3rd ESOESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3)

Note: These Guidelines were developed by ESO and ESMO and are published simultaneously in Annals of Oncology (2016; doi:10.1093/annonc/mdw544) and The Breast and should both be cited.

# Introduction
Advanced Breast Cancer (ABC) comprises both locally advanced (LABC) and metastatic breast cancer (MBC). Although treatable, MBC remains an incurable disease with a median overall survival of $2-3 years and a 5-year survival of only $25% [bib_ref] SEER data submission, posted to the SEER web site, Howlader [/bib_ref] [bib_ref] Trends in survival in metastatic breast, Sundquist [/bib_ref]. Some more recent series seem to indicate an improvement in median overall survival [bib_ref] Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic..., Kobayashi [/bib_ref] [bib_ref] The impact of new chemotherapeutic and hormone agents on survival in a..., Chia [/bib_ref].
A recent comprehensive reportof 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 V C The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits noncommercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com

## 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.
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 (Federati on LatinoAmericana de Mastologia). There was also official representation of ASCO (American Society of Clinical

## Section i continued

## Guideline statement loe consensus
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% [bib_ref] Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast..., Smyth [/bib_ref] Abstain: 5.1%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% [bib_ref] PALOMA-2: primary results from a phase III trial of palbociclib (P) with..., Finn [/bib_ref] 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. [bib_ref] Locoregional treatment versus no treatment of the primary tumour in metastatic breast..., Badwe [/bib_ref] 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. 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% [bib_ref] The SystHERs registry: an observational cohort study of treatment patterns and outcomes..., Tripathy [/bib_ref] 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. 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.

## 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.

## 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.

## 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 nonmeasurable metastatic disease. A change in tumor markers alone should not be used to initiate a change in treatment.

## 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
Continued Annals of Oncology 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## 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.

## B 72
Because patients with HER2ve 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.

## 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).

## 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.

## A 100
Early introduction of expert palliative care, including effective control of pain and other symptoms, should be a priority.

## A 100
Access to effective pain treatment (including morphine, which is inexpensive) is necessary for all patients in need of pain relief.

## 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.

# 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 [fig_ref] Table 1: Grading system[7] [/fig_ref] , 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. [fig_ref] Table 1: Grading system[7] [/fig_ref] describes the grading system used [bib_ref] Grading strength of recommendations and quality of evidence in clinical guidelines: report..., Guyatt [/bib_ref]. ABC1 [bib_ref] 1st International consensus guidelines for advanced breast cancer (ABC1), Cardoso [/bib_ref] and ABC2statements with only minor updates or with no updates are listed in.

## 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 [bib_ref] A standardised, generic, validated approach to stratify the magnitude of clinical benefit..., Cherny [/bib_ref] and the ASCO Value Framework [bib_ref] American Society of Clinical Oncology Statement: a conceptual framework to assess the..., Schnipper [/bib_ref] 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. 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.

## A 100
For Triple Negative LABC, Anthracycline-and-taxane-based chemotherapy is recommended as initial treatment. 1 A 85 For HER-21 LABC, concurrent taxane and anti-HER-2 therapy is recommended since it increases the rate of pCR.
1 A 92 For HER-21 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 HR1 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.

## B 98
INFLAMMATORY LABC For inflammatory LABC, overall treatment recommendations are similar to those for non-inflammatory LABC, with systemic therapy as first treatment.

## 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.

## B 98
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 [bib_ref] 1st International consensus guidelines for advanced breast cancer (ABC1), Cardoso [/bib_ref]. 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 [bib_ref] Delivering high-quality cancer care: charting a new course for a system in..., Levit [/bib_ref].
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 [bib_ref] Evolving psychosocial, emotional, functional, and support needs of women with advanced breast..., Cardoso [/bib_ref] , 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 [bib_ref] Breast cancer during followup and progression -a population based cohort on new..., Karlsson [/bib_ref] [bib_ref] Prospective comparison of switches in biomarker status between primary and recurrent breast..., Thompson [/bib_ref] [bib_ref] Prospective study evaluating the impact of tissue confirmation of metastatic disease in..., Amir [/bib_ref]. 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 [bib_ref] Recommendations for retesting breast cancer metastases for HER2 and hormone receptor status, Penault-Llorca [/bib_ref] [bib_ref] Influence of decalcification procedures on immunohistochemistry and molecular pathology in breast cancer, Schrijver [/bib_ref] , as experienced in Safir01/UNICANCER trial [bib_ref] Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic..., Andre [/bib_ref]. For that reason, decalcification using EDTA is recommended for bone biopsies, when it is the only metastatic site [bib_ref] Influence of decalcification procedures on immunohistochemistry and molecular pathology in breast cancer, Schrijver [/bib_ref]. 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 [bib_ref] Locoregional treatment versus no treatment of the primary tumour in metastatic breast..., Badwe [/bib_ref] [bib_ref] A randomized controlled trial evaluating resection of the primary breast tumor in..., Soran [/bib_ref]. 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 [bib_ref] A randomized controlled trial evaluating resection of the primary breast tumor in..., Soran [/bib_ref]. 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 (4) For patients with ER/HER-2 MBC, for whom CTanti-HER2 therapy was chosen as 1st line therapy and provided a benefit, it is reasonable to use ETanti-HER2 therapy as maintenance therapy, after stopping CT, although this strategy has not been studied in randomized trials.

