Introduction
Advanced Breast Cancer (ABC) comprises both locally advanced (LABC) and metastatic
breast cancer (MBC) [1]. Although treatable, MBC remains an incurable disease with
a median overall survival of ∼2–3 years and a 5-year survival of only ∼25% [2–4].
Some more recent series seem to indicate an improvement in median overall survival
[5, 6].
A recent comprehensive report [2] of the advances in this field in the last decade
shows that progress has been slow in terms of improved outcomes, quality of life,
awareness and information regarding ABC.
The level of evidence used to base many recommendations remains low, and more and
better designed trials are needed to address clinically important questions. An improved
understanding of the biology of ABC, its heterogeneity, and of the mechanisms of resistance
to the different types of therapies is being acquired and it is anticipated that the
application of new technologies, such as next generation sequencing, patient xenographs,
systems biology, and computer modelling, among others, will accelerate advances.
Aiming at providing clinically oriented guidelines on how to best manage ABC, the
3rd International Consensus Conference for Advanced Breast Cancer (ABC 3) took place
in Lisbon, Portugal on November 5th–7th, 2015, bringing together over 1100 participants
from 84 countries, including health professionals, patient advocates and journalists.
The ABC guidelines are developed as a joint effort from ESO (European School of Oncology)
and ESMO (European Society of Medical Oncology), and are endorsed by EUSOMA (European
Society of Breast Cancer Specialists), ESTRO (European Society of Radiation Oncology),
UICC (Union for International Cancer Control), SIS (Senologic International Society)
and FLAM (Federatión LatinoAmericana de Mastologia). There was also official representation
of ASCO (American Society of Clinical Oncology) in the consensus panel. The ABC Conference
was also organized under the auspices of OECI (Organization of European Cancer Institutes),
and with the support of the BCRF (Breast Cancer Research Foundation) and the Susan
G Komen for the Cure.
The present article summarizes the guidelines developed at ABC3 and is supported with
the level of evidence, the percentage of consensus reached at the Conference, and
supporting references.
Methodology
Prior to the ABC 3 Conference, a set of preliminary recommendation statements on the
management of ABC were prepared, based on available published data and following the
ESMO guidelines methodology. These recommendations were circulated to all 44 panel
members by email for comments and corrections on content and wording. A final set
of recommendations was presented, discussed and voted upon during the consensus session
of ABC 3. All panel members were instructed to vote on all questions, with members
with a potential conflict of interest or who did not feel comfortable answering the
question (e.g. due to lack of expertise in a particular field) instructed to vote
‘abstain’. Additional changes in the wording of statements were made during the session.
The statements related to management of side effects and difficult symptoms, included
under the Supportive and Palliative care section, were not voted on during the consensus
session, but discussed and unanimously agreed by email, and are considered to have
100% agreement.
Supplementary Table S1, available at Annals of Oncology online, lists all members
of the ABC 3 consensus panel and their disclosures of any relationships with the pharmaceutical
industry that could be perceived as a potential conflict of interest.
Table 1 describes the grading system used [7]. ABC1 [10] and ABC2 [1] statements with
only minor updates or with no updates are listed in Table 2.
Table 1
Grading system [7]
Grade of recommendation/description
Benefit versus risk and burdens
Methodological quality of supporting evidence
Implications
1A/Strong recommendation, high quality evidence
Benefits clearly outweigh risk and burdens, or vice versa
RCTs without important limitations or overwhelming evidence from observational studies
Strong recommendation, can apply to most patients in most circumstances without reservation
1B/Strong recommendation, moderate quality evidence
Benefits clearly outweigh risk and burdens, or vice versa
RCTs with important limitations (inconsistent results, methodological flaws, indirect,
or imprecise) or exceptionally strong evidence from observational studies
Strong recommendation, can apply to most patients in most circumstances without reservation
1C/Strong recommendation, low quality evidence
Benefits clearly outweigh risk and burdens, or vice versa
Observational studies or case series
Strong recommendation, but may change when higher quality evidence becomes available
2A/Weak recommendation, high quality evidence
Benefits closely balanced with risks and burden
RCTs without important limitations or overwhelming evidence from observational studies
Weak recommendation, best action may differ depending on circumstances or patients’
or societal values
2B/Weak recommendation, moderate quality evidence
Benefits closely balanced with risks and burden
RCTs with important limitations (inconsistent results, methodological flaws, indirect,
or imprecise) or exceptionally strong evidence from observational studies
Weak recommendation, best action may differ depending on circumstances or patients’
or societal values
2C/Weak recommendation, low quality evidence
Benefits closely balanced with risks and burden
Observational studies or case series
Very weak recommendation, other alternatives may be equally reasonable
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, and rapid progression of disease. Visceral crisis is not the mere
presence of visceral metastases but implies important visceral compromise leading
to a clinical indication for a more rapidly efficacious therapy, particularly since
another treatment option at progression will probably not be possible.
Expert opinion
95
PRIMARY ENDOCRINE RESISTANCE is defined as: Relapse while on the first 2 years of
adjuvant ET, or PD within 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
Expert opinion
67
GENERAL STATEMENTS
The management of ABC is complex and, therefore, involvement of all appropriate specialties
in a multidisciplinary team (including but not restricted to medical, radiation, surgical
oncologists, imaging experts, pathologists, gynecologists, psycho-oncologists, social
workers, nurses and palliative care specialists), is crucial.
Expert opinion
100
From the time of diagnosis of ABC, patients should be offered appropriate psychosocial
care, supportive care, and symptom-related interventions as a routine part of their
care. The approach must be personalized to meet the needs of the individual patient.
Expert opinion
100
Following a thorough assessment and confirmation of MBC, the potential treatment
goals of care should be discussed. Patients should be told that MBC is incurable but
treatable, and that some patients can live with MBC for extended periods of time (many
years in some circumstances).
This conversation should be conducted in accessible language, respecting patient
privacy and cultural differences, and whenever possible, written information should
be provided.
Expert opinion
97
Patients (and their families, caregivers or support network, if the patient agrees)
should be invited to participate in the decision-making process at all times. When
possible, patients should be encouraged to be accompanied by persons who can support
them and share treatment decisions (e.g. family members, caregivers, support network).
Expert opinion
100
There are few proven standards of care in ABC management. After appropriate informed
consent, inclusion of patients in well-designed, prospective, independent trials must
be a priority whenever such trials are available and the patient is willing to participate.
Expert opinion
100
The medical community is aware of the problems raised by the cost of ABC treatment.
Balanced decisions should be made in all instances; patients’ well-being, length of
life and preferences should always guide decisions.
Expert opinion
100
Specialized oncology nurses (if possible specialized breast nurses) should be part
of the multidisciplinary team managing ABC pts. In some countries this role may be
played by a physician assistant or another trained and specialized health care practitioner.
Expert opinion
92
All ABC patients should be offered comprehensive, culturally sensitive, up-to-date
and easy to understand information about their disease and its management.
1 B
97
The age of the patient should not be the sole reason to withhold effective therapy
(in elderly patients) nor to overtreat (in young patients). Age alone should not determine
the intensity of treatment.
1 B
100
ASSESSMENT GUIDELINES
Minimal staging workup for MBC includes a history and physical examination, hematology
and biochemistry tests, and imaging of chest, abdomen and bone.
