5)
apy, because it provides an OS benefit.
However, there are no data on the use of T-DM1 after dual blockade with trastuzumabþpertuzumab.
In case of progression on trastuzumab-based therapy, the combination trastuzumabþlapatinib is a reasonable 1B Voters: 43
treatment option for some patients. There are however, no data on the use of this combination after pro- Yes: 84% (36)
gression on pertuzumab or T-DM1. Abstain: 12% (5)
All patients with HER-2þ MBC who relapse after adjuvant or any line metastatic anti-HER-2 therapy should be 1B Voters: 40
considered for further anti-HER-2 therapy, except in the presence of contraindications. The choice of the Yes: 86% (36)
anti-HER-2 agent will depend on country-specific availability, the specific anti-HER-2 therapy previously ad- Abstain: 12.5% (5)
ministered, and the relapse free interval. The optimal sequence of all available anti-HER-2 therapies is cur-
rently unknown.
Regarding the CT component of HER-2 positive MBC treatment:
When pertuzumab is not given, 1st line regimens for HER-2 MBC can include trastuzumab combined with 1A Voters: 41
vinorelbine or a taxane. Differences in toxicity between these regimens should be considered and discussed Yes: 88% (36)
with the patient in making a final decision. Abstain: 10% (4)
Other CT agents can be administered with trastuzumab but are not as well studied and are not preferred.
For later lines of therapy, trastuzumab can be administered with several CT agents, including but not limited 2A Voters: 43
to, vinorelbine (if not given in 1st line), taxanes (if not given in 1st line), capecitabine, eribulin, liposomal Yes: 91% (39)

Continued

24 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
SECTION 3 Continued
GUIDELINE STATEMENT LoE Consensus

anthracyclines, platinum, gemcitabine, or metronomic CM. The decision should be individualized and take Abstain: 9% (4)
into account different toxicity profiles, previous exposure, patient preferences, and country availability.
CT agents to combine with a dual blockade of trastuzumabþpertuzumab are docetaxel (LoE: 1A) or paclitaxel See in statement Voters: 43
(LoE: 1B). Also possible are vinorelbine (LoE: 2 A), nab-paclitaxel (LoE: 2B) and capecitabine (LoE: 2A). Yes: 86% (37)
Abstain: 11.6% (5)
HER-21 ABC and BRAIN METASTASES
In patients with HER-2-positive ABC with brain metastases and stable extracranial disease, systemic therapy 1C Voters: 42
should not be changed. Yes: 95% (40)
Abstain: 5% (2)
For patients with HER-2-positive cancers where brain metastases are the only site of recurrence, the addition 1C Voters: 42
of CT to local therapy is not known to alter the course of the disease. It is recommended to re-start the Y: 83% (35)
anti-HER-2 therapy (trastuzumab) if this had been stopped. A: 7% (3)

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement; ET, endocrine therapy; CT, chemotherapy;
DFI, disease-free interval, CM, cyclophosphamide þ methotrexate.

consider surgery if it can be performed with a high quality proced- HER-2 positive ABC
ure [21].
Among all breast cancer subtypes, HER2-positive ABC has had
The definition of oligometastatic disease (see next section) has
the largest progress over the last decade. The introduction of new
been enlarged to encompass low volume metastatic disease, i.e.
anti-HER2 therapies, such as pertuzumab and T-DM1 [23–27],
limited number and size of metastatic lesions (up to five and not
was a significant step forward but also created a number of new
necessarily in the same organ) and potentially amenable for local
uncertainties related to optimal combination/sequence of all
treatment which is aimed at achieving a complete remission. The
available treatments.
development of minimally invasive surgical techniques and
In view of the overall survival (OS) results obtained with most
highly conformal ablative radiotherapy allow for safe and effect-
combinations of chemotherapy plus anti-HER-2 agents, the role
ive ablation of metastatic lesions in most locations. Although
of endocrine therapy plus anti-HER-2 agents for the subgroup of
some retrospective studies have suggested that achieving a sus-
patients with ERþ/HER-2þ disease has been questioned.
tained complete remission seems to be associated with a longer
Although published studies have not demonstrated an OS benefit
survival [22], the true impact of these local-regional therapies on
of this combination, long-term data were not collected in these
long-term outcome remains unknown, and prospective and if
trials. Of note, the OS analysis of the TAnDEM trial, excluding
possible randomized trials are needed.
patients who crossed over to trastuzumab, demonstrated a bor-
derline OS benefit for the combination arm [28]. In the absence
of valuable biomarkers, this approach should be reserved for
ABC important definitions highly selected patients, including those with contraindications
Most clinical situations occur as a continuum and dividing them to chemotherapy, patient’s with a strong preference against
into categories of stage, grade, risk group, or other factors is al- chemotherapy or those with a long disease-free interval, minimal
ways artificial and based on oversimplification of thresholds. disease burden, in particular in terms of visceral involvement,
Such a categorization is, however, useful to guide treatment and/or strong ER/PgR expression. Trials directly comparing
choices, to help assure adherence to guidelines and recommenda- chemotherapy plus anti-HER2 therapy versus endocrine therapy
tions, and to facilitate clinical research. Following the effort of plus anti-HER2 therapy are currently ongoing (Detect
previous editions, ABC provides two additional definitions: ‘oli- V/CHEVENDO (NCT02344472), SYSUCC-002 (NCT01950182)
gometastatic disease’ discussed above and the complex clinical and PERNETTA trials) and their results will allow for better
situation of ‘multiple chronic conditions’. The latter is becoming recommendations. In addition, in several countries anti-HER2
increasingly important and more frequent in view of the aging of therapy, namely trastuzumab, can only be used once in the meta-
the population in general and of cancer patients in particular. static setting since its use beyond progression is either not
Managing advanced cancer, the consequences of the disease and approved or not reimbursed; in those cases, preference should be
of the rapidly increasing number and type of pharmacologic and given to a combination of chemotherapy plus anti-HER-2
non-pharmacologic interventions in patients with several coex- therapy.
isting conditions is a major challenge. Furthermore, these pa- The combination of endocrine therapy plus anti-HER2 therapy
tients are systematically excluded from clinical trials and hence is particularly useful as maintenance therapy for ERþ/
available data, in particular regarding the use of new agents in HER2þ ABC, after initial cycles of chemotherapy plus anti-HER-
these situations, are scarce and eagerly needed. 2 therapy. Despite the absence of randomized trials, clinical

