5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)



# Introduction
For the purpose of advanced breast cancer (ABC) guidelines, ABC comprises both inoperable locally advanced breast cancer (LABC) and metastatic breast cancer (MBC). 1,2 Advanced/metastatic breast cancer remains a virtually incurable disease, with a median overall survival (OS) of about 3 years and a 5-year survival rate of around 25%, [bib_ref] Global analysis of advanced/ metastatic breast cancer: decade report, Cardoso [/bib_ref] [bib_ref] Available at https:// seer.cancer.gov/archive/csr/1975_2013, Howlader [/bib_ref] even in countries without major accessibility problems. Survival is strongly related to breast cancer subtype, with the major advances seen in human epidermal growth factor receptor 2 (HER2)-positive ABC. [bib_ref] Improved survival in metastatic breast cancer 1985-2016, Sundquist [/bib_ref] [bib_ref] Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic..., Kobayashi [/bib_ref] [bib_ref] Palliative systemic therapy and overall survival of 1,395 patients with advanced breast..., Fietz [/bib_ref] [bib_ref] Time trends of overall survival among metastatic breast cancer patients in the..., Gobbini [/bib_ref] [bib_ref] Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre..., Deluche [/bib_ref] ABC is a treatable disease with several available therapies and many others in development. However, their impact on survival and quality of life (QoL) of ABC patients has been slow 3 and different for de novo versus recurrent ABC, with the latter becoming much harder to treat in recent years. [bib_ref] Differential presentation and survival of de novo and recurrent metastatic breast cancer..., Malmgren [/bib_ref] Outcomes are also strongly related to access to the best available care, which includes not only the most efficacious medicines, but also multidisciplinary, specialised care, implementation of guidelines, high-quality pathology, imaging and radiotherapy (RT). Lack of any of these crucial pillars of modern oncological care inevitably results in substantially worse outcomes, as exemplified in the New Zealand report "I am still here".While mortality rates have decreased in the majority of developed countries, most deaths are currently seen in less developed societies, and access issues explain the majority of these inequalities. [bib_ref] Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for..., Bray [/bib_ref] The application of the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) [bib_ref] ESMO-magnitude of clinical benefit scale version 1.1, Cherny [/bib_ref] to the field of ABC (P Shimon, personal communication) shows that the quality of clinical research has improved over the last decade and that better therapies have been developed, providing hope that a substantial improvement in the median OS of ABC patients might soon be seen. However, some clinically relevant questions are still unanswered and may be difficult to address through traditional clinical trials, such as the best sequence of therapies for each individual patient. The application of computer analytics to big data and real-world data is one of the potential ways forward. In-depth discussion must take place regarding the impact of this 'new' level of evidence (LoE) in current treatment guidelines and their integration with clinical trial data.
The 5th International Consensus Conference for Advanced Breast Cancer (ABC 5) took place in Lisbon, Portugal, on 14th-16th November 2019, bringing together 1500 participants from 94 countries worldwide, including health professionals, patient advocates and journalists. Since its first edition in 2011, the main goal of the ABC conference has been the development of high-quality international consensus guidelines for the management of ABC. These guidelines are based on available evidence and on expert opinion when evidence is lacking. They represent the best management options for ABC patients globally, assuming accessibility to all available therapies. Adaptation of these guidelines is often needed in settings where access to care is suboptimal.
The This manuscript summarises the guidelines developed at ABC 5, each of which are accompanied by the LoE, grade of recommendation (GoR), percentage of consensus reached at the conference and supporting references. In addition, the ESMO-MCBS version 1.1 13 (v1.1) was used to calculate scores for new therapies/indications approved by the European Medicines Agency (EMA) since the last ABC guidelines, as well as a few new therapies that have been scored but are still under EMA evaluation (https://www. esmo.org/Guidelines/ESMO-MCBS). A table with these scores is included (see , available at https://doi/org/10.1016/j.annonc.2020.09.010).