2 C
67
Brain imaging should not be routinely performed in asymptomatic patients. This approach
is applicable to all patients with MBC including those patients with HER-2+ and/or
TNBC MBC.
Expert opinion
94
The clinical value of tumor markers is not well established for diagnosis or follow-up
after adjuvant therapy, but 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.
2 C
89
Evaluation of response to therapy should generally occur every 2–4 months for ET
or after two to four cycles for CT, 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.
Expert opinion
81
TREATMENT GENERAL GUIDELINES
Treatment choice should take into account at least these factors: HR and HER-2 status,
previous therapies and toxicities, disease-free interval, tumour burden (defined as
number and site of metastases), biological age, performance 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 patient preference.
Expert opinion
100
ER +/HER-2 NEGATIVE ABC
Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable
option, although this approach has not been assessed in randomized trials.
1 C
88
Concomitant CT+ET has not shown a survival benefit and should not be performed outside
of a clinical trial.
1 B
100
CHEMOTHERAPY AND BIOLOGICAL THERAPY
Both combination and sequential single agent CT are reasonable options. Based on
the available data, we recommend 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
1 B
96
In the absence of medical contraindications or patient concerns, anthracycline or
taxane based regimens, preferably as single agents, would usually be considered as
first line CT for HER-2 negative MBC, in those patients who have not received these
regimens 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.
1 A
71
In patients with taxane-naive and anthracycline-resistant MBC or with anthracycline
maximum cumulative dose or 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.
1 A
59
In patients pre-treated (in the adjuvant and/or metastatic setting) with an anthracycline
and a taxane, and who do 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 individualized
and take into account different toxicity profiles, previous exposure, patient preferences,
and country availability.
1 B
77
If given in the adjuvant setting, a taxane can be re-used as 1st line therapy, particularly
if there has been at least 1 year of disease-free survival.
1 A
92
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.
What is considered unacceptable should be defined together with the patient.
1 B
72
OTHER AGENTS
Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides
only a moderate benefit in PFS and no benefit in OS. The absence of known predictive
factors for bevacizumab efficacy renders recommendations on its use difficult. Bevacizumab
can only therefore be considered as an option in selected cases in these settings
and is not recommended after 1st/2nd line.
1 A
74
SPECIFIC POPULATIONS: TREATMENT OF METASTATIC MALE MBC
For ER+ Male MBC, which represents the majority of the cases, ET is the preferred
option, unless there is concern or proof of endocrine resistance or rapidly progressive
disease needing a fast response.
Expert opinion
100
For ER+ 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 preferred option. AI monotherapy may also be considered, with
close monitoring of response.
Clinical trials are needed in this patient population.
Expert opinion
86
SPECIFIC SITES OF METASTASES
BONE METASTASES
Radiological assessments are required in patients with persistent and localized pain
due to bone metastases to determine 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.
1 A
96
Neurological symptoms and signs which suggest the possibility of spinal cord compression
must be investigated 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.
1 B
100
BRAIN METASTASES
Patients with a single or small number of potentially resectable brain metastases
should be treated with surgery or radiosurgery. Radiosurgery is also an option for
some unresectable brain metastases.
1 B
92
If surgery/radiosurgery is performed it may be followed by whole brain radiotherapy
but this should be discussed in detail with the patient, balancing the longer duration
of intracranial disease control and the risk of neurocognitive effects.
1 B
72
Because patients with HER2+ve MBC and brain metastases can live for several years,
consideration of long-term 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).
1C
89
LIVER METASTASES
Prospective randomized clinical trials of local therapy for BC liver metastases are
urgently needed, since available evidence comes only from series in highly selected
patients. Since there are no randomized data supporting the effect 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 disease. Currently,
there are no data to select the best technique for the individual patient (surgery,
stereotactic RT, intra-hepatic CT…).
Expert opinion
83
MALIGNANT PLEURAL EFFUSIONS
Malignant pleural effusions require systemic treatment with/without local management.
Thoracentesis for diagnosis 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 helpful. Clinical trials evaluating the best technique
are needed.
2B
86
CHEST WALL AND REGIONAL (NODAL) RECURRENCES
Due to the high risk of concomitant distant metastases, patients with chest wall
or regional (nodal) recurrence should undergo full restaging, including assessment
of chest, abdomen and bone.
Expert opinion
100
Chest wall and regional recurrences should be treated with surgical excision when
feasible with limited risk of morbidity.
1 B
97
Locoregional radiotherapy is indicated for patients not previously irradiated.
1 B
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 (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).
1 B
95
In patients with disease not amenable to radical local treatment, the choice of palliative
systemic therapy should be made according to principles previously defined for metastatic
BC.
These patients may still be considered for palliative local therapy.
Expert opinion
97
SUPPORTIVE AND PALLIATIVE CARE
Supportive care allowing safer and more tolerable delivery of appropriate treatments
should always be part of the treatment plan.
1 A
100
Early introduction of expert palliative care, including effective control of pain
and other symptoms, should be a priority.
1 A
100
Access to effective pain treatment (including morphine, which is inexpensive) is
necessary for all patients in need of pain relief.
1 A
100
Optimally, discussions about patient preferences at the end of life should begin
early in the course of metastatic disease. However, when active treatment no longer
is able to control widespread and life-threatening disease, and the toxicities of
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.
Expert Opinion
96
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) expression is indispensable to guide treatment decisions.
1 B
97
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.
1 B
100
PET-CT, if available, may be used (instead of and not on top of CTs and bone scan).
2 B
100
Systemic therapy (not surgery or RT) should be the initial treatment.
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.
Expert opinion
100
A combined treatment modality based on a multidisciplinary approach (systemic therapy,
surgery and radiotherapy) is strongly indicated in the vast majority of cases.
1 A
100
For Triple Negative LABC, Anthracycline- and-taxane-based chemotherapy is recommended
as initial treatment.
1 A
85
For HER-2+ LABC, concurrent taxane and anti-HER-2 therapy is recommended since it
increases the rate of pCR.
1 A
92
For HER-2+ LABC, anthracycline-based chemotherapy should be incorporated in the treatment
regimen.
1 A
72
When an anthracycline is given, it should be administered sequentially with the anti-HER-2
therapy.
1 A
87
Options for HR+ LABC include an anthracycline- and taxane-based chemotherapy regimen,
or endocrine therapy.
1 A
85
The choice of CT versus ET, as initial treatment, will depend on tumor (grade, biomarker
expression) and patient (menopausal status, performance status, comorbidities, preference)
considerations.
Expert Opinion
85
Following effective neoadjuvant systemic therapy with or without radiotherapy, surgery
will be possible in many patients. This will consist of mastectomy with axillary dissection
in the vast majority of cases, but in selected patients with a good response, breast
conserving surgery may be possible.
2 B
98
INFLAMMATORY LABC
For inflammatory LABC, overall treatment recommendations are similar to those for
non-inflammatory LABC, with systemic therapy as first treatment.
1 B
93
Mastectomy with axillary dissection is recommended in almost all cases, even when
there is good response to primary systemic therapy.
I B
95
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 therapy.