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 25


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
SECTION 4. ER POSITIVE/HER-2 NEGATIVE (LUMINAL) ABC

GUIDELINE STATEMENT LoE Consensus

Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of 1A Voters: 41
visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance. Yes: 93% (38)
Abstain: 7% (3)
The preferred 1st line ET for postmenopausal patients depends on type and duration of adjuvant ET as well as 1A Voters: 44
time elapsed from the end of adjuvant ET; it can be an aromatase inhibitor, tamoxifen or fulvestrant. Yes: 84% (37)
Abstain: 7% (3)
The combination of a nonsteroidal AI and fulvestrant as first-line therapy for postmenopausal patients resulted 2B Voters: 43
in significant improvement in both PFS and OS compared to AI alone in one phase III trial and no benefit in Yes: 33% (14)
a second trial with a similar design. Subset analysis suggested that the benefit was limited to patients with- No: 53% (23)
out prior exposure to adjuvant ET (tamoxifen). Based on these data, combination ET may be offered to Abstain: 14% (6)
some patients with MBC without prior exposure to adjuvant ET.
The addition of everolimus to an AI is a valid option for some postmenopausal patients with disease progres- 1B Voters: 40
sion after a non-steroidal AI, since it significantly prolongs PFS, albeit without OS benefit. The decision to treat Yes: 84% (34)
must take into account the individual relevant toxicities associated with this combination and should be Abstain: 13% (5)
made on a case by case basis.
Tamoxifen can also be combined with everolimus. 2B
The addition of the CDK4/6 inhibitor palbociclib to an aromatase inhibitor, as 1st line therapy, for postmeno- 1A Voters: 37
pausal patients (except patients relapsing <12 months from the end of adjuvant AI), provided a significant im- Yes: 92% (34)
provement in PFS (10 months), with an acceptable toxicity profile, and is therefore one of the preferred Abstain: 3% (1)
treatment options, where available. OS results are still awaited.
ESMO MCBS: 3*
The addition of CDK4/6 inhibitor palbociclib to Fulvestrant, beyond 1st line therapy, for pre/peri/postmeno- 1A Voters: 42
pausal patients, provided significant improvement in PFS (5 months) as well as improvement of QoL, and is Yes: 86% (36)
a treatment option. OS results are awaited. Abstain: 10% (4)
For pre/peri-menopausal pts, an LHRH-agonist must also be used.
At present, no predictive biomarker other than hormone receptor status exists to identify patients who will
benefit from these type of agents and research efforts must continue.
ESMO MCBS: 4*
The optimal sequence of endocrine agents after 1st line ET is uncertain. It depends on which agents were used 1A Voters: 40
in the (neo)adjuvant and 1st line ABC settings. Available options include AI, tamoxifen, fulvestrantþpalbociclib, Yes: 93% (37)
AIþeverolimus, tamoxifenþeverolimus, fulvestrant, megestrol acetate and estradiol. Abstain: 5% (2)
It is currently unknown how the different combinations of endocrineþbiological agents compare with each
other, and with single agent CT. Several trials are ongoing.
For pre-menopausal women, for whom ET was decided, ovarian suppression/ablation combined with add- 1B Voters: 43
itional endocrine therapy is the preferred choice. Yes: 93% (40)
Abstain: 5% (2)
Ovarian ablation by laparoscopic bilateral oophorectomy ensures definitive estrogen suppression and contra- Expert Opinion Voters: 43
ception, avoids potential initial tumor flare with LHRH agonist, and may increase eligibility for clinical trials. Yes: 91% (39)
Patients should be informed on the options of OS/OA and decision should be made on a case by case. Abstain: 7% (3)
For pre-menopausal women, the additional endocrine agent can be AI or tamoxifen, according to type and 1B Voters: 42
duration of prior adjuvant endocrine therapy but AI absolutely mandates the use of ovarian suppression/ Y: 95% (40)
ablation. 1C Abstain: 5% (2)
Fulvestrant is also a valuable option, but for the moment also mandates the use of ovarian suppression/
ablation.

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement; ET, endocrine therapy; CT, chemotherapy;
QoL, quality-of-life.
ESMO MBCS ¼ ESMO Magnitude of Clinical Benefit Scale; * 5 very important explanation in text.

experience and low toxicity (in particular if trastuzumab is used), are sufficient data [29, 30] to recommend continuing trastuzu-
makes this a reasonable option, most probably delaying disease mab beyond progression, but the optimal duration of this treat-
progression and the consequent need for chemotherapy. ment and how many lines beyond progression should it be used is
The issue of duration of anti-HER-2 therapy in the metastatic currently unknown. Data are very scarce related to the use beyond
setting is of crucial importance, in view of the potential benefits progression of other anti-HER2 agents and no data exist support-
as well as the substantial costs associated with these agents. There ing the use of dual blockade beyond progression.