# Methodology
Before the ABC 5 conference, preliminary recommendation statements on the management of ABC were prepared based on available published data and following the ESMO guidelines methodology (see http://www.esmo.org/ Guidelines/ESMO-Guidelines-Methodology). These recommendations were circulated to all 44 panel members by e-mail 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 5. All panel members were instructed to vote on all questions, and any 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) were instructed to vote 'abstain'. Additional changes in the wording of statements were made during the session. As some important studies were presented a few weeks later at the 2019 San Antonio Breast Cancer Symposium, particularly for new anti-HER2 therapies, three additional statements were developed after the ABC 5 conference, circulated for revision and voted by all panel members. Statements related to the management of side-effects and difficult symptoms, included under the supportive and palliative care section, were not voted on during the consensus session, but were discussed and unanimously agreed by e-mail, and are therefore considered to have 100% consensus agreement. Previous ABC recommendations that did not require update or only minor changes were not re-voted but were reviewed by all panel members by e-mail and remain valid. To provide a full overview of all ABC guidelines currently approved, this manuscript includes a list of all recommendations per subject, highlighting those that were discussed, voted and approved in ABC 5. However, this manuscript only describes the evidence for newly developed or updated guidelines. We refer the reader to the manuscripts of previous ABC guidelines for the detailed explanation of guidelines not updated/added during ABC 5.
Supplementary , available https://doi/org/10. 1016/j.annonc.2020.09.010, describes the LoE and GoR system used, [bib_ref] Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell..., Dykewicz [/bib_ref] Slides with all ABC guideline statements are available online at http://www.abc-lisbon.org/ and https://www. esmo.org/guidelines/breast-cancer/consensus-recommend ations-advanced-breast-cancer-abc-5.
Given the aim of standardising definitions and homogenising the use of certain medical terms, ABC has provided several definitions throughout the years. At ABC 5, the definition of visceral crisis was revisited, with some examples added (i.e. liver and lung visceral crisis) to better clarify the definition and avoid any misunderstanding between the mere existence of visceral metastases and the presence of visceral crisis. This situation is estimated to occur in only around 10%-15% of first-line ABC cases and requires the use of the most rapidly efficacious therapy, which is not necessarily chemotherapy (ChT) in all situations.
A more subjective and difficult to define situation is 'impending visceral crisis', where the criteria for visceral crisis are not yet met but, without rapidly efficacious measures, it is foreseen to happen. An example is a situation where more than 70% of the liver is occupied by metastases, the liver enzymes are substantially altered but bilirubin is still normal. In this type of situation, we also recommend the use of the most rapidly efficacious therapy.

## Annals of oncology
Fortunately, these last few years have seen the development and approval of several new therapies for ABC, some with an impact on OS. Consequently, some ABC patients can live many years with their disease under control or in complete remission. Since the usual methods for systemic imaging of metastatic disease do not provide good imaging of the breast, the panel believes that breast imaging is an option to consider in the surveillance follow-up of these patients. Additionally, and importantly, if at any time locoregional relapse or progression is suspected, breast imaging must be carried out. At ABC 5, several discussions took place regarding how best to provide information regarding prognosis and length of life to ABC patients. Conversations about prognosis, priorities and end-of-life care are vitally important for those affected by advanced cancer and should be part of routine care. [bib_ref] End-of-life discussions, goal attainment, and distress at the end of life: predictors..., Mack [/bib_ref] Information about prognosis and likely survival time with and without different anticancer treatments is important to enable fully informed and educated decision making by patients. It also helps patients to plan for the future, arrange finances and work, maximise time with loved ones, plan special events and prepare for death. Misunderstandings about prognosis are common [bib_ref] Estimating survival in advanced cancer: a comparison of estimates made by oncologists..., Smith-Uffen [/bib_ref] [bib_ref] Communicating prognosis in cancer care: a systematic review of the literature, Hagerty [/bib_ref] [bib_ref] Prognosis communication in serious illness: perceptions of older patients, caregivers, and clinicians, Fried [/bib_ref] and are associated with increased exposure to futile treatments. [bib_ref] Associations between end-of-life discussion characteristics and care received near death: a prospective..., Mack [/bib_ref] [bib_ref] Associations between end-of-life discussions, patient mental health, medical care near death, and..., Wright [/bib_ref] [bib_ref] Relationship between cancer patients' predictions of prognosis and their treatment preferences, Weeks [/bib_ref] [bib_ref] What do advanced cancer patients know of their disease? A report from..., Pronzato [/bib_ref] Most patients want considerably more information than many healthcare professionals expect, but the type and amount of information sought should be clarified. [bib_ref] Information needs of patients with cancer: results from a large study in..., Jenkins [/bib_ref] There are some significant cultural variations, in particular the involvement of the family in filtering information, which can make disclosure about prognosis and survival especially challenging. [bib_ref] Cross-cultural differences in information disclosure evaluated through the EORTC questionnaires, Arraras [/bib_ref] Although some physicians may avoid discussing prognosis for fear of upsetting the patient or destroying hope, there is no evidence that increased information about prognosis with sensitive communication is harmful to patients, or that it increases anxiety or distress. [bib_ref] Truth may hurt but deceit hurts more: communication in palliative care, Fallowfield [/bib_ref] [bib_ref] Does it hurt to know the worst?epsychological morbidity, information preferences and understanding..., Barnett [/bib_ref] [bib_ref] Outcomes of prognostic disclosure: associations with prognostic understanding, distress, and relationship with..., Enzinger [/bib_ref] [bib_ref] When the treatment goal is not cure: are cancer patients equipped to..., Gattellari [/bib_ref] [bib_ref] Communicating with realism and hope: incurable cancer patients' views on the disclosure..., Hagerty [/bib_ref] [bib_ref] Giving honest information to patients with advanced cancer maintains hope, Smith [/bib_ref] For patients wanting quantitative information on life expectancy, providing ranges for worst-case, typical and best-case scenarios is more helpful and conveys more hope than providing a single point estimate of median survival. [bib_ref] Using scenarios to explain life expectancy in advanced cancer: attitudes of people..., Kiely [/bib_ref] Ranges for survival scenarios are also more accurate than a single point estimate of expected survival. [bib_ref] Estimating survival in advanced cancer: a comparison of estimates made by oncologists..., Smith-Uffen [/bib_ref] [bib_ref] Disarming the guarded prognosis: predicting survival in newly referred patients with incurable..., Stockler [/bib_ref] [bib_ref] The median informs the message: accuracy of individualized scenarios for survival time..., Kiely [/bib_ref] Oncologists should offer prognostic information to all patients with ABC, allowing patients to determine the type and extent of information required. The patient's needs for prognostic information are likely to fluctuate over time, and as their disease progresses, so it is important for oncologists to repeatedly determine the information required throughout the illness from diagnosis to death. Oncologists also need guidance and communication skills training on how to handle these difficult discussions, as there is evidence that some oncologists are overly optimistic about survival benefits from anticancer treatments while others are unduly nihilistic about the benefits of good quality supportive care.Section II. Continued