1 B
98
SECTION I
GENERAL RECOMMENDATIONS
GUIDELINE STATEMENT
LoE
Consensus
The ABC community strongly calls for clinical trials addressing important unanswered
clinical questions in this setting, and not just for regulatory purposes. Clinical
trials should continue to be performed, even after approval of a new treatment, providing
real world performance of the therapy.
Expert opinion
Voters: 43
Yes: 100%
Every advanced breast cancer patient must have access to optimal cancer treatment
and supportive care according to the highest standards of patient centered care, as
defined by:
• 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.
Expert opinion
Voters: 44
Yes: 100%
We strongly recommend the use of objective scales, such as the ESMO Magnitude of Clinical
Benefit Scale or the ASCO Value Framework, to evaluate the real magnitude of benefit
provided by a new treatment and help prioritize funding, particularly in countries
with limited resources.
Expert opinion
Voters: 40
Yes: 87.5% (35)
Abstain: 5% (2)
The use of telemedicine oncology to help management of patients with ABC living in
remote places, is an important option to consider when geographic distances are a
problem and provided that issues of connectivity are solved.
Expert opinion
Voters: 42
Yes: 92.8% (39)
Abstain: 4.7% (2)
Strong consideration should be given to the use of validated PROMs (patient-reported
outcome measures) for patients to record the symptoms of disease and side effects
of treatment experienced as a regular part of clinical care. These PROMs should be
simple, and user-friendly to facilitate their use in clinical practice, and thought
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
1 C
Voters: 39
Yes: 87.1% (34)
Abstain: 5.1% (2)
As survival is improving in many patients with ABC, consideration of survivorship
issues should be part of the routine care of these patients. Health professionals
should therefore be ready to change and adapt treatment strategies to disease status,
treatment adverse effects and quality of life, patients’ priorities and life plans.
Attention to chronic needs for home and family care, job and social requirements,
should be incorporated in the treatment planning and periodically updated.
Expert opinion
Voters: 40
Yes: 95% (38)
Abstain: 5% (2)
ABC patients who desire to work or need to work for financial reasons should have
the opportunity to do so, with needed and reasonable flexibility in their working
schedules to accommodate continuous treatment and hospital visits.
Expert opinion
Voters: 42
Yes: 100%
ABC patients with stable disease, being treated as a ‘chronic condition’, should have
the option to undergo breast reconstruction.
Expert opinion
Voters: 39
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 confirm diagnosis particularly when metastasis is diagnosed
for the first time.
1 B
Voters: 43
Yes: 98% (42)
Biological markers (especially HR and HER-2) should be reassessed at least once in
the metastatic setting, if clinically feasible. Depending on the metastatic site (e.g.
bone tissue), technical considerations need to be discussed with the pathologist.
1 B
Voters: 44
Yes: 98% (43)
If the results of tumour biology in the metastatic lesion differ from the primary
tumor, it is currently unknown 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
receptors are positive in at least one biopsy, regardless of timing.
Expert Opinion
87%
To date, the removal of the primary tumor in patients with de novo stage IV breast
cancer has not been associated with prolongation of survival, with the possible exception
of the subset of patients with bone only disease. However, it can be considered in
selected patients, particularly to improve quality of life, always taking into account
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
2 B
Voters: 44
Yes: 70.4% (31)
A small but very important subset of patients with ABC, for example those with oligo-metastatic
disease or low volume metastatic disease that is highly sensitive to systemic therapy,
can achieve complete remission and a long survival.
A multimodal approach, including local-regional treatments with curative intent,
should be considered for these selected patients.
Expert opinion
Voters: 43
Yes: 91% (39)
LoE, available level of evidence; consensus, percentage of panel members in agreement
with the statement.
General recommendations
The continuous increase in cancer care costs has inevitably led to inequalities in
access both between countries and within each country. Cost, value and access are
now central discussion points and important factors in treatment-decision making.
Both ESMO and ASCO have put considerable effort into the development of validated
objective scales aiming at evaluating the real magnitude of benefit provided by each
new treatment, including efficacy measures (e.g. impact on DFS, OS or PFS) and toxicity/quality
of life measures. The ESMO Magnitude of Clinical Benefit Scale [8] and the ASCO Value
Framework [9] are user-friendly tools that can greatly assist decision-makers at the
country and/or hospital level in the difficult decisions regarding approval and reimbursement.
The ABC3 experts also emphasize the responsibility of the academic and medical communities
to advance the knowledge on breast cancer and other relevant unanswered issues, by
involvement in clinical research aimed at addressing important clinical questions,
and not only in studies conducted for regulatory purposes.
The importance of providing patients with full information in appropriate, understandable
and culturally sensitive way, as well as involving them in sharing the decision-making
regarding all aspects of their management has been repeatedly stressed in all ABC
guidelines [1, 10]. A high standard of patient centred care includes the following
elements: appropriate information, good communication with health professionals, patient
education, proactive advocacy, sensitivity to the patient’s preferences, values and
needs, and providing patients with the capabilities to improve their own quality of
life [11].
Although the overall survival of ABC has remained stable, for some subtypes, and in
particular HER-2-positive metastatic breast cancer, prolonged survival, well beyond
the median 2–3 years, has become a frequent reality. For these long-term survivors,
survivorship issues which are specific for advanced cancer patients, have emerged
and need appropriate attention, research and management. Work-related issues are central
and solutions not easy to implement. A recently published survey [12], found that
approximately half of the women in employment had to change their work situation due
to ABC and that 37% of them had to give up work temporarily or permanently. Due to
these income problems and those related to the cost of care, the same survey found
that 56% of ABC patients experienced a decline in household income as a result of
their disease. The ABC community strongly advocates for the right of ABC patients
to return or maintain their work, since a substantial proportion of these patients
are in their most productive years. Furthermore, in some countries, health coverage
is dependent on being employed. For that to occur, we need flexibility of working
schedules, new communication technologies and home-based work which the ABC community
supports. In many countries this may imply a change in the current labour-related
laws.
Survivorship issues also include the potential discussion of breast reconstruction,
in those cases where the metastatic disease is either in complete remission or in
a durable stable situation. No consensus could be reached regarding the use of breast
imaging to follow-up the unaffected breast, but the experts agreed that imaging should
be performed in case of suspicion of disease progression in the breast.
Regarding the need to biopsy metastatic disease and re-evaluate the common biomarkers,
the ABC recommendations had only minor changes. There are situations where the need
for a biopsy in the metastatic setting is very clear, such as single lesions, history
of two or more malignancies, suspicion of benign histology or doubt between progression
or post-treatment necrosis. There is also consensus regarding the importance of such
biopsy in situations where when a change in biomarkers would impact the treatment
choice, which would mainly occur when biomarkers were negative in the primary tumor.
There is some controversy about the benefits of a biopsy in situations where there
is no doubt about the nature of the lesion(s) and where all receptors were positive
in the primary tumor, since the clinical implementation of new technologies such as
next generation sequencing for management decision-making s not yet validated. However,
the exact nature of a lesion is hard to ascertain without the confirmation by a biopsy
as shown in some retrospective and prospective studies [13–15]. There is also an undisputable
importance of collection of material for research purposes, both ongoing and future.
Technical issues should be discussed with the breast pathologist, in particular in
case of bone biopsies with the inherent decalcification problems, which may interfere
with the biomarker analysis [16, 17], as experienced in Safir01/UNICANCER trial [18].