26 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
A particularly difficult situation, albeit also a fortunate one, re- studies, such as the SystHERs Registry Study [31] and
lates to the optimal duration of trastuzumab therapy in patients registHER, as well as collection of treatment and outcome data
achieving long-term complete remission. This needs to be bal- beyond progression in all HER-2-positive ABC clinical trials,
anced against toxicity, logistical burden and cost. Currently no are of great importance.
data exist to support therapeutic decisions in this setting, and the In ABC3, the optimal chemotherapy component for the
panel supported a cautious statement approving consideration of treatment of HER-2þ disease was discussed. The panel has
stopping trastuzumab in these circumstances in some patients, stressed the importance of treatment decisions that are based
particularly if treatment re-challenge is available in case of pro- not only on efficacy, but also on toxicity profile, and patients’
gression, which is not the case in all countries. preferences.
Dual blockade with trastuzumab and pertuzumab in combin- For 1st line therapy, when trastuzumab is used as sole anti-
ation with chemotherapy as 1st line therapy, provides substantial Her2 agent, the preferred agents are vinorelbine or a taxane.
benefit in terms of OS and PFS [23]. It is therefore considered by Importantly, single agent vinorelbine in association with trastu-
the panel as the standard of care for patients previously untreated zumab has shown superior or equal efficacy compared to either
with trastuzumab, in the (neo)adjuvant setting, and an important paclitaxel or docetaxel, in the TRAVIOTA and HERNATA trials,
treatment option for patients previously treated with trastuzu- and has a better tolerability [32, 33]. For later lines of therapy,
mab. The difference in the strength of recommendation is due to trastuzumab can be administered with almost all chemotherapy
the fact that very few patients (only 88) who were previously agents, including but not limited to, vinorelbine (if not given in
treated with trastuzumab were enrolled in the Cleopatra trial. In 1st line), taxanes (if not given in 1st line), capecitabine, eribulin,
addition, in the Marianne trial [26] the dual blockade strategy liposomal anthracyclines, platinum, gemcitabine, or metronomic
did not prove to be superior to chemotherapy and trastuzumab, CM (low dose, oral, cyclophosphamide and methotrexate). The
albeit with a different combination of agents—T-DM1 and decision should be individualized and take into account different
Pertuzumab. The reasons for this lack of benefit are currently un- toxicity profiles, previous exposure, patient preferences, and
known and could be related to the different patient populations country availability. Combinations of other anti-HER2 agents,
enrolled in both trials (more (30%) patients in Marianne had namely TKIs, with chemotherapy are more limited due to tox-
been previously treated with trastuzumab), the choice of agents icity. There are currently no data to decide on the best sequence
with the presence or absence of synergistic effects, the absence of for each individual patient.
standard chemotherapy agents (DM1 being a cytotoxic agent not When dual blockade with trastuzumab and pertuzumab is
used as single agent) or other factors. used, possible agents to combine are docetaxel [23], weekly pacli-
After the discussion and voting during ABC3, the Pherexa [27] taxel [34], vinorelbine [35] and nab-paclitaxel [36]. After the vot-
study was presented, evaluating the role of dual blockade with ing that took place in ABC3, the Pherexa trial [27], presented at
trastuzumab þ pertuzumab þ capecitabine for patients previ- ASCO 2016, provided some evidence regarding the combination
ously treated with a taxane and trastuzumab in the metastatic set- of dual blockade with capecitabine.
ting. Surprisingly, a non-significant benefit of only 2 months was
seen in the primary endpoint PFS, while an 8-month benefit was
observed in OS albeit non-statistically significant (in view of the
lack of significant PFS benefit). ER positive/HER-2 negative (luminal) ABC
Many questions remain unanswered in the management of One of the most important recommendations relates to the pre-
HER-2þ ABC. We have no data on the role of dual blockade for ferred treatment for luminal ABC, which should be endocrine
patients relapsing during and within 12 months of adjuvant tras- therapy in the majority of cases, excluding those with visceral cri-
tuzumab, since these patients have been excluded from clinical sis and concern or proof of endocrine resistance. All breast cancer
trials. This aggressive situation is a clear unmet need for which guidelines concur with this recommendation but unfortunately
data must be generated. Following the approval, both by FDA real life data studies show that most of these patients still receive
and EMA, of pertuzumab use in the neoadjuvant setting, there is chemotherapy as their first treatment, despite the lower efficacy
an urgent need to evaluate the best treatment options for the [37].
patients who relapse after receiving chemother- Visceral crisis and endocrine resistance have been defined dur-
apy þ trastuzumab þ pertuzumab in the early setting. It is also ing ABC 2 and published [1]. However, better predictive factors
currently unknown how trastuzumab þ pertuzumab þ chemo- are urgently needed to clearly identify those patients whose
therapy compares to T-DM1, as 1st or later lines of therapy. We tumors have primary endocrine resistance and are responsible for
also have no data on the best treatment option after progression the early and rapid progression seen in 20–25% of luminal ABC
on dual blockade with pertuzumab þ trastuzumab, namely how patients treated with endocrine therapy [38]. Possible reasons
T-DM1 performs in this setting. may include ER loss [39] or ER mutations [40].
While trastuzumab þ lapatinib (without chemotherapy) is a The most important advance in the management of luminal
valuable option for some patients, after progression on chemo- ABC over the last 2 years has undoubtedly been the introduction
therapy þ trastuzumab, there are no data on the use of this com- of a new class of agents, the CDK4/6 inhibitors, in combination
bination after progression on pertuzumab or T-DM1. with an endocrine agent.
All these unanswered questions and the definition of the best The value of the CDK4/6 inhibitor palbociclib, combined with
sequence of therapies for the individual patient may prove dif- an aromatase inhibitor as 1st line therapy was evaluated initially
ficult to evaluate in prospective, randomized trials, with the in a randomized phase II study, the PALOMA 1 trial [41], which
absence of specific biomarkers. In this scenario, registry showed a substantial 10-month benefit in progression-free-

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 27


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
SECTION 5. TRIPLE NEGATIVE ABC

GUIDELINE STATEMENT LoE Consensus

For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommen- 1A Voters: 44
dations. Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC. Yes: 98% (43)
Abstain: 2% (1)
In triple-negative ABC patients (regardless of BRCA status), previously treated with anthracyclines with or with- 1A Voters: 43
out taxanes in the (neo)adjuvant setting, carboplatin demonstrated comparable efficacy and a more favor- Yes: 91% (39)
able toxicity profile, compared to docetaxel, and is therefore an important treatment option. Abstain: 5% (2)

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement; CT, chemotherapy.