# Guideline statement
LoE/GoR Consensus supportive care (i.e. growth factors). To be used, the biosimilar must be approved after passing the stringent development and validation processes required by the EMA or the FDA or other similarly strict authority.

## I/a 71%
In patients with taxane-naive and anthracycline-resistant ABC or with anthracycline maximum cumulative dose or toxicity (i.e. cardiac) who are being considered for further ChT, taxane-based therapy, preferably as single agent, would usually be considered as the treatment of
[formula] I/A 59% [/formula]

## Continued

## Annals of oncology
Germline BRCA status, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) for estrogen receptor (ER)-positive ABC and programmed death-ligand 1 (PD-L1) for triple-negative ABC were included as important factors to take into consideration when making treatment decisions. Details about how to evaluate these factors and their clinical implications are discussed in the respective sections of the guidelines. The statement about the use of bevacizumab was rewritten but consensus was still not achieved. In the discussion, it became clear that the main reasons for this lack of consensus were the withdrawal of approval by the Food and Drug Administration (FDA), rendering it an unavailable option in the United States, and the fact that for many panellists, bevacizumab should not be considered a treatment option. The available data show that bevacizumab combined with ChT as first-line therapy for ABC provides a moderate benefit in progression-free survival (PFS) and no benefit in OS. The ESMO-MCBS v1.1 score for bevacizumab is two. [bib_ref] A systematic review and metaanalysis of bevacizumab in first-line metastatic breast cancer:..., Hey [/bib_ref] Some experts believe it can be a good option for situations of extensive cutaneous inflammatory disease due to its potential antiangiogenic effect. n/a/D 66%
The addition of everolimus to an AI is a valid option for some patients [for pre-and perimenopausal women with OFS/OFA, men (preferably with an LHRH agonist) and postmenopausal women] previously exposed to or naive of (in case CDK4/6 inhibitors are not available) ET, since it significantly prolongs PFS, albeit without evidence of an OS benefit. ESMO-MCBS v1.1 score: 2 The decision to treat must take into account the toxicities associated with this combination, the lack of a statistically I/B 88%

## Continued

## Section iv. continued
Guideline statement LoE/GoR Consensus significant OS benefit, cost and availability. Tamoxifen or fulvestrant can also be combined with everolimus. Adequate prevention, close monitoring and proactive treatment of AEs is needed, particularly in older patients treated with everolimus due to the increased incidence of toxic deaths reported in the BOLERO-2 trial.
[formula] II/B I/B 80% 97% [/formula]
Everolimus and CDK4/6 inhibitors should not be used after PD on that specific agent (i.e. beyond progression), outside a clinical trial.

## N/a/e 74%
Alpelisib with fulvestrant is a treatment option for patients with PIK3CA-mutated tumours (in exons 9 or 20), previously exposed to an AI and with appropriate HbA1c levels, since it provided about 5 months of benefit in median PFS. The decision to give alpelisib should take into consideration the inclusion/exclusion criteria in the SOLAR-1 study (i.e. pre-existing diabetes and baseline HbA1c), as well as the toxicity profile of alpelisib. Its efficacy after exposure to CDK4/6 inhibitors is unknown, since only 6% of patients in the SOLAR-1 trial had been previously treated with those agents. ESMO-MCBS v1.1 score: 3
[formula] I/B 88% [/formula]
Patients receiving alpelisib in combination with ET for PIK3CA-mutated ABC should be instructed to take non-sedating antihistamines to prevent rash at the start of therapy. Antihistamines can be discontinued after 4 weeks as the risk for rash is primarily in the first 2 weeks of therapy.