## 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.

## 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% [bib_ref] Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma, Weigel [/bib_ref] 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. (2) The standard 1st line therapy for patients previously untreated with anti-HER-2 therapy is the combination of CTtrastuzumab and pertuzumab, because it has proven to be superior to CTtrastuzumab in terms of OS in this population. In case of progression on trastuzumab-based therapy, the combination trastuzumablapatinib 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.

## 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.

## 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. Continued consider surgery if it can be performed with a high quality procedure [bib_ref] Initial surgery and survival in stage IV breast cancer in the United..., Thomas [/bib_ref]. 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 [bib_ref] Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic..., Greenberg [/bib_ref] , the true impact of these local-regional therapies on long-term outcome remains unknown, and prospective and if possible randomized trials are needed.

## 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.

## 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 [bib_ref] Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall..., Swain [/bib_ref] [bib_ref] Trastuzumab emtansine for HER2-positive advanced breast cancer, Verma [/bib_ref] [bib_ref] Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast..., Krop [/bib_ref] [bib_ref] Phase III, randomized study of trastuzumab emtansine (T-DM1) 6 pertuzumab (P) vs..., Ellis [/bib_ref] [bib_ref] PHEREXA: a phase III study of trastuzumab (H)  capecitabine (X) 6..., Urruticoechea [/bib_ref] , 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 [bib_ref] Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women..., Kaufman [/bib_ref]. 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 [bib_ref] Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast..., Von Minckwitz [/bib_ref] [bib_ref] Trastuzumab beyond progression for HER2 positive metastatic breast cancer: progression-free survival on..., Rayson [/bib_ref] 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.

## 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. (3) The combination of a nonsteroidal AI and fulvestrant as first-line therapy for postmenopausal 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.

## B voters: 43
Yes: 33% [bib_ref] Prospective comparison of switches in biomarker status between primary and recurrent breast..., Thompson [/bib_ref] 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) The addition of CDK4/6 inhibitor palbociclib to Fulvestrant, beyond 1st line therapy, for pre/peri/postmenopausal 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. (2) For pre-menopausal women, for whom ET was decided, ovarian suppression/ablation combined with additional endocrine therapy is the preferred choice.

## 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. 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 [bib_ref] Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall..., Swain [/bib_ref]. 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 [bib_ref] Phase III, randomized study of trastuzumab emtansine (T-DM1) 6 pertuzumab (P) vs..., Ellis [/bib_ref] 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 [bib_ref] The SystHERs registry: an observational cohort study of treatment patterns and outcomes..., Tripathy [/bib_ref] 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 [bib_ref] Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab..., Andersson [/bib_ref] [bib_ref] Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the..., Burstein [/bib_ref]. 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 [bib_ref] Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall..., Swain [/bib_ref] , weekly paclitaxel [bib_ref] Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast..., Smyth [/bib_ref] , vinorelbine [bib_ref] The co-administration of pertuzumab (P) and trastuzumab (T) as a single infusion,..., Andersson [/bib_ref] and nab-paclitaxel [bib_ref] Nab-paclitaxel versus solventbased paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG..., Untch [/bib_ref]. After the voting that took place in ABC3, the Pherexa trial [bib_ref] PHEREXA: a phase III study of trastuzumab (H)  capecitabine (X) 6..., Urruticoechea [/bib_ref] , presented at ASCO 2016, provided some evidence regarding the combination of dual blockade with capecitabine.