survival (PFS) coupled with a favorable toxicity profile (main Another possible therapy is the combination of endocrine ther-
toxicity being neutropenia). Based on these results, FDA granted apy with the mTOR inhibitor, everolimus. This combination has
accelerated approval, which resulted in the drug being commer- shown a PFS benefit of 6 months, without a significant OS
cially available in USA. At the 2016 ASCO meeting, the phase III benefit, and with significant toxicity [44, 45]. However, as with
PALOMA 2 trial was presented and confirmed the 10-month many agents, as more experience is gained regarding the use of
benefit in PFS, with the main toxicities being hematological everolimus and the management of its toxicities, its clinical use
(mainly neutropenia) and fatigue [41]. OS results are still becomes easier. In addition, patient education is fundamental for
awaited. In view of these results, the initial statement developed prevention and early management of associated side effects. Of
at ABC3 was modified and re-voted by email and considers this particular attention is the possibility of an excess mortality of this
option as one of the preferred treatment options, where available. combination in elderly patients (>70 years of age) [44, 46].
Very recently (September 2016) EMA also started the approval Currently, and in spite of intensive research, no predictive bio-
process of Palbociclib. However, its approval/reimbursement in marker, other than hormone receptor status, exists to identify pa-
all individual countries is still pending and the issue of cost is of tients who will benefit the most from either m-TOR or CDK4-6
crucial importance for its implementation in clinical practice, as inhibitors and research efforts must continue.
it is for many targeted agents namely anti-HER-2 agents. The panel did not support (53.4% against) the 1st line combin-
Beyond 1st line endocrine therapy, addition of palbociclib to ation of non-steroidal aromatase inhibitor and fulvestrant based
fulvestrant resulted in significant albeit lower 5-month PFS pro- on the results of the SWOG S0226 trial [47]. There may be a bene-
longation in the PALOMA 3 phase III trial [42]. The quality of fit for the minority of postmenopausal patients who are endo-
life substudy has shown both an overall improvement and a crine-naı̈ve.
delayed deterioration of this important endpoint, with greater The definition of the best 1st line approach for postmeno-
improvement in baseline pain, in the palbociclib arm [43]. pausal patients will soon have additional data through the phase
Importantly, the PALOMA-3 study accrued both postmeno- III FALCON data that will be presented this year.
pausal and pre/perimenopausal (in combination with ovarian The optimal sequence of single endocrine agents and combin-
function suppression) patients, allowing for assessment of the ations with targeted agents is currently unknown and is a research
drug efficacy in a breast cancer population usually excluded from priority. It is crucial to collect data from clinical trials beyond
ABC endocrine therapy trials. OS results are still awaited. In view progression to better understand the efficacy of each class of agent
of available results, the ABC panel considers this as a treatment when given after the other (e.g. CDK4-6 inhibitors after m-TOR
option, where available. inhibitors and vice-versa).
The ESMO Magnitude of Clinical Benefit Scale (MCBS) was
calculated for the recently approved Palbociclib, for use in 1st
line and in 2nd line. As a reminder, the MCBS scores a given
treatment in a given setting, and based on published trials. At the Triple negative ABC
time of publishing the ABC3 guidelines, PALOMA 2 main results The treatment of triple-negative breast cancer (TN-ABC) still re-
and the accompanying quality of life substudy have been pre- mains the largest unmet need within ABC. In spite of extensive re-
sented but not yet published. For this reason, the MCBS for the search, no treatments apart from chemotherapy have so far proven
use of palbociclib in 1st line was calculated using the PALOMA 1 to be effective for this population. For this reason, no specific recom-
trial efficacy data, which scores a 3 for efficacy. Once the mendations can be made for this ABC subtype, with the possible ex-
PALOMA 2 data is published the MCBS will be updated an e-up- ception of platinum compounds for BRCA-mutated patients.
date made available through the ESMO guidelines website. For Probably the largest achievement of the last 2 years was the
the use of palbociclib as 2nd line therapy, data from PALOMA 3, TNT study, comparing ‘standard’ docetaxel to carboplatin in
both efficacy and quality of life, were used. The MCBS was 3 for unselected TNBC patients (with pre-specified subgroup analysis
efficacy, and due to the improvement in quality of life upgraded of BRCA-mutation carriers). The superiority of carboplatin was
to 4, which is the final score for this setting. demonstrated only among BRCA-positive patients, while in the

28 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
SECTION 6. OTHER RECOMMENDATIONS

GUIDELINE STATEMENT LoE Consensus

CHEMOTHERAPY OTHER
Metronomic chemotherapy is a reasonable treatment option, for patients not requiring rapid tumor re- 1B Voters: 43
sponse. The better studied regimen is CM (low dose oral cyclophosphamide and methotrexate); other regi- Yes: 88% (38)
mens are being evaluated (including capecitabine and vinorelbine). Randomized trials are needed to Abstain: 5% (2)
accurately compare metronomic CT with standard dosing regimens.
Even if given in the adjuvant setting, provided that cumulative dose has not been achieved and that there are 1C Voters: 44
no cardiac contra-indications, anthracyclines can be re-used in MBC, particularly if there has been at least Yes: 93% (41)
1 year of disease-free survival. Abstain: 5% (2)
BRCA-ASSOCIATED ABC
In patients with BRCA-associated triple negative or endocrine-resistant MBC previously treated with an 1A Voters: 44
anthracycline with or without a taxane (in the adjuvant and/or metastatic setting), a platinum regimen is Yes: 86% (38)
the preferred option, if not previously administered and no suitable clinical trial is available. Abstain: 9% (4)
In patients with TN or Luminal MBC, genetic counseling and possibly BRCA testing should be discussed Expert Opinion Voters: 43
with the patient, if the results can impact on treatment decisions and/or on clinical trials entry. Yes: 91% (39)
Abstain: 7% (3)
BONE METASTASES
A bone modifying agent (bisphosphonate, denosumab) should be routinely used in combination with other 1A Voters: 44
systemic therapy in patients with MBC and bone metastases. Yes: 95% (42)
Three-monthly zolendronic acid seems to be not inferior to standard monthly schedule. 1B Abstain: 5% (2)
Supplementation of calcium and vitamin D3 is mandatory, unless contraindications exist. 1C
OTHERÅBIOMARKERS
Multigene panels, such as those obtained using next generation sequencing (NGS) or other technology, re- 1C Voters: 44
garding evolving molecular changes in ABC tumors has not yet proven beneficial in clinical trials, their im- Yes: 95% (42)
pact on outcome remains undefined and should only be considered investigational. Abstain: 5% (2)

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement; MBC, metastatic breast cancer.

unselected TN-ABC population docetaxel and carboplatin seem on their efficacy and toxicity profile, are capecitabine, vinorelbine
to have a similar efficacy [48], although the study was not de- and eribulin. The latter is one of the few agents to provide a survival
signed as a non-inferiority study. Of note, in this study, 15% of gain, albeit small (2.5 months) in a heavily pretreated population of
patients had no prior adjuvant chemotherapy and only 35% had ABC patients [51]. In a head-to-head comparison between eribulin
received (neo)adjuvant taxanes. Importantly, due to the signifi- and capecitabine, as first or second line therapy, there were no major
cantly better toxicity profile of carboplatin, it remains an at- differences between the drugs in efficacy but a different toxicity pro-
tractive treatment choice even for unselected TN-ABC patients. file [52].
Unfortunately, other putative predictive factors of increased It is also possible to re-challenge with anthracyclines, particu-
sensitivity to platinum, such as homologous recombination def- larly if there has been at least 1 year of disease-free survival, and if
icit (HRD) and the basal-like Prosigna PAM50 signature were the cumulative dose has not been reached, a common situation
not proven of value for making treatment decisions in this nowadays because of the lower doses of anthracyclines used in
setting. the adjuvant setting. Re-challenge with taxanes is also possible,
The future of TN-ABC treatment seems to lie in a better biolo- provided that there has been at least 1 year of disease-free
gical characterization of this breast cancer subtype into further survival.
subgroups, followed by the development of specific therapies for Another very attractive option is the use of metronomic
each of the subgroups. An example is the Luminal AR subtype, chemotherapy, defined as the use of low doses and short intervals,
characterized by the expression of the androgen receptor; antian- which has been evaluated in the advanced setting with interesting
drogens have recently demonstrated some activity and are being efficacy results and an excellent toxicity profile [53]. The best
further evaluated, and where a potential predictive marker, the evaluated regimen is oral cyclophosphamide and oral methotrex-
Predict AR assay, is also being tested [49, 50]. ate but other agents are being studied such as vinorelbine and
capecitabine.
In view of the lack of substantial efficacy differences among the
Other recommendations different available options, their toxicity profile must be discussed
Several options exist for chemotherapy both for first and subsequent with the patient and her/his preferences taken into account.
lines of therapy. The ABC panel maintains that for patients pre- ABC3 also further endorsed the use of bone-modifying
treated with anthracyclines and taxanes the preferred agents, based agents (bisphosphonate, denosumab) in combination with