## I/b 93%
At present, no validated predictive biomarkers other than hormone receptor status exist to identify patients who will/will not benefit from the addition of a CDK4/6 inhibitor or an mTOR inhibitor to ET and none of the studied biomarkers is ready for use in clinical practice. Research efforts must continue. Alpelisib should only be used in cases of PIK3CA-mutated tumours.
[formula] I/E II/A 95% 95% [/formula]
The combination of a non-steroidal AI and fulvestrant as first-line therapy for postmenopausal patients resulted in significant improvement in both PFS and OS compared with AI alone in one phase III trial and no benefit in a second trial with a similar design. Notably, a suboptimal dose of fulvestrant was used in the study that demonstrated benefit. 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 ABC without prior exposure to adjuvant ET in cases where a CDK4/6 inhibitor will not be given. ESMO-MCBS v1.1 score: 2 Comparative data between this combination and a CDK4/6 inhibitor with ET are not available.
II/D Yes: 38% No: 60% Abstain: 2%
The optimal sequence of endocrine-based therapy is uncertain. It depends on which agents were previously used [in the (neo) adjuvant or advanced settings], duration of response to those agents, burden of the The last 2 years have seen the establishment of cyclindependent kinase (CDK)4/6 inhibitors combined with endocrine therapy (ET) as the standard of care for ER-positive/HER2-negative ABC in view of the OS benefit seen in several trials, [bib_ref] Overall survival with ribociclib plus endocrine therapy in breast cancer, Im [/bib_ref] [bib_ref] Overall survival with ribociclib plus fulvestrant in advanced breast cancer, Slamon [/bib_ref] [bib_ref] Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human..., Slamon [/bib_ref] [bib_ref] The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive,..., Sledge [/bib_ref] [bib_ref] MONARCH 2: abemaciclib in combination with fulvestrant in women with HR/HER2-advanced breast..., Sledge [/bib_ref] [bib_ref] Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer..., Tripathy [/bib_ref] [bib_ref] Abstract GS2-05: first-line ribociclib vs placebo with goserelin and tamoxifen or a..., Tripathy [/bib_ref] both in the firstand second-line settings, substantial PFS benefit and good toxicity profile. These agents can be combined with an aromatase inhibitor (AI) or fulvestrant, and are effective in de novo or recurrent ABC, in first or second line, in cases of primary or secondary resistance, in postmenopausal and premenopausal women (the latter with ovarian function suppression/ablation), and in men (preferably with a luteinising hormone-releasing hormone agonist). Of note, the combination of tamoxifen and ribociclib led to increased cardiotoxicity (arrhythmia) and should be avoided. [bib_ref] Overall survival with ribociclib plus endocrine therapy in breast cancer, Im [/bib_ref] Notwithstanding these results, the panel acknowledges that there is a small group of patients who can be treated with ET alone; although clear identification of these patients is not possible at this time, factors such as limited burden of metastatic disease and features of less aggressive biology [i.e. very long disease-free interval (DFI)] can help with this identification.There are currently no biomarkers to enable accurate identification of these patients. The ESMO-MCBS scores provided are based on available data at the time of publication of this manuscript. These scores may change in the future, with new data being published, and updates will be provided on the ESMO website. The SOLAR-1 phase III, randomised, placebo-controlled trial evaluated the role of alpelisib, an oral inhibitor of the phosphoinositide 3-kinase alpha (PI3Ka) isoform, in combination with fulvestrant, for postmenopausal women and men who had previously been treated with an AI. [bib_ref] Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer, Andre [/bib_ref] In the PIK3CA-mutated cohort, alpelisib provided a PFS benefit of 11.0 months versus 5.7 months [hazard ratio (HR) for progression or death: 0.65; 95% confidence interval (CI) 0.50-0.85, P < 0.001]. OS data are not yet available. Toxicity was substantially increased in the alpelisib arm, especially hyperglycaemia, rash, gastrointestinal (GI) complaints (nausea, vomiting, loss of appetite, mucositis, diarrhoea) and fatigue, which lead to dose reductions/interruptions in around 70% of patients and discontinuations in 25%. Alpelisib, in combination with fulvestrant, was EMAapproved for use in this setting in July 2020. The ESMO-MCBS for alpelisib in combination with fulvestrant was established at three because this scoring system does not consider the percentages of dose alterations and/or discontinuations as a marker of important toxicity, which in the opinion of the ABC panel, is a shortcoming of the v1.1 of the scale (scheduled to be changed in the upcoming version 1.2 of the ESMO-MCBS). In view of the balance between efficacy and toxicity, it is crucial to carefully select patients who may be candidates for this treatment, considering the inclusion/exclusion criteria in SOLAR-1 and comorbidities, especially pre-existing diabetes and baseline HbA1c levels. It is also recommended that patients take nonsedating antihistamines to prevent rash at the start of therapy 59,60 ; these can be discontinued after 4 weeks as the risk of rash is primarily in the first 2 weeks of therapy. The ABC panel considers alpelisib a treatment option for patients with ERpositive/HER2-negative PIK3CA-mutated ABC, but in view of the higher benefit provided by CDK4/6 inhibitors, alpelisib plus ET should be used after CDK4/6 plus ET. Only 20 patients (6%) in SOLAR-1 had been previously exposed to a CDK4/6 inhibitor. However, this is a common issue in oncology, where standards of care might change during the course of a trial. Furthermore, the large phase II BYLieve trial has shown efficacy of alpelisib after CDK4/6 inhibitor use. [bib_ref] Alpelisib (ALP)  fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone..., Rugo [/bib_ref] Based on all of the available data, the ABC panel acknowledges that no data exist to determine the best sequence of therapies for this ABC subtype but believes that the most adequate sequence, in settings where availability of all drugs exist, is the use of a CDK4/6 inhibitor plus ET as first line, followed by alpelisib plus ET in patients with PIK3CAmutated tumours or everolimus plus ET in patients with PIK3CAwild type or unknown tumours. Section V. HER2-positive ABC

## Guideline statement loe/gor consensus
Anti-HER2 therapy should be offered early (as first line) to all patients with HER2-positive ABC, except in the presence of contraindications to the use of such therapy.