For that reason, decalcification using EDTA is recommended for bone biopsies, when
it is the only metastatic site [17]. Adding to the complexity of this issue is the
fact that negative biomarker results may limit the eligibility for reimbursement of
therapies dedicated to specific subtypes, in some countries.
A number of prospective randomized trials have assessed or are assessing the role
of removing the primary tumor in patients with de novo metastatic disease. So far
only two small studies have been published/presented [19, 20]. A subgroup analysis
of the Turkish study suggested a potential benefit in patients with ER/PgR+, HER-2
negative, solitary bone metastasis, who are younger than 55 years of age, while patients
with multiple pulmonary and liver metastasis did worse with an overall 3-year survival
of 31% in the surgery group versus 67% for the systemic therapy group [20]. In the
Indian trial, a decrease in distant progression-free survival was observed in patients
allocated to surgery. Results of larger, prospective studies are awaited. Until then,
the recommendation is to discuss surgery on a case-by-case basis and importantly,
only consider surgery if it can be performed with a high quality procedure [21].
The definition of oligometastatic disease (see next section) has been enlarged to
encompass low volume metastatic disease, i.e. limited number and size of metastatic
lesions (up to five and not necessarily in the same organ) and potentially amenable
for local treatment which is aimed at achieving a complete remission. The development
of minimally invasive surgical techniques and highly conformal ablative radiotherapy
allow for safe and effective ablation of metastatic lesions in most locations. Although
some retrospective studies have suggested that achieving a sustained complete remission
seems to be associated with a longer survival [22], the true impact of these local-regional
therapies on long-term outcome remains unknown, and prospective and if possible randomized
trials are needed.
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 metastatic lesions (up to five and not necessarily in the same
organ), potentially amenable for local treatment, aimed at achieving a complete remission
status.
Expert opinion
Voters: 36
Yes: 78% (28)
Abstain: 6% (2)
PATIENTS WITH MULTIPLE CHRONIC CONDITIONS are defined as patients with additional
comorbidities (e.g. cardiovascular, impaired renal or liver function, autoimmune disease)
making it difficult to account for all of the possible extrapolations to develop specific
recommendations for care.
Expert opinion
Voters: 42
Yes:100%
LoE, available level of evidence; consensus, percentage of panel members in agreement
with the statement.
ABC important definitions
Most clinical situations occur as a continuum and dividing them into categories of
stage, grade, risk group, or other factors is always artificial and based on oversimplification
of thresholds. Such a categorization is, however, useful to guide treatment choices,
to help assure adherence to guidelines and recommendations, and to facilitate clinical
research. Following the effort of previous editions, ABC provides two additional definitions:
‘oligometastatic disease’ discussed above and the complex clinical situation of ‘multiple
chronic conditions’. The latter is becoming increasingly important and more frequent
in view of the aging of the population in general and of cancer patients in particular.
Managing advanced cancer, the consequences of the disease and of the rapidly increasing
number and type of pharmacologic and non-pharmacologic interventions in patients with
several coexisting conditions is a major challenge. Furthermore, these patients are
systematically excluded from clinical trials and hence available data, in particular
regarding the use of new agents in these situations, are scarce and eagerly needed.
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-2+
ABC, except in the presence of contra-indications to the use of such therapy
1 A
Voters: 43
Yes: 98% (42)
For highly selected patients* with ER+/HER-2+ MBC, for whom ET is chosen over CT,
ET should be given in combination with anti-HER-2 therapy (either trastuzumab or lapatinib)
since the combination provides PFS benefit (i.e. ‘time without CT’) compared to ET
alone. The addition of anti-HER-2 therapy to ET in the 1st line 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 CT+anti-HER2
therapy. (*see definition in text)
1 A
Voters: 43
Yes: 72% (31)
Abstain: 9% (4)
For patients with ER+/HER-2+ MBC, for whom CT+anti-HER2 therapy was chosen as 1st
line therapy and provided a benefit, it is reasonable to use ET+anti-HER2 therapy
as maintenance therapy, after stopping CT, although this strategy has not been studied
in randomized trials.
1 C
Voters: 39
Yes: 79% (31)
Abstain: 10% (4)
Patients progressing on an anti-HER-2 therapy combined with a cytotoxic or endocrine
agent should be offered additional anti-HER-2 therapy with subsequent treatment since
it is beneficial to continue suppression of the HER-2 pathway. The optimal duration
of anti-HER-2 therapy for MBC (i.e. when to stop these agents) is currently unknown.
1 B
Voters: 43
Yes: 91% (39)
Abstain: 7% (3)
In patients achieving a complete remission, the optimal duration of maintenance anti-HER2
therapy is unknown and needs to be balanced against treatment toxicity, logistical
burden and cost. Stopping anti-HER2 therapy after several years of sustained complete
remission may be considered in some patients, particularly if treatment re-challenge
is available in case of progression.
Expert Opinion
Voters: 42
Yes: 93% (39)
No: 7% (3)
Patients who have received any type of (neo)adjuvant anti-HER-2 therapy should not
be excluded from clinical trials for HER-2+ MBC. These patients remain candidates
for anti-HER-2 therapies.
1 B
Voters: 40
Yes: 100%
In the 1st line setting, for HER-2+ MBC previously treated (in the adjuvant setting
with DFI >12 months) or untreated with trastuzumab, combinations of CT+trastuzumab
are superior to combinations of CT+lapatinib in terms of PFS and OS.
1 A
Voters: 44
Yes: 95% (42)
Abstain: 5% (2)
The standard 1st line therapy for patients previously untreated with anti-HER-2 therapy
is the combination of CT+trastuzumab and pertuzumab, because it has proven to be superior
to CT+trastuzumab in terms of OS in this population.
1 A
Voters: 42
Yes: 86% (36)
Abstain: 12% (5)
For patients previously treated (in the (neo)adjuvant setting) with anti-HER-2 therapy,
the combination of CT+trastuzumab and pertuzumab is an important option for 1st line
therapy. Few (88) of these patients were treated in the Cleopatra trial and all with
trastuzumab-free interval >12 months.
1 A
Voters: 41
Yes: 76% (31)
Abstain: 22% (9)
There are currently no data supporting the use of dual blockade with trastuzumab+pertuzumab
and CT beyond progression (i.e. continuing dual blockade beyond progression) and therefore
this 3 drug regimen should not be given beyond progression outside clinical trials.
1 A (against its use)
Voters: 43
Yes: 86% (37)
Abstain: 9% (4)
In a HER-2+ MBC patient, previously untreated with the combination of CT+trastuzumab+pertuzumab,
it is acceptable to use this treatment after 1st line.
Expert Opinion
Voters: 37
Yes: 76% (28)
Abstain: 16% (6)
After 1st line trastuzumab-based therapy, T-DM1 provides superior efficacy relative
to other HER-2-based therapies in the 2nd line (versus lapatinib+capecitabine) and
beyond (versus treatment of physician’s choice).
T-DM1 should be preferred in patients who have progressed through at least 1 line
of trastuzumab-based therapy, because it provides an OS benefit.
However, there are no data on the use of T-DM1 after dual blockade with trastuzumab+pertuzumab.