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 29


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
SECTION 7. SUPPORTIVE AND PALLIATIVE CARE

GUIDELINE STATEMENT LoE Consensus

Management of CANCER RELATED FATIGUE 100%


Cancer related fatigue is frequently experienced by patients with ABC, exerts a deleterious impact on QoL and
limits physical, functional, psychological and social well-being. The etiology of this fatigue is complex so effect- as in the text
ive management needs to be multidimensional. It is important to assess it using appropriate PRO measures
before implementing various non-pharmacological (such as exercise—LoE: 1 A) and if needed pharmaco-
logical interventions (LoE: 2 B).
Management of CDK Inhibitor Induced Neutropenia 2A 100%
Neutropenia is the most common toxicity associated with CDK 4/6 inhibition and is not generally associated
with febrile neutropenia although an increase in infections has been reported. Treatment should be delayed
until neutrophils have recovered to at least 1000/ll; dose reduction can also be considered.
Management of Non-Infectious Pneumonitis (NIP) 2A 100%
NIP is an uncommon complication of mTOR inhibition. Patient education is critical to ensure early reporting of
respiratory symptoms.
Treatment interruption and dose reduction are generally effective for grade 2 symptomatic NIP with use of sys-
temic steroids and treatment discontinuation for grade 3 or greater toxicity.
Management of MUCOSITIS/STOMATITIS
Mild toothpaste and gentle hygiene are recommended for the treatment of stomatitis. Early intervention is rec- Expert opinion 100%
ommended. For grade 2 or higher stomatitis, delaying treatment until the toxicity resolves and considering
lowering the dose of the targeted agent are also recommended. Consider adding steroid dental paste to treat
developing ulcerations.
Steroid mouthwash can be used for prevention of stomatitis (suggested schedule: 0.5 mg/5 ml dexamethasone, 1B
10 ml to swish2 min then spit out qid).
Management of DYSPNEA
Treatable causes like pleural effusion, pulmonary emboli, cardiac insufficiency, anemia or drug toxicity must be 1 A, 100%
ruled out. Patient support is essential. Oxygen is of no use in non-hypoxic patients. Opioids are the drugs of 2 A,
choice in the palliation of dyspnea (LoE: 1 A). Benzodiazepines can be used in patients experiencing anxiety Expert opinion
(LoE: 2A). Steroids can be effective in dyspnea caused by lymphangitis carcinomatosis, radiation or drug-
induced pneumonitis, superior vena cava syndrome, an inflammatory component, or in (cancer-induced) ob-
struction of the airways (in which case laser/stent is to be considered).
Management of NAUSEA and VOMITING
ESMO/MASCC GUIDELINES are available for management of chemotherapy-induced and morphine-induced
nausea and vomiting, and these are endorsed by ABC3.
There is a need to study nausea and vomiting related to chronic use of anticancer drugs. Expert Opinion 100%
Management of endocrine toxicities of mTOR inhibition 2A 100%
Hyperglycemia and hyperlipidemia are common sub-acute complications of mTOR inhibition. Evaluation of
preexisting diabetes or hyperglycemia at baseline is essential. Regular careful monitoring of glycemia and lipid
panel is needed to identify these toxicities.
Management of grade 1 and 2 hyperglycemia include treatment with oral antidiabetics and basal insulin, in ac-
cordance with international recommendation for diabetes mellitus treatment. Statins are indicated to treat
grade 2 and 3 hypercholesterolemia, and fibrates should be introduced if triglyceride level >500 mg/dl (with
attention to possible drug–drug interaction between everolimus and fibrates). Treatment interruption and
dose reduction are generally effective for grade 2 and 3. Treatment should be discontinued for grade 4
toxicity.

LoE, available level of evidence; consensus, percentage of panel members in agreement with the statement; QoL, quality of life.
NOTE: The statements of this section were not voted during the ABC Consensus panel but were developed and agreed upon by email, by all
panel members.

calcium þ vitamin D3 supplementation as a routine component of 4 weekly administration of intravenous bisphosphonates by 3-


management of patients with bone metastases. Denosumab has monthly zoledronic acid after an initial period of monthly use [55,
demonstrated slightly better efficacy and better tolerability, com- 56]. Early 3-monthly use seems associated with increased need for
pared to zoledronic acid [54], having the advantage of a subcutane- major surgeries [57], so a reasonable compromise may be to start
ous route of administration and the disadvantage of a substantially with the monthly schedule for the first year and then change to 3-
higher cost in most countries; where available, it can be considered a monthly regimen. No data exist on the optimal overall treatment
preferred option. Currently available data support replacing routine duration of bone modifying agents, and their efficacy must be