## I/a 98%
Patients progressing on an anti-HER2 therapy combined with a cytotoxic or endocrine agent should be offered additional anti-HER2 therapy with subsequent treatment, except in the presence of contraindications, since it is beneficial to continue suppression of the HER2 pathway. The choice of the anti-HER2 agent will depend on country-specific availability, the specific anti-HER2 therapy previously administered and the relapse-free interval. The optimal sequence of all available anti-HER2 therapies is currently unknown. The optimal duration of anti-HER2 therapy for MBC (i.e. when to stop these agents) is currently unknown.

## I/a 91%
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 rechallenge is available in case of progression.
Expert opinion/C 93% Patients who have received any type of (neo) adjuvant anti-HER2 therapy should not be excluded from clinical trials for HER2-positive ABC. These patients remain candidates for anti-HER2 therapies.

## I/b 100%
For highly selected patients a with ER-positive/ HER2-positive ABC, for whom ET  anti-HER2 therapy was chosen as first-line therapy, dual anti-HER2 blockade (with either pertuzumab  trastuzumab or lapatinib  trastuzumab) can be used since it provides a benefit in PFS. This decision must be balanced against the higher side-effects, higher costs and lack of OS benefit so far, as compared with ET  anti-HER2 monotherapy.

## I/b 80%
For patients with ER-positive/HER2-positive ABC, for whom ChT  anti-HER2 therapy was chosen as first-line therapy and provided a benefit, it is reasonable to use ET  anti-HER2 therapy as maintenance therapy after stopping ChT, although this strategy has not been studied in randomised trials. Duration of maintenance therapy should be until progression, unacceptable toxicity or patient request, and needs to be evaluated in clinical trials. There are no data to decide between singleagent anti-HER2 or dual blockade to combine with maintenance ET after stopping ChT in ER-positive/HER2-positive ABC. [bib_ref] Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer, Murthy [/bib_ref] This was achieved at the expense of increased toxicity, mostly diarrhoea and elevated aminotransferase levels of grade !3, but did not lead to frequent treatment discontinuation. Importantly, a reduction in the risk of CNS progression or death by 69% was observed in patients with stable brain metastases, while a confirmed objective response rate of 47% and a reduced risk of death by 51% were observed in patients with active brain metastases. [bib_ref] Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously..., Lin [/bib_ref] Trastuzumab deruxtecan (DS-8201), an ADC composed of trastuzumab, a cleavable tetrapeptide-based linker and a cytotoxic topoisomerase I inhibitor, demonstrated a response rate of 60.6% (95% CI 53.4-68.0) and an unprecedented median PFS of 16.4 months (95% CI 12.7dnot reached) in a phase II study of heavily pretreated patients (median six lines, range 2-27 lines, including trastuzumab and T-DM1). [bib_ref] Trastuzumab deruxtecan in previously treated HER2-positive breast cancer, Modi [/bib_ref] Trastuzumab deruxtecan was associated with a 13.6% risk of interstitial lung disease (ILD)/pneumonitis, fatal in 2.2% of cases, which needed appropriate and rapid diagnosis and treatment. For the safe utilisation of this compound in clinical practice (i.e. outside clinical trials), active surveillance and education regarding the signs and symptoms, for both patients and healthcare professionals, are crucial to enable rapid diagnosis and management. Confirmatory results from phase III studies are eagerly awaited and needed to accurately determine the role of this very promising drug in the HER2-positive ABC setting.
Both tucatinib and trastuzumab deruxtecan are FDAapproved and await evaluation by the EMA.
Another two agents which demonstrated formally positive (although clinically of questionable value) trial results in pretreated HER2-positive ABC patients are margetuximab (a monoclonal antibody) and neratinib. Margetuximab resulted in only a 0.9-month PFS prolongation (HR 0.76; 95% CI 0.59-0.98, P 14 0.033) compared with trastuzumab (both combined with ChT of physician's choice), no OS benefit and a good toxicity profile. [bib_ref] SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) ..., Rugo [/bib_ref] The potential role of CD16A genotype as a predictor of anti-HER2 antibody efficacy was explored and initial results were encouraging and deserve further evaluation. Margetuximab is currently under evaluation by the