1 A
Voters: 42
Yes: 88% (37)
Abstain: 129% (5)
In case of progression on trastuzumab-based therapy, the combination trastuzumab+lapatinib
is a reasonable treatment option for some patients. There are however, no data on
the use of this combination after progression on pertuzumab or T-DM1.
1 B
Voters: 43
Yes: 84% (36)
Abstain: 12% (5)
All patients with HER-2+ MBC who relapse after adjuvant or any line metastatic anti-HER-2
therapy should be considered for further anti-HER-2 therapy, except in the presence
of contraindications. The choice of the anti-HER-2 agent will depend on country-specific
availability, the specific anti-HER-2 therapy previously administered, and the relapse
free interval. The optimal sequence of all available anti-HER-2 therapies is currently
unknown.
1 B
Voters: 40
Yes: 86% (36)
Abstain: 12.5% (5)
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 vinorelbine or a taxane. Differences in toxicity between these regimens
should be considered and discussed with the patient in making a final decision.
Other CT agents can be administered with trastuzumab but are not as well studied
and are not preferred.
1 A
Voters: 41
Yes: 88% (36)
Abstain: 10% (4)
For later lines of therapy, trastuzumab can be administered with several CT agents,
including but not limited to, vinorelbine (if not given in 1st line), taxanes (if
not given in 1st line), capecitabine, eribulin, liposomal anthracyclines, platinum,
gemcitabine, or metronomic CM. The decision should be individualized and take into
account different toxicity profiles, previous exposure, patient preferences, and country
availability.
2 A
Voters: 43
Yes: 91% (39)
Abstain: 9% (4)
CT agents to combine with a dual blockade of trastuzumab+pertuzumab are docetaxel
(LoE: 1A) or paclitaxel (LoE: 1B). Also possible are vinorelbine (LoE: 2 A), nab-paclitaxel
(LoE: 2B) and capecitabine (LoE: 2A).
See in statement
Voters: 43
Yes: 86% (37)
Abstain: 11.6% (5)
HER-2+ ABC and BRAIN METASTASES
In patients with HER-2-positive ABC with brain metastases and stable extracranial
disease, systemic therapy should not be changed.
1 C
Voters: 42
Yes: 95% (40)
Abstain: 5% (2)
For patients with HER-2-positive cancers where brain metastases are the only site
of recurrence, the addition of CT to local therapy is not known to alter the course
of the disease. It is recommended to re-start the anti-HER-2 therapy (trastuzumab)
if this had been stopped.
1 C
Voters: 42
Y: 83% (35)
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 + methotrexate.
HER-2 positive ABC
Among all breast cancer subtypes, HER2-positive ABC has had the largest progress over
the last decade. The introduction of new anti-HER2 therapies, such as pertuzumab and
T-DM1 [23–27], was a significant step forward but also created a number of new uncertainties
related to optimal combination/sequence of all available treatments.
In view of the overall survival (OS) results obtained with most combinations of chemotherapy
plus anti-HER-2 agents, the role of endocrine therapy plus anti-HER-2 agents for the
subgroup of patients with ER+/HER-2+ disease has been questioned. Although published
studies have not demonstrated an OS benefit of this combination, long-term data were
not collected in these trials. Of note, the OS analysis of the TAnDEM trial, excluding
patients who crossed over to trastuzumab, demonstrated a borderline OS benefit for
the combination arm [28]. In the absence of valuable biomarkers, this approach should
be reserved for highly selected patients, including those with contraindications to
chemotherapy, patient’s with a strong preference against chemotherapy or those with
a long disease-free interval, minimal disease burden, in particular in terms of visceral
involvement, and/or strong ER/PgR expression. Trials directly comparing chemotherapy
plus anti-HER2 therapy versus endocrine therapy plus anti-HER2 therapy are currently
ongoing (Detect V/CHEVENDO (NCT02344472), SYSUCC-002 (NCT01950182) and PERNETTA trials)
and their results will allow for better recommendations. In addition, in several countries
anti-HER2 therapy, namely trastuzumab, can only be used once in the metastatic setting
since its use beyond progression is either not approved or not reimbursed; in those
cases, preference should be given to a combination of chemotherapy plus anti-HER-2
therapy.
The combination of endocrine therapy plus anti-HER2 therapy is particularly useful
as maintenance therapy for ER+/HER2+ ABC, after initial cycles of chemotherapy plus
anti-HER-2 therapy. Despite the absence of randomized trials, clinical experience
and low toxicity (in particular if trastuzumab is used), makes this a reasonable option,
most probably delaying disease progression and the consequent need for chemotherapy.
The issue of duration of anti-HER-2 therapy in the metastatic setting is of crucial
importance, in view of the potential benefits as well as the substantial costs associated
with these agents. There are sufficient data [29, 30] to recommend continuing trastuzumab
beyond progression, but the optimal duration of this treatment and how many lines
beyond progression should it be used is currently unknown. Data are very scarce related
to the use beyond progression of other anti-HER2 agents and no data exist supporting
the use of dual blockade beyond progression.
A particularly difficult situation, albeit also a fortunate one, relates to the optimal
duration of trastuzumab therapy in patients achieving long-term complete remission.
This needs to be balanced against toxicity, logistical burden and cost. Currently
no data exist to support therapeutic decisions in this setting, and the panel supported
a cautious statement approving consideration of stopping trastuzumab in these circumstances
in some patients, particularly if treatment re-challenge is available in case of progression,
which is not the case in all countries.
Dual blockade with trastuzumab and pertuzumab in combination with chemotherapy as
1st line therapy, provides substantial benefit in terms of OS and PFS [23]. It is
therefore considered by the panel as the standard of care for patients previously
untreated with trastuzumab, in the (neo)adjuvant setting, and an important treatment
option for patients previously treated with trastuzumab. The difference in the strength
of recommendation is due to the fact that very few patients (only 88) who were previously
treated with trastuzumab were enrolled in the Cleopatra trial. In addition, in the
Marianne trial [26] the dual blockade strategy did not prove to be superior to chemotherapy
and trastuzumab, albeit with a different combination of agents—T-DM1 and Pertuzumab.
The reasons for this lack of benefit are currently unknown and could be related to
the different patient populations enrolled in both trials (more (30%) patients in
Marianne had been previously treated with trastuzumab), the choice of agents with
the presence or absence of synergistic effects, the absence of standard chemotherapy
agents (DM1 being a cytotoxic agent not used as single agent) or other factors.
After the discussion and voting during ABC3, the Pherexa [27] study was presented,
evaluating the role of dual blockade with trastuzumab + pertuzumab + capecitabine
for patients previously treated with a taxane and trastuzumab in the metastatic setting.
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).
Many questions remain unanswered in the management of HER-2+ ABC. We have no data
on the role of dual blockade for patients relapsing during and within 12 months of
adjuvant trastuzumab, since these patients have been excluded from clinical trials.
This aggressive situation is a clear unmet need for which data must be generated.
Following the approval, both by FDA and EMA, of pertuzumab use in the neoadjuvant
setting, there is an urgent need to evaluate the best treatment options for the patients
who relapse after receiving chemotherapy + trastuzumab + pertuzumab in the early setting.