30 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
weighed against long-term toxicity (such as osteonecrosis of the jaw Conference, the ESMO Committees will apply the MCBS and the
and atypical fractures). result will be made available as an e-update to the present
When a bone modifying agent is given, supplements of calcium guidelines.
and vitamin D are mandatory, except in the presence of contra- Following on the success of the ABC Consensus Conference,
indications. the ABC community has come together to create the ABC Global
Unfortunately, no multigene testing technology has been proven Alliance. This Alliance will function as a platform where all
to be beneficial in supporting treatment choices in ABC patients involved partners (advocacy groups, pharma, cooperative
[18] and the panel strongly discourages their use in clinical prac- groups, societies, individuals) will be able to work together, in
tice. They should continue to be considered investigational. projects designed to improve the lives of ABC patients. The
Global Status of ABC Decade Report [2] has highlighted several
areas of unmet needs. Based on these findings, a global Call-To-
Supportive and palliative care Action is being developed, with tangible objectives that need to
be achieved within the next decade to meaningfully impact the
The ABC panel decided to dedicate several recommendations to outcomes of ABC patients.
the management of disease and treatment-related symptoms, a
problem faced daily by patients and every practicing oncologist,
that can significantly affect a patient’s quality of life Funding
Unfortunately, little high-quality data exist in many areas of
symptom management, probably due to difficulties in conduct- None declared.
ing research in this field, including the lack of well-defined end-
points, of patient-reported symptoms and side effects, and of
optimal tools to evaluate impact on quality of life for advanced Disclosure
cancer patients. New classes of drugs introduced into breast can- Detailed CoI for all panel members are described in online
cer management have brought into the clinical practice new tox- supplement.
icities, poorly understood in the beginning and unfamiliar to
most oncologists. Undoubtedly this is an area of unmet need,
which should be a research priority. References
The ABC3 guidelines provide guidance on the management of 1. Cardoso F, Costa A, Norton L et al. ESO-ESMO 2nd International
drug-induced pneumonitis, mucositis [58, 59], endocrine and Consensus Guidelines for Advanced Breast Cancer (ABC2).
metabolic disorders and CDK4/6 inhibitor-related neutropenia. Simultaneous publication in The Breast 2014, 23: 489–502; http://dx.doi.
For nausea and vomiting ABC fully endorses the guidelines de- org/10.1016/j.breast.2014.08.009) and Annals of Oncology (Ann Oncol
2014; 25: 1871–1888; doi:10.1093/annonc/mdu385).
veloped by ESMO/MASCC [60].
2. Global Status of Advanced/Metastatic Breast Cancer 2005–2015 Decade
The ABC panel continues to discuss and provide guidance on Report. www.breastcancervision.com and www.abc-lisbon.org (27
the management of frequent and difficult to manage cancer- October 2016, date last accessed).
associated symptoms. In this edition, dyspnea and fatigue were 3. Howlader N, Noone AM, Krapcho M et al. (eds). SEER Cancer Statistics
discussed. Cancer related fatigue is frequently experienced by Review, 1975–2013. Bethesda, MD: National Cancer Institute. http://
advanced cancer patients, exerts a deleterious impact on their seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data
submission, posted to the SEER web site, April 2016 (updated September
quality of life and limits physical, functional, psychological and
12 2016, 27 October 2016, date last accessed).
social well-being. Its etiology is complex and therefore effective 4. Sundquist M, Eriksson Z, Tejler G, Brudin L. Trends in survival in meta-
management needs to be multidimensional [61–63]. It is import- static breast. Cancer Eur J Cancer 2010; 8(3): 191. Abstract 453.
ant to assess cancer related fatigue using appropriate patient- 5. Kobayashi K, Ito Y, Matsuura M et al. Impact of immunohistological
reported outcome measures before implementing various subtypes on the long-term prognosis of patients with metastatic breast
pharmacological and non-pharmacological interventions. cancer. Surg Today 2016; 46: 821–826.
Randomized studies have suggested improvement of fatigue by 6. Chia SK, Speers CH, D’yachkova Y et al. The impact of new chemothera-
peutic and hormone agents on survival in a population-based cohort of
various types of exercise quite convincingly [64], and meditation
women with metastatic breast cancer. Cancer 2007; 110: 973–979.
and some pharmacologic interventions are under evaluation. The 7. Guyatt G, Gutterman D, Baumann MH et al. Grading strength of recom-
use of good evidence-based algorithms for management of cancer mendations and quality of evidence in clinical guidelines: report from an
related fatigue can also be helpful [65]. american college of chest physicians task force. Chest 2006; 129:
174–181.
8. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated ap-
Conclusions proach to stratify the magnitude of clinical benefit that can be anticipated
from anti-cancer therapies: the European Society for Medical Oncology
Since the ABC3 Conference two important initiatives have al- Magnitude of Clinical Benefit Scale (ESMO-MCBS). Annals of Oncology
ready been initiated. 2015; 26: 1547–1573.
The ESMO Magnitude of Clinical Benefit Scale (MCBS) [8] 9. Schnipper LE, Davidson NE, Wollins DS et al. American Society of
Clinical Oncology Statement: a conceptual framework to assess the value
has been published and is being applied to all new anticancer
of cancer treatment options. J Clin Oncol 2015; 33: 2563–2577.
treatments approved by EMA. The latest drug for which EMA 10. Cardoso F, Costa A, Norton L et al. 1st International consensus guide-
started the approval process was Palbociclib in September 2016 lines for advanced breast cancer (ABC1). The Breast 2012; 21: 242–252.
and its MCBS evaluation is included in the present article. Should 11. Key components of Patient Centered Care, adapted from Levit L et al.
another agent be approved before the next ABC Consensus Delivering high-quality cancer care: charting a new course for a system in

