Abc3 Esmo
Abc3 Esmo
Abc3 Esmo
doi:10.1093/annonc/mdw544
Published online 5 December 2016
SPECIAL ARTICLE
*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.
C The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
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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
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
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
Continued
Continued
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
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.
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
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
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
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.
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
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
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.