It is also currently unknown how trastuzumab + pertuzumab + chemotherapy compares
to T-DM1, as 1st or later lines of therapy. We also have no data on the best treatment
option after progression on dual blockade with pertuzumab + trastuzumab, namely how
T-DM1 performs in this setting.
While trastuzumab + lapatinib (without chemotherapy) is a valuable option for some
patients, after progression on chemotherapy + trastuzumab, there are no data on the
use of this combination after progression on pertuzumab or T-DM1.
All these unanswered questions and the definition of the best sequence of therapies
for the individual patient may prove difficult to evaluate in prospective, randomized
trials, with the absence of specific biomarkers. In this scenario, registry studies,
such as the SystHERs Registry Study [31] and registHER, as well as collection of treatment
and outcome data beyond progression in all HER-2-positive ABC clinical trials, are
of great importance.
In ABC3, the optimal chemotherapy component for the treatment of HER-2+ disease was
discussed. The panel has stressed the importance of treatment decisions that are based
not only on efficacy, but also on toxicity profile, and patients’ preferences.
For 1st line therapy, when trastuzumab is used as sole anti-Her2 agent, the preferred
agents are vinorelbine or a taxane. Importantly, single agent vinorelbine in association
with trastuzumab has shown superior or equal efficacy compared to either paclitaxel
or docetaxel, in the TRAVIOTA and HERNATA trials, and has a better tolerability [32,
33]. For later lines of therapy, trastuzumab can be administered with almost all chemotherapy
agents, including but not limited to, vinorelbine (if not given in 1st line), taxanes
(if not given in 1st line), capecitabine, eribulin, liposomal anthracyclines, platinum,
gemcitabine, or metronomic CM (low dose, oral, cyclophosphamide and methotrexate).
The decision should be individualized and take into account different toxicity profiles,
previous exposure, patient preferences, and country availability. Combinations of
other anti-HER2 agents, namely TKIs, with chemotherapy are more limited due to toxicity.
There are currently no data to decide on the best sequence for each individual patient.
When dual blockade with trastuzumab and pertuzumab is used, possible agents to combine
are docetaxel [23], weekly paclitaxel [34], vinorelbine [35] and nab-paclitaxel [36].
After the voting that took place in ABC3, the Pherexa trial [27], presented at ASCO
2016, provided some evidence regarding the combination of dual blockade with capecitabine.
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 visceral disease, unless there is visceral crisis or concern/proof
of endocrine resistance.
1 A
Voters: 41
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 time elapsed from the end of adjuvant ET; it can be an aromatase
inhibitor, tamoxifen or fulvestrant.
1 A
Voters: 44
Yes: 84% (37)
Abstain: 7% (3)
The combination of a nonsteroidal AI and fulvestrant as first-line therapy for post
menopausal patients resulted in significant improvement in both PFS and OS compared
to AI alone in one phase III trial and no benefit in a second trial with a similar
design. Subset analysis suggested that the benefit was limited to patients without
prior exposure to adjuvant ET (tamoxifen). Based on these data, combination ET may
be offered to some patients with MBC without prior exposure to adjuvant ET.
2 B
Voters: 43
Yes: 33% (14)
No: 53% (23)
Abstain: 14% (6)
The addition of everolimus to an AI is a valid option for some postmenopausal patients
with disease progression after a non-steroidal AI, since it significantly prolongs
PFS, albeit without OS benefit. The decision to treat must take into account the individual
relevant toxicities associated with this combination and should be made on a case
by case basis.
Tamoxifen can also be combined with everolimus.
1 B
2 B
Voters: 40
Yes: 84% (34)
Abstain: 13% (5)
The addition of the CDK4/6 inhibitor palbociclib to an aromatase inhibitor, as 1st
line therapy, for postmenopausal patients (except patients relapsing <12 months from
the end of adjuvant AI), provided a significant improvement in PFS (10 months), with
an acceptable toxicity profile, and is therefore one of the preferred treatment options,
where available. OS results are still awaited.
ESMO MCBS: 3*
1 A
Voters: 37
Yes: 92% (34)
Abstain: 3% (1)
The addition of CDK4/6 inhibitor palbociclib to Fulvestrant, beyond 1st line therapy,
for pre/peri/post
menopausal patients, provided significant improvement in PFS (∼5 months) as well as
improvement of QoL, and is a treatment option. OS results are awaited.
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*
1 A
Voters: 42
Yes: 86% (36)
Abstain: 10% (4)
The optimal sequence of endocrine agents after 1st line ET is uncertain. It depends
on which agents were used in the (neo)adjuvant and 1st line ABC settings. Available
options include AI, tamoxifen, fulvestrant+palbociclib, AI+everolimus, tamoxifen+everolimus,
fulvestrant, megestrol acetate and estradiol.
It is currently unknown how the different combinations of endocrine+biological agents
compare with each other, and with single agent CT. Several trials are ongoing.
1 A
Voters: 40
Yes: 93% (37)
Abstain: 5% (2)
For pre-menopausal women, for whom ET was decided, ovarian suppression/ablation combined
with additional endocrine therapy is the preferred choice.
1 B
Voters: 43
Yes: 93% (40)
Abstain: 5% (2)
Ovarian ablation by laparoscopic bilateral oophorectomy ensures definitive estrogen
suppression and contraception, avoids potential initial tumor flare with LHRH agonist,
and may increase eligibility for clinical trials.
Patients should be informed on the options of OS/OA and decision should be made on
a case by case.
Expert Opinion
Voters: 43
Yes: 91% (39)
Abstain: 7% (3)
For pre-menopausal women, the additional endocrine agent can be AI or tamoxifen,
according to type and duration of prior adjuvant endocrine therapy but AI absolutely
mandates the use of ovarian suppression/ablation.
Fulvestrant is also a valuable option, but for the moment also mandates the use of
ovarian suppression/ablation.
1 B
1 C
Voters: 42
Y: 95% (40)
Abstain: 5% (2)
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 = ESMO Magnitude of Clinical Benefit Scale; * = very important explanation
in text.
ER positive/HER-2 negative (luminal) ABC
One of the most important recommendations relates to the preferred treatment for luminal
ABC, which should be endocrine therapy in the majority of cases, excluding those with
visceral crisis and concern or proof of endocrine resistance. All breast cancer guidelines
concur with this recommendation but unfortunately real life data studies show that
most of these patients still receive chemotherapy as their first treatment, despite
the lower efficacy [37].
Visceral crisis and endocrine resistance have been defined during ABC 2 and published
[1]. However, better predictive factors are urgently needed to clearly identify those
patients whose tumors have primary endocrine resistance and are responsible for the
early and rapid progression seen in ∼20–25% of luminal ABC patients treated with endocrine
therapy [38]. Possible reasons may include ER loss [39] or ER mutations [40].
The most important advance in the management of luminal ABC over the last 2 years
has undoubtedly been the introduction of a new class of agents, the CDK4/6 inhibitors,
in combination with an endocrine agent.
The value of the CDK4/6 inhibitor palbociclib, combined with an aromatase inhibitor
as 1st line therapy was evaluated initially in a randomized phase II study, the PALOMA
1 trial [41], which showed a substantial 10-month benefit in progression-free-survival
(PFS) coupled with a favorable toxicity profile (main toxicity being neutropenia).