FDA and EMA and is not yet approved for use in ABC. Neratinib provided a small reduction in the risk of disease progression of 24% (95% CI 0.63-0.93; P 14 0.006, medians not provided), a marginal difference in PFS and no impact on OS (co-primary end point) compared with lapatinib (both in combination with capecitabine), at the cost of increased toxicity. [bib_ref] Neratinib  capecitabine versus lapatinib  capecitabine in patients with HER2 metastatic..., Saura [/bib_ref] Furthermore, the NALA study has a severe limitation of not having a comparator arm with trastuzumab plus capecitabine, which was previously shown to provide superior OS to lapatinib plus capecitabine in the firstand second-line settings. [bib_ref] CEREBEL (EGF111438): a phase III, randomized, open-label study of lapatinib plus capecitabine..., Pivot [/bib_ref] As of October 2020, neratinib in combination with capecitabine is FDA-approved for pretreated metastatic HER2-positive breast cancer, but is still under evaluation by the EMA in this setting.
It is especially important to emphasise that there are no comparative data between these four new anti-HER2 agents and that the question regarding the optimal sequence of treatments after trastuzumab, pertuzumab and T-DM1 is currently unknown.
Recent years have brought about the beginning of a significant change in the approach to triple-negative ABC with the recognition that both clinically and molecularly this is not one but many diseases. For most patients, ChT remains the only available non-investigational systemic treatment option for non-BRCA-mutated triple-negative ABC, with no specific recommendations regarding types of agents, with the possible exception of platinum compounds for patients with BRCA-mutated triple-negative ABC. However, immunotherapy has emerged as an option in the first-line setting for those with PD-L1 !1% in immune cells. IMpassion-130 is a phase III randomised, placebo-controlled trial that compared atezolizumab and nab-paclitaxel with nabpaclitaxel alone. [bib_ref] Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer, Schmid [/bib_ref] The study had co-primary end points of PFS and OS in the intention-to-treat (ITT) population and had a hierarchal design that allowed for evaluation of OS in the PD-L1-positive population if the OS in the ITT population was significantly improved from the addition of atezolizumab. In the ITT population, atezolizumab provided a benefit in PFS of 7.2 versus 5.5 months with a HR of 0.8 (95% CI 0.69-0.92, P 14 0.002). In the PD-L1 positive group, atezolizumab provided a PFS benefit of 7.5 versus 5 months with a HR of 0.62 (95% CI 0.49-0.78, P < 0.001). In the ITT population, there was no significant benefit in OS with the addition of atezolizumab; median OS was 21.3 months versus 17.6 months (HR 0.84; 95% CI 0.69-1.02, P 14 0.08). However, despite the hierarchal statistical design that precluded an OS analysis in the PD-L1-positive population if the OS in the ITT population was not significant, an analysis was conducted and presented, and showed an OS of 25 months versus 15.1 months favouring the atezolizumab arm. Based on these data, atezolizumab in combination with nabpaclitaxel was approved and may be considered an option in the first-line setting for de novo advanced/metastatic disease or disease that has developed at least 12 months after completion of (neo)adjuvant ChT in tumours that have PD-L1 expression !1% based on staining of the immune cells using the companion test of SP142 PD-L1 immunohistochemical assay (Ventana Medical Systems). [bib_ref] Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer, Schmid [/bib_ref] Recently, Section VI. Triple-negative ABC

## Guideline statement loe/gor consensus
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 favourable toxicity profile compared with docetaxel and is, therefore, an important treatment option.

## I/a 91%
For non-BRCA-associated triple-negative ABC, there are no data supporting different or specific ChT recommendations, besides platinum. Therefore, all ChT recommendations for HER2-negative disease also apply for triple-negative ABC.

## I/a 98%
The AR is a potential target in triple-negative ABC. There are, however, no standardised methods to assay AR. Limited data suggest a low level of efficacy for AR antagonist agents such as bicalutamide and enzalutamide. At this time, these agents should not be used in routine clinical practice. More definitive trials are needed, and research efforts must continue to optimise and standardise the determination of AR.