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 31


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Special article Annals of Oncology
crisis. National Academy of Science: Institute of Medicine, The National 30. Rayson D, Lutes S, Walsh G et al. Trastuzumab beyond progression for
Academies, 2013; 20,1. 3 p.3.4–3.7. HER2 positive metastatic breast cancer: progression-free survival on first-
12. Cardoso F, Harbeck N, Mertz S, Fenech D. Evolving psychosocial, emo- line therapy predicts overall survival impact. Breast J 2014; 20: 408–413.
tional, functional, and support needs of women with advanced breast 31. Tripathy D, Rugo HS, Kaufman PA et al. The SystHERs registry: an observa-
cancer: results from the count us, know us, join us and here & now sur- tional cohort study of treatment patterns and outcomes in patients with
veys. The Breast 2016; 28: 5–12. human epidermal growth factor receptor 2-positive metastatic breast cancer.
13. Karlsson E, Appelgren J, Solterbeck A et al. Breast cancer during follow- BMC Cancer 2014; 14: 307.
up and progression – a population based cohort on new cancers and 32. Andersson M, Lidbrink E, Bjerre K et al. Phase III randomized study
changed biology. Eur J Cancer 2014; 50: 2916–2924. comparing docetaxel plus trastuzumab with vinorelbine plus trastuzu-
14. Thompson AM, Jordan LB, Quinlan P et al. Prospective comparison of mab as first-line therapy of metastatic or locally advanced human epider-
switches in biomarker status between primary and recurrent breast can- mal growth factor receptor 2-positive breast cancer: the HERNATA
cer: the Breast Recurrence In Tissues Study (BRITS). Breast Cancer Res study. J Clin Oncol 2011; 29: 264–271.
2010; 12: R92. 33. Burstein HJ, Keshaviah A, Baron AD et al. Trastuzumab plus vinorelbine
15. Amir E, Miller N, Geddie W et al. Prospective study evaluating the im- or taxane chemotherapy for HER2-overexpressing metastatic breast can-
pact of tissue confirmation of metastatic disease in patients with breast cer: the trastuzumab and vinorelbine or taxane study. Cancer 2007; 110:
cancer. J Clin Oncol 2012; 30: 587–592. 965–972.
16. Penault-Llorca F, Coudry RA, Hanna WM et al. Recommendations for 34. Smyth LM, Iyengar NM, Chen MF et al. Weekly paclitaxel with trastuzu-
retesting breast cancer metastases for HER2 and hormone receptor sta- mab and pertuzumab in patients with HER2-overexpressing metastatic
tus. Breast 2013; 22: 200–202. breast cancer: overall survival and updated progression-free survival re-
17. Schrijver WA, van der Groep P, Hoefnagel LD et al. Influence of decalci- sults from a phase II study. Breast Cancer Res Treat 2016; 158: 91–97.
fication procedures on immunohistochemistry and molecular pathology 35. Andersson M, L opez-Vega JM, Petit T et al. The co-administration of per-
in breast cancer. Mod Pathol 2016; doi:10.1038/modpathol.2016.116.
tuzumab (P) and trastuzumab (T) as a single infusion, followed by vinorel-
18. André F, Bachelot T, Commo F et al. Comparative genomic hybridisa-
bine (V), in first-line (1L) treatment of HER2-positive locally advanced or
tion array and DNA sequencing to direct treatment of metastatic breast
metastatic breast cancer (MBC) patients (pts): VELVET study interim ana-
cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet
lysis. J Clin Oncol 2015; 33(15_suppl): 586.
Oncol 2014; 15: 267–274.
36. Untch M, Jackisch C, Schneeweiss A et al. Nab-paclitaxel versus solvent-
19. Badwe R, Hawaldar R, Nair N et al. Locoregional treatment versus no
based paclitaxel in neoadjuvant chemotherapy for early breast cancer
treatment of the primary tumour in metastatic breast cancer: an open-
(GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 2016;
label randomised controlled trial. Lancet Oncol 2015; 16: 1380–1388.
20. Soran A, Ozmen V, Ozbas S et al. A randomized controlled trial evaluat- 17: 345–356.
ing resection of the primary breast tumor in women presenting with de 37. Lobbezoo DJ, van Kampen RJ, Voogd AC et al. In real life, one-quarter
novo stage IV breast cancer: Turkish Study (Protocol MF07-01). J Clin of patients with hormone receptor-positive metastatic breast cancer re-
Oncol 2016; 34(suppl): abstr 1005. ceive chemotherapy as initial palliative therapy: a study of the Southeast
21. Thomas A, Khan SA, Chrischilles EA, Schroeder MC. Initial surgery and Netherlands Breast Cancer Consortium. Ann Oncol 2016; 27: 256–262.
survival in stage IV breast cancer in the United States, 1988-2011. JAMA 38. Finn RS, Martin M, Rugo HS et al. PALOMA-2: primary results from a
Surg 2016; 151: 424–431. phase III trial of palbociclib (P) with letrozole (L) compared with letro-
zole alone in postmenopausal women with ERþ/HER2– advanced breast
22. Greenberg PA, Hortobagyi GN, Smith TL et al. Long-term follow-up of
cancer (ABC). J Clin Oncol 2016; 34 (suppl): abstr 507.
patients with complete remission following combination chemotherapy
39. Weigel RJ, deConinck EC. Transcriptional control of estrogen receptor
for metastatic breast cancer. J Clin Oncol 1996; 14: 2197–2205.
in estrogen receptor-negative breast carcinoma. Cancer Res 1993; 53:
23. Swain SM, Kim SB, Cortés J et al. Pertuzumab, trastuzumab, and doce-
3472–3474.
taxel for HER2-positive metastatic breast cancer (CLEOPATRA study):
40. Fribbens C, O’Leary B, Kilburn L et al. Plasma ESR1 mutations and the
overall survival results from a randomised, double-blind, placebo-con-
treatment of estrogen receptor-positive advanced breast cancer. J Clin
trolled, phase 3 study. Lancet Oncol 2013; 14: 461–471.
Oncol 2016; 34: 2961–2968.
24. Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-
41. Finn RS, Crown JP, Lang I et al. The cyclin-dependent kinase 4/6 inhibi-
positive advanced breast cancer. N Engl J Med 2012; 367: 1783–1791.
tor palbociclib in combination with letrozole versus letrozole alone as
25. Krop IE, Kim SB, Gonzalez-Martın A et al. Trastuzumab emtansine versus first-line treatment of estrogen receptor-positive, HER2-negative,
treatment of physician’s choice for pretreated HER2-positive advanced advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2
breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet study. Lancet Oncol 2015; 16: 25–35.
Oncol 2014; 1: 689–699. 42. Turner NC, Ro J, André F et al. Palbociclib in hormone-receptor-
26. Ellis P, Barrios C, Eiermann W et al. Phase III, randomized study of tras- positive advanced breast cancer. N Engl J Med 2015; 373: 209–219.
tuzumab emtansine (T-DM1) 6 pertuzumab (P) vs trastuzumab þ tax- 43. Harbeck N, Iyer S, Turner N et al. Quality of life with palbociclib plus
ane (HT) for first-line treatment of HER2-positive MBC: primary results fulvestrant in previously treated hormone receptor-positive, HER2-nega-
from the MARIANNE study. J Clin Oncol 2015; 33(suppl): abstr 507. tive metastatic breast cancer: patient-reported outcomes from the
27. Urruticoechea A, Rizwanullah M, Im SA et al. PHEREXA: a phase III PALOMA-3 trial. Ann Oncol 2016; 27: 1047–1054.
study of trastuzumab (H) þ capecitabine (X) 6 pertuzumab (P) for pa- 44. Piccart M, Hortobagyi GN, Campone M et al. Everolimus plus exemes-
tients (pts) who progressed during/after one line of H-based therapy in tane for hormone-receptor-positive, human epidermal growth factor
the HER2-positive metastatic breast cancer (MBC) setting. J Clin Oncol receptor-2-negative advanced breast cancer: overall survival results from
2016; 34(15_suppl): abstr. 504. BOLERO-2. Ann Oncol 2014; 25: 2357–2362.
28. Kaufman B, Mackey JR, Clemens MR et al. Trastuzumab plus anastrozole 45. Bachelot T, Bourgier C, Cropet C et al. Randomized phase II trial of
versus anastrozole alone for the treatment of postmenopausal women with everolimus in combination with tamoxifen in patients with hormone
human epidermal growth factor receptor 2-positive, hormone receptor- receptor-positive, human epidermal growth factor receptor 2-negative
positive metastatic breast cancer: results from the randomized phase III metastatic breast cancer with prior exposure to aromatase inhibitors: a
TAnDEM study. J Clin Oncol 2009; 27: 5529–5537. GINECO study. J Clin Oncol 2012; 30: 2718–2724.
29. von Minckwitz G, du Bois A, Schmidt M et al. Trastuzumab beyond pro- 46. Pritchard KI, Burris HA III, Ito Y et al. Safety and efficacy of everolimus
gression in human epidermal growth factor receptor 2-positive advanced with exemestane vs. exemestane alone in elderly patients with HER2-
breast cancer: a German Breast Group 26/breast international group 03- negative, hormone receptor-positive breast cancer in BOLERO-2. Clin
05 study. J Clin Oncol 2009; 27: 1999–2006. Breast Cancer 2013; 13: 421–432.