## 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 [bib_ref] In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer..., Lobbezoo [/bib_ref].
Visceral crisis and endocrine resistance have been defined during ABC 2 and published. 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 [bib_ref] PALOMA-2: primary results from a phase III trial of palbociclib (P) with..., Finn [/bib_ref]. Possible reasons may include ER loss [bib_ref] Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma, Weigel [/bib_ref] or ER mutations [bib_ref] Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer, Fribbens [/bib_ref].
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 [bib_ref] The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole..., Finn [/bib_ref] , 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 [bib_ref] The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole..., Finn [/bib_ref]. 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 [bib_ref] Palbociclib in hormone-receptorpositive advanced breast cancer, Turner [/bib_ref]. 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 [bib_ref] Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive,..., Harbeck [/bib_ref]. 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 [bib_ref] Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast..., Piccart [/bib_ref] [bib_ref] Randomized phase II trial of everolimus in combination with tamoxifen in patients..., Bachelot [/bib_ref]. 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) [bib_ref] Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast..., Piccart [/bib_ref] [bib_ref] Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly..., Pritchard [/bib_ref].
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 [bib_ref] Combination anastrozole and fulvestrant in metastatic breast cancer, Mehta [/bib_ref]. There may be a benefit for the minority of postmenopausal patients who are endocrine-naive.
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).

## 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 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.

## 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.
unselected TN-ABC population docetaxel and carboplatin seem to have a similar efficacy [bib_ref] TNT: a randomized phase III trial of carboplatin compared to docetaxel for..., Tutt [/bib_ref] , 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 [bib_ref] Overall survival (OS) from the phase 2 study of enzalutamide, an androgen..., Cortes [/bib_ref].

## 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 [bib_ref] Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast..., Cortes [/bib_ref]. 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 [bib_ref] Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients..., Kaufman [/bib_ref].
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 [bib_ref] Clinical overview of metronomic chemotherapy in breast cancer, Munzone [/bib_ref]. 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 (2) OTHERABIOMARKERS 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. [bib_ref] Denosumab compared with zoledronic acid for the treatment of bone metastases in..., Stopeck [/bib_ref] , 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 3monthly zoledronic acid after an initial period of monthly use [bib_ref] Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment..., Amadori [/bib_ref] [bib_ref] Efficacy and safety of continued zoledronic acid every 4 weeks versus every..., Hortobagyi [/bib_ref]. Early 3-monthly use seems associated with increased need for major surgeries [bib_ref] Alliance): a randomized phase III study of standard dosing vs. longer interval..., Himelstein [/bib_ref] , so a reasonable compromise may be to start with the monthly schedule for the first year and then change to 3monthly regimen. No data exist on the optimal overall treatment duration of bone modifying agents, and their efficacy must be

## 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/ll; dose reduction can also be considered.

## 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.

## 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 swishA2 min then spit out qid). 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.

## 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.
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 contraindications.
Unfortunately, no multigene testing technology has been proven to be beneficial in supporting treatment choices in ABC patients [bib_ref] Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic..., Andre [/bib_ref] and the panel strongly discourages their use in clinical practice. They should continue to be considered investigational.

## 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 [bib_ref] Evaluation of miracle mouthwash (MMW) plus hydrocortisone versus prednisolone mouth rinses as..., Jones [/bib_ref] [bib_ref] Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive..., Rugo [/bib_ref] , endocrine and metabolic disorders and CDK4/6 inhibitor-related neutropenia. For nausea and vomiting ABC fully endorses the guidelines developed by ESMO/MASCC [bib_ref] MASCC and ESMO Consensus Guidelines for the prevention of chemotherapy and radiotherapyinduced..., Roila [/bib_ref].
The ABC panel continues to discuss and provide guidance on the management of frequent and difficult to manage cancerassociated 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 [bib_ref] Interventions for fatigue and weight loss in adults with advanced progressive illness, Payne [/bib_ref] [bib_ref] Screening, evaluation and management of cancer-related fatigue: ready for implementation to practice, Berger [/bib_ref] [bib_ref] A practical approach to fatigue management in colorectal cancer, Aapro [/bib_ref]. It is important to assess cancer related fatigue using appropriate patientreported outcome measures before implementing various pharmacological and non-pharmacological interventions. Randomized studies have suggested improvement of fatigue by various types of exercise quite convincingly [bib_ref] Effects of an 18-week exercise programme started early during breast cancer treatment:..., Travier [/bib_ref] , 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 [bib_ref] Management of fatigue in patients with cancer -a practical overview, Koornstra [/bib_ref].

# Conclusions
Since the ABC3 Conference two important initiatives have already been initiated.
The ESMO Magnitude of Clinical Benefit Scale (MCBS) [bib_ref] A standardised, generic, validated approach to stratify the magnitude of clinical benefit..., Cherny [/bib_ref] 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 Reporthas 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.
[table] Table 1: Grading system[7] [/table]