## Ii/d 85%
Atezolizumab  nab-paclitaxel is an option for first-line therapy for PD-L1-positive a triple-negative ABC, either de novo or at least 12 months since (neo)adjuvant ChT. ESMO-MCBS v1. Annals of Oncology these data were updated showing a PFS difference of 2.5 months and an OS difference of 7 months in the PD-L1positive population. [bib_ref] Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic..., Schmid [/bib_ref] More recently, at ASCO 2020 virtual meeting, data from the KEYNOTE-355 trial was presented. KEYNOTE-355 was a randomised double-blind, phase III trial evaluating the role of pembrolizumab plus ChT for previously untreated triple-negative ABC, which showed an improvement in PFS with the addition of pembrolizumab (9.7 versus 5.6 months; HR 0.65; CI 0.49-0.86, P 14 0.0012) for PD-L1-positive (combined positive score !10), triplenegative ABC. [bib_ref] KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab  chemotherapy versus placebo..., Cortes [/bib_ref] Checkpoint inhibitor monotherapy in later lines for triplenegative ABC is not recommended due to low response rates, as seen in the KEYNOTE-199 trial. [bib_ref] KEYNOTE-119: phase 3 study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for..., Cortes [/bib_ref] In patients with triple-negative ABC and a germline BRCA mutation, a polyadenosine diphosphate ribose polymerase (PARP) inhibitor is a preferred treatment option (please refer to section on hereditary ABC). In the small proportion of patients with both PD-L1-positive disease and BRCA1/2 mutations, the selection of immunotherapy or a PARP inhibitor for first-line treatment remains an area of debate.
No further data to support antiandrogen therapy for triple-negative ABC with expression of the androgen receptor has been published since ABC 4 and therefore it cannot be recommended for routine clinical use outside a clinical trial.
Sacituzumab govitecan-hziy has demonstrated promising activity in advanced lines for triple-negative ABC in a phase I/II study of 108 patients who had received a range of 2-10 prior treatments for metastatic disease. [bib_ref] Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer, Bardia [/bib_ref] The overall response rate was 33.3% (95% CI 24.6-43.1), with a median duration of response of 7.7 months (95% CI 4.9-10.8). Of the patients with a response to sacituzumab govitecan-hziy, 55.6% maintained their response for !6 months and 16.7% maintained their response for !12 months. Based on these preliminary results, the FDA has granted accelerated approval. However, phase III results are needed to confirm efficacy and establish the role of this agent in the management of triple-negative ABC. For ABC patients, results from germline genetic testing for a mutation in BRCA1/2 have therapeutic implications and should therefore be discussed with the patient and carried out as early as possible. Genetic testing should be guided by national/international guidelines, [bib_ref] Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer..., Paluch-Shimon [/bib_ref] should be proposed to all male breast cancer patients and may also be considered for all patients with triple-negative disease. Genes to be tested depend on personal and family history. However, at present, only germline mutations in BRCA1/2 have any clinical utility and therapeutic impact. Although BRCA1/2 are the most frequently mutated genes, testing for other additional moderate-to high-penetrance genes may be considered, if deemed appropriate by the geneticist/genetic counsellor, but it must be clarified to the patient that, at present, a mutation in another moderate-to high-penetrance gene has limited clinical implications in the setting of ABCdthis is an area of research with several ongoing clinical trials and emerging phase II data suggesting a benefit of PARP inhibitors (PARPis) in patients with germline PALB2 mutations. [bib_ref] TBCRC 048: a phase II study of olaparib monotherapy in metastatic breast..., Tung [/bib_ref] Since ABC 4, further data from the OlympiAD study suggested an OS benefit for olaparib when given in the firstline setting, with a median OS of 22.6 versus 14.7 months (HR 0.51; 95% CI 0.29-0.90, P 14 0.02) in a subgroup analysis of predefined stratification subgroups, [bib_ref] OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of..., Robson [/bib_ref] lending further support to existing data for a PFS benefit with olaparib in the ITT population of the study. [bib_ref] Olaparib for metastatic breast cancer in patients with a germline BRCA mutation, Robson [/bib_ref] The EMBRACA study 77 had a similar design to the OlympiAD study, comparing talazoparib with ChT monotherapy per physician's choice (capecitabine, eribulin, vinorelbine or gemcitabine). Most patients had not received prior platinum-based therapy. At a median follow-up of 11.2 months, PFS was longer in the talazoparib arm (8.6 versus 5.6 months, HR 0.54; 95% CI 0.41-0.71, P < 0.0001). Recently, at the American Association for Cancer Research (AACR) 2020 virtual meeting, an update was presented and no benefit was demonstrated in OS. [bib_ref] Talazoparib in germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results..., Litton [/bib_ref] However, it is worth noting that nearly 60% of patients in the control arm went on to receive a PARP inhibitor or platinum agent. At the ESMO 2019 annual meeting, data was presented from the BROCADE3 studydthe first phase III study in ABC comparing the addition of a PARPi (veliparib) to a platinum-containing regimen (paclitaxel and carboplatin) for germline BRCA-mutated ABC. [bib_ref] Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic..., Dieras [/bib_ref] The study demonstrated a PFS benefit favouring the veliparib arm, with a median PFS of 14.5 versus 12.6 months (HR 0.71; 95% CI 0.57-0.88, P 14 0.002) and a suggestion of sustained response at 2 and 3 years favouring the arm that was receiving maintenance veliparib but at the expense of significant toxicity. Peer-reviewed publication of the data is awaited, and further data are needed before this combination can be recommended for germline BRCAmutated ABC.
Further studies are also needed to clarify the value of PARPis in platinum-resistant disease, as well as their value compared with platinum compounds.