32 | Cardoso et al. Volume 28 | Issue 1 | 2017


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018
Annals of Oncology Special article
47. Mehta RS, Barlow WE, Albain KS et al. Combination anastrozole and bone metastases from breast cancer: results of the OPTIMIZE-2 trial. J
fulvestrant in metastatic breast cancer. N Engl J Med 2012; 367: 435–444. Clin Oncol 2014; 32: 5s (suppl): abstr LBA9500̂.
48. Tutt A, Ellis P, Kilbum L et al. TNT: a randomized phase III trial of car- 57. Himelstein AL, Qin R, Novotny PJ et al. CALGB 70604 (Alliance): a
boplatin compared to docetaxel for patients with metastatic or recurrent randomized phase III study of standard dosing vs. longer interval dosing
locally advanced triple-negative or BRCA1/2 breast cancer. Cancer Res of zoledronic acid in metastatic cancer. J Clin Oncol 2015; 33: (suppl):
2015; 75 (9 Suppl): S3–01. abstr 9501.
49. Cortes J, Crown J, Awada A et al. Overall survival (OS) from the phase 2 58. Jones VE, Jensen LL, McIntyre KJ et al. Evaluation of miracle mouthwash
study of enzalutamide, an androgen receptor (AR) signaling inhibitor, in (MMW) plus hydrocortisone versus prednisolone mouth rinses as
arþ advanced triple-negative breast cancer (aTNBC). Eur J Cancer 2015; prophylaxis for everolimus-associated stomatitis: preliminary results of a
51(Suppl. S3): S265. abstr. 1802. randomized phase II study. 2015 San Antonio Breast Cancer
50. Bonnefoi H, Grellety T, Tredan O et al. A phase II trial of abiraterone Symposium; December 5–8, 2015; San Antonio, TX. Abstract P1-15-06.
acetate plus prednisone in patients with triple-negative androgen recep- 59. Rugo HS, Seneviratne L, Beck JT et al. Prevention of everolimus/exemes-
tor positive locally advanced or metastatic breast cancer (UCBG 12-1). tane (EVE/EXE) stomatitis in postmenopausal (PM) women with hor-
Ann Oncol 2016; 27: 812–818. mone receptor-positive (HRþ) metastatic breast cancer (MBC) using a
51. Cortes J, O’Shaughnessy J, Loesch D et al. Eribulin monotherapy versus dexamethasone-based mouthwash (MW): results of the SWISH trial. J
treatment of physician’s choice in patients with metastatic breast cancer Clin Oncol 2016; 34 (suppl); abstr 525.
(EMBRACE): a phase 3 open-label randomized study. Lancet 2011; 377: 60. Roila F, Molassiotis A, Herrstedt J et al. MASCC and ESMO Consensus
914–923. Guidelines for the prevention of chemotherapy and radiotherapy-
52. Kaufman PA, Awada A, Twelves C et al. Phase III open-label randomized induced nausea and vomiting: ESMO clinical practice guidelines. Ann
study of eribulin mesylate versus capecitabine in patients with locally Oncol 2016; 27(suppl 5): v119–v133.
advanced or metastatic breast cancer previously treated with an anthra- 61. Payne C, Wiffen PJ, Martin S. Interventions for fatigue and weight loss in
cycline and a taxane. J Clin Oncol 2015; 33: 594–601. adults with advanced progressive illness. Cochrane Database Syst Rev
53. Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy 2012; 1: CD008427.
in breast cancer. Nat Rev Clin Oncol 2015; 12: 631–644. 62. Berger A, Mitchell SA, Jacobsen PB, Pirl WF. Screening, evaluation and
54. Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zole- management of cancer-related fatigue: ready for implementation to prac-
dronic acid for the treatment of bone metastases in patients with tice. CA Cancer J Clin 2015; 65: 190–211.
advanced breast cancer: a randomized, double-blind study. J Clin Oncol 63. Aapro M, Scotte F, Bouillet T et al. A practical approach to fatigue man-
2010; 28: 5132–5139. agement in colorectal cancer. Clin Colorectal Cancer 2016; doi: 10.1016/
55. Amadori D, Aglietta M, Alessi B et al. Efficacy and safety of 12-weekly j.clcc.2016.04.010.
versus 4-weekly zoledronic acid for prolonged treatment of patients with 64. Travier N, Velthuis MJ, Steins Bisschop CN et al. Effects of an 18-week
bone metastases from breast cancer (ZOOM): a phase 3, open-label, exercise programme started early during breast cancer treatment: a
randomised, non-inferiority trial. Lancet Oncol 2013; 14: 663–670. randomized controlled trial. BMC Med 2015, 8: 121.
56. Hortobagyi GH, Lipton A, Chew HK et al. Efficacy and safety of contin- 65. Koornstra RH, Peters M, Donofrio S et al. Management of fatigue in patients
ued zoledronic acid every 4 weeks versus every 12 weeks in women with with cancer – a practical overview. Cancer Treat Rev 2014; 40: 791–799.

Volume 28 | Issue 1 | 2017 doi:10.1093/annonc/mdw544 | 33


Downloaded from https://academic.oup.com/annonc/article-abstract/28/1/16/2660178
by guest
on 18 May 2018

You might also like