Based on these results, FDA granted accelerated approval, which resulted in the drug
being commercially available in USA. At the 2016 ASCO meeting, the phase III PALOMA
2 trial was presented and confirmed the 10-month benefit in PFS, with the main toxicities
being hematological (mainly neutropenia) and fatigue [41]. OS results are still awaited.
In view of these results, the initial statement developed at ABC3 was modified and
re-voted by email and considers this option as one of the preferred treatment options,
where available. Very recently (September 2016) EMA also started the approval process
of Palbociclib. However, its approval/reimbursement in all individual countries is
still pending and the issue of cost is of crucial importance for its implementation
in clinical practice, as it is for many targeted agents namely anti-HER-2 agents.
Beyond 1st line endocrine therapy, addition of palbociclib to fulvestrant resulted
in significant albeit lower 5-month PFS prolongation in the PALOMA 3 phase III trial
[42]. The quality of life substudy has shown both an overall improvement and a delayed
deterioration of this important endpoint, with greater improvement in baseline pain,
in the palbociclib arm [43]. Importantly, the PALOMA-3 study accrued both postmenopausal
and pre/perimenopausal (in combination with ovarian function suppression) patients,
allowing for assessment of the drug efficacy in a breast cancer population usually
excluded from ABC endocrine therapy trials. OS results are still awaited. In view
of available results, the ABC panel considers this as a treatment option, where available.
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
time of publishing the ABC3 guidelines, PALOMA 2 main results and the accompanying
quality of life substudy have been presented but not yet published. For this reason,
the MCBS for the use of palbociclib in 1st line was calculated using the PALOMA 1
trial efficacy data, which scores a 3 for efficacy. Once the PALOMA 2 data is published
the MCBS will be updated an e-update made available through the ESMO guidelines website.
For the use of palbociclib as 2nd line therapy, data from PALOMA 3, both efficacy
and quality of life, were used. The MCBS was 3 for efficacy, and due to the improvement
in quality of life upgraded to 4, which is the final score for this setting.
Another possible therapy is the combination of endocrine therapy with the mTOR inhibitor,
everolimus. This combination has shown a PFS benefit of ∼6 months, without a significant
OS benefit, and with significant toxicity [44, 45]. However, as with many agents,
as more experience is gained regarding the use of everolimus and the management of
its toxicities, its clinical use becomes easier. In addition, patient education is
fundamental for prevention and early management of associated side effects. Of particular
attention is the possibility of an excess mortality of this combination in elderly
patients (>70 years of age) [44, 46].
Currently, and in spite of intensive research, no predictive biomarker, other than
hormone receptor status, exists to identify patients who will benefit the most from
either m-TOR or CDK4-6 inhibitors and research efforts must continue.
The panel did not support (53.4% against) the 1st line combination of non-steroidal
aromatase inhibitor and fulvestrant based on the results of the SWOG S0226 trial [47].
There may be a benefit for the minority of postmenopausal patients who are endocrine-naïve.
The definition of the best 1st line approach for postmenopausal patients will soon
have additional data through the phase III FALCON data that will be presented this
year.
The optimal sequence of single endocrine agents and combinations with targeted agents
is currently unknown and is a research priority. It is crucial to collect data from
clinical trials beyond progression to better understand the efficacy of each class
of agent when given after the other (e.g. CDK4-6 inhibitors after m-TOR inhibitors
and vice-versa).
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 recommendations. Therefore, all CT recommendations for HER-2 negative
disease also apply for triple negative ABC.
1 A
Voters: 44
Yes: 98% (43)
Abstain: 2% (1)
In triple-negative ABC patients (regardless of BRCA status), previously treated with
anthracyclines with or without taxanes in the (neo)adjuvant setting, carboplatin demonstrated
comparable efficacy and a more favorable toxicity profile, compared to docetaxel,
and is therefore an important treatment option.
1 A
Voters: 43
Yes: 91% (39)
Abstain: 5% (2)
LoE, available level of evidence; consensus, percentage of panel members in agreement
with the statement; CT, chemotherapy.
Triple negative ABC
The treatment of triple-negative breast cancer (TN-ABC) still remains the largest
unmet need within ABC. In spite of extensive research, no treatments apart from chemotherapy
have so far proven to be effective for this population. For this reason, no specific
recommendations can be made for this ABC subtype, with the possible exception of platinum
compounds for BRCA-mutated patients.
Probably the largest achievement of the last 2 years was the TNT study, comparing
‘standard’ docetaxel to carboplatin in unselected TNBC patients (with pre-specified
subgroup analysis of BRCA-mutation carriers). The superiority of carboplatin was demonstrated
only among BRCA-positive patients, while in the unselected TN-ABC population docetaxel
and carboplatin seem to have a similar efficacy [48], although the study was not designed
as a non-inferiority study. Of note, in this study, 15% of patients had no prior adjuvant
chemotherapy and only 35% had received (neo)adjuvant taxanes. Importantly, due to
the significantly better toxicity profile of carboplatin, it remains an attractive
treatment choice even for unselected TN-ABC patients. Unfortunately, other putative
predictive factors of increased sensitivity to platinum, such as homologous recombination
deficit (HRD) and the basal-like Prosigna PAM50 signature were not proven of value
for making treatment decisions in this setting.
The future of TN-ABC treatment seems to lie in a better biological characterization
of this breast cancer subtype into further subgroups, followed by the development
of specific therapies for each of the subgroups. An example is the Luminal AR subtype,
characterized by the expression of the androgen receptor; antiandrogens have recently
demonstrated some activity and are being further evaluated, and where a potential
predictive marker, the Predict AR assay, is also being tested [49, 50].
SECTION 6
OTHER RECOMMENDATIONS
GUIDELINE STATEMENT
LoE
Consensus
CHEMOTHERAPY OTHER
Metronomic chemotherapy
is a reasonable treatment option, for patients not requiring rapid tumor response.
The better studied regimen is CM (low dose oral cyclophosphamide and methotrexate);
other regimens are being evaluated (including capecitabine and vinorelbine). Randomized
trials are needed to accurately compare metronomic CT with standard dosing regimens.
1 B
Voters: 43
Yes: 88% (38)
Abstain: 5% (2)
Even if given in the adjuvant setting, provided that cumulative dose has not been
achieved and that there are no cardiac contra-indications,
anthracyclines
can be re-used in MBC, particularly if there has been at least 1 year of disease-free
survival.
1 C
Voters: 44
Yes: 93% (41)
Abstain: 5% (2)
BRCA-ASSOCIATED ABC
In patients with
BRCA-associated
triple negative or endocrine-resistant MBC previously treated with an anthracycline
with or without a taxane (in the adjuvant and/or metastatic setting), a platinum regimen
is the preferred option, if not previously administered and no suitable clinical trial
is available.
1 A
Voters: 44
Yes: 86% (38)
Abstain: 9% (4)
In patients with TN or Luminal MBC,
genetic counseling and possibly BRCA testing
should be discussed with the patient, if the results can impact on treatment decisions
and/or on clinical trials entry.
Expert Opinion
Voters: 43
Yes: 91% (39)
Abstain: 7% (3)
BONE METASTASES
A
bone modifying agent
(bisphosphonate, denosumab) should be routinely used in combination with other systemic
therapy in patients with MBC and bone metastases.
Three-monthly zolendronic acid seems to be not inferior to standard monthly schedule.
Supplementation of calcium and vitamin D3 is mandatory, unless contraindications
exist.
1 A
1 B
1 C
Voters: 44
Yes: 95% (42)
Abstain: 5% (2)
OTHER—BIOMARKERS
Multigene panels, such as those obtained using next generation sequencing (NGS) or
other technology, regarding evolving molecular changes in ABC tumors has not yet proven
beneficial in clinical trials, their impact on outcome remains undefined and should
only be considered investigational.
1 C
Voters: 44
Yes: 95% (42)
Abstain: 5% (2)
LoE, available level of evidence; consensus, percentage of panel members in agreement
with the statement; MBC, metastatic breast cancer.
Other recommendations
Several options exist for chemotherapy both for first and subsequent lines of therapy.
The ABC panel maintains that for patients pretreated with anthracyclines and taxanes
the preferred agents, based on their efficacy and toxicity profile, are capecitabine,
vinorelbine and eribulin. The latter is one of the few agents to provide a survival
gain, albeit small (2.5 months) in a heavily pretreated population of ABC patients
[51]. In a head-to-head comparison between eribulin and capecitabine, as first or
second line therapy, there were no major differences between the drugs in efficacy
but a different toxicity profile [52].
It is also possible to re-challenge with anthracyclines, particularly if there has
been at least 1 year of disease-free survival, and if the cumulative dose has not
been reached, a common situation nowadays because of the lower doses of anthracyclines
used in the adjuvant setting. Re-challenge with taxanes is also possible, provided
that there has been at least 1 year of disease-free survival.
Another very attractive option is the use of metronomic chemotherapy, defined as the
use of low doses and short intervals, which has been evaluated in the advanced setting
with interesting efficacy results and an excellent toxicity profile [53]. The best
evaluated regimen is oral cyclophosphamide and oral methotrexate but other agents
are being studied such as vinorelbine and capecitabine.
In view of the lack of substantial efficacy differences among the different available
options, their toxicity profile must be discussed with the patient and her/his preferences
taken into account.
ABC3 also further endorsed the use of bone-modifying agents (bisphosphonate, denosumab)
in combination with calcium + vitamin D3 supplementation as a routine component of
management of patients with bone metastases. Denosumab has demonstrated slightly better
efficacy and better tolerability, compared to zoledronic acid [54], having the advantage
of a subcutaneous route of administration and the disadvantage of a substantially
higher cost in most countries; where available, it can be considered a preferred option.
Currently available data support replacing routine 4 weekly administration of intravenous
bisphosphonates by 3-monthly zoledronic acid after an initial period of monthly use
[55, 56]. Early 3-monthly use seems associated with increased need for major surgeries
[57], so a reasonable compromise may be to start with the monthly schedule for the
first year and then change to 3-monthly regimen. No data exist on the optimal overall
treatment duration of bone modifying agents, and their efficacy must be weighed against
long-term toxicity (such as osteonecrosis of the jaw and atypical fractures).
When a bone modifying agent is given, supplements of calcium and vitamin D are mandatory,
except in the presence of contra-indications.
Unfortunately, no multigene testing technology has been proven to be beneficial in
supporting treatment choices in ABC patients [18] and the panel strongly discourages
their use in clinical practice. They should continue to be considered investigational.
SECTION 7
SUPPORTIVE AND PALLIATIVE CARE
GUIDELINE STATEMENT
LoE
Consensus
Management of CANCER RELATED FATIGUE
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 effective 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 pharmacological interventions
(LoE: 2 B).
as in the text
100%
Management of CDK Inhibitor Induced Neutropenia
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/μl; dose reduction can also be considered.
2 A
100%
Management of Non-Infectious Pneumonitis (NIP)
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 systemic steroids and treatment discontinuation for grade 3 or greater
toxicity.
2 A
100%
Management of MUCOSITIS/STOMATITIS
Mild toothpaste and gentle hygiene are recommended for the treatment of stomatitis.
Early intervention is recommended. 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, 10 ml to swish×2 min then spit out qid).
Expert opinion
1 B
100%
Management of DYSPNEA
Treatable causes like pleural effusion, pulmonary emboli, cardiac insufficiency,
anemia or drug toxicity must be ruled out. Patient support is essential. Oxygen is
of no use in non-hypoxic patients. Opioids are the drugs of choice in the palliation
of dyspnea (LoE: 1 A). Benzodiazepines can be used in patients experiencing anxiety
(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) obstruction of the airways (in which case laser/stent
is to be considered).
1 A,
2 A,
Expert opinion
100%
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
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 accordance 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.
2 A
100%
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
.
Supportive and palliative care
The ABC panel decided to dedicate several recommendations to 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
Unfortunately, little high-quality data exist in many areas of symptom management,
probably due to difficulties in conducting research in this field, including the lack
of well-defined endpoints, of patient-reported symptoms and side effects, and of optimal
tools to evaluate impact on quality of life for advanced cancer patients. New classes
of drugs introduced into breast cancer management have brought into the clinical practice
new toxicities, poorly understood in the beginning and unfamiliar to most oncologists.
Undoubtedly this is an area of unmet need, which should be a research priority.
The ABC3 guidelines provide guidance on the management of drug-induced pneumonitis,
mucositis [58, 59], endocrine and metabolic disorders and CDK4/6 inhibitor-related
neutropenia. For nausea and vomiting ABC fully endorses the guidelines developed by
ESMO/MASCC [60].
The ABC panel continues to discuss and provide guidance on the management of frequent
and difficult to manage cancer-associated symptoms. In this edition, dyspnea and fatigue
were discussed. Cancer related fatigue is frequently experienced by advanced cancer
patients, exerts a deleterious impact on their quality of life and limits physical,
functional, psychological and social well-being. Its etiology is complex and therefore
effective management needs to be multidimensional [61–63]. It is important to assess
cancer related fatigue using appropriate patient-reported outcome measures before
implementing various pharmacological and non-pharmacological interventions. Randomized
studies have suggested improvement of fatigue by various types of exercise quite convincingly
[64], and meditation and some pharmacologic interventions are under evaluation. The
use of good evidence-based algorithms for management of cancer related fatigue can
also be helpful [65].
Conclusions
Since the ABC3 Conference two important initiatives have already been initiated.
The ESMO Magnitude of Clinical Benefit Scale (MCBS) [8] has been published and is
being applied to all new anticancer treatments approved by EMA. The latest drug for
which EMA started the approval process was Palbociclib in September 2016 and its MCBS
evaluation is included in the present article. Should another agent be approved before
the next ABC Consensus Conference, the ESMO Committees will apply the MCBS and the
result will be made available as an e-update to the present guidelines.
Following on the success of the ABC Consensus Conference, the ABC community has come
together to create the ABC Global Alliance. This Alliance will function as a platform
where all involved partners (advocacy groups, pharma, cooperative groups, societies,
individuals) will be able to work together, in 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-Action is being developed,
with tangible objectives that need to be achieved within the next decade to meaningfully
impact the outcomes of ABC patients.
Funding
None declared.
Disclosure
Detailed CoI for all panel members are described in online supplement.
Supplementary Material
Supplementary Data
Click here for additional data file.