## Annals of oncology
Circulating DNA assays assess cell-free tumour DNA qualitatively and quantitatively for molecular alterations in a noninvasive fashion from a simple blood sample. Different technologies are available from single-gene assay by quantitative polymerase chain reaction (qPCR) to whole genome sequencing by next-generation sequencing (NGS). [bib_ref] Liquid biopsies: genotyping circulating tumor DNA, Diaz [/bib_ref] [bib_ref] Liquid biopsy in breast cancer: a comprehensive review, Alimirzaie [/bib_ref] Standardisation is a critical point, especially for NGS-based analysis. There is insufficient evidence of clinical validity and utility for the majority of circulating tumour DNA (ctDNA) assays in advanced cancer. [bib_ref] Circulating tumor DNA analysis in patients with cancer: American Society of Clinical..., Merker [/bib_ref] Thus, ctDNA assessment is not recommended for demonstration of disease progression in ABC. However, for single biomarkers using targeted assays, ctDNA assessment is an option for the detection of PIK3CA mutations for selection of patients eligible for alpelisib. The progress of precision medicine has helped to describe around 40 recurrent driver alterations in breast cancer. ESMO has recently developed a scale for clinical actionability of molecular targets (ESCAT) to interpret the targetability of genomic alterations in the context of clinical practice. [bib_ref] Genomic alterations in breast cancer: level of evidence for actionability according to..., Condorelli [/bib_ref] The aim is to help clinicians to prioritise treatment after NGS results. The tool ranks genomic alterations in tiers, based on the strength of their clinical validation (from I to V and X). ERBB2 amplification, germline deleterious BRCA 1 and 2 mutations and PIK3CA mutations are all classified as tier IA. The majority of PIK3CA mutations affect hot spots i.e. the three most frequent in exons 9 and 20 (exon 9: E542K, E545K, helicase domain; exon 20: H1047R, kinase domain). They are present in up to 40% of metastatic luminal breast cancer. The mutations activate the alpha isoform of PI3K and drive oncogenicity. There were three sub-analyses of the SOLAR-1 trial 58 which showed that the benefit seen with alpelisib was independent of the type of PIK3CA test, i.e. tissue biopsy from the primary or the metastasis, liquid or tissue biopsy, NGS or targeted PCR test. [bib_ref] Abstract CT142: prevalence of PIK3CA mutations in patients with hormone receptor-positive, human..., Rugo [/bib_ref] [bib_ref] Abstract GS3-08: Alpelisib  fulvestrant for advanced breast cancer: subgroup analyses from..., Juric [/bib_ref] [bib_ref] Abstract P4-10-04: clinical outcomes of alpelisib in hormone receptor-positive, human epidermal growth..., Juric [/bib_ref] If treatment with the PI3K inhibitor, alpelisib, is available, patients should be tested for PIK3CA mutation (in exons 9 and 20) in tissue (metastasis or primary) and/or by ctDNA testing in blood. Patients who do not have an available archival tissue sample and have an uninformative result using the liquid biopsy test could consider undergoing a new biopsy for PIK3CA mutation testing.
Acquisition of ESR1 mutations, frequent in ABC patients previously treated by AIs (20%-40%), is one of the mechanisms of resistance to hormonal therapies. The consequence is a ligand-independent, constitutive activity of ER. To assess the impact of the presence of ESR1 mutations in plasma samples of ABC patients, the post hoc prospectiveretrospective analysis of the SOFEA trial failed to demonstrate a statistically significant impact of ESR1 mutations on response to AI versus fulvestrant (interaction test between the two regimens P 14 0.07). The analysis of the PALOMA-3 trial showed that the presence of plasma ESR1 mutations had no impact on response to palbociclib (interaction test between the two regimens P 14 0.74). [bib_ref] Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer, Fribbens [/bib_ref] Despite promising preclinical data and statistical trends, the ESCAT scale for ESR1 mutations is tier II. [bib_ref] Genomic alterations in breast cancer: level of evidence for actionability according to..., Condorelli [/bib_ref] Therefore, ESR1 mutation status assessment is not ready for routine clinical use and is not recommended, either for demonstration of disease progression or selection of hormonal treatment (such as a switch from AI to fulvestrant).
Increased counts of tumour-infiltrating lymphocytes (TILs) are prognostic for survival in triple-negative breast cancer (TNBC), making this disease a potential target for immunotherapy.Based on the results of the IMpassion-130 trial, [bib_ref] Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer, Schmid [/bib_ref] atezolizumab was approved with the Ventana PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry (IHC) assay. Therefore, PD-L1 status should be tested in cases of first-line triple-negative ABC if treatment with immune checkpoint inhibitors is available. Several IHC assays are available to assess PD-L1 status. 89 SP263 (Ventana) and 22-C3 (Dako), both of which are widely used in pathology laboratories for other tumour types, have been evaluated for their clinical validity in the context of the IMpassion-130 trial but failed to reproduce SP142 clinical validity. [bib_ref] Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic..., Rugo [/bib_ref] Thus, PD-L1 status by SP142 is the companion test for the use of atezolizumab in combination with a taxane for first-line therapy in triple-negative ABC, with a cut-off of 1% positive staining on immune cells. It is critical for medical oncologists and pathologists to know the available assays and their relevance to the therapeutic options in order to develop a workflow for IHC testing.

## Section viii. continued

## Guideline statement loe/gor consensus
Patients with low (1%-10%) ERpositive (and PgR-positive), HER2-negative ABC should not be considered for ET exclusively. Patients with low (1%-10%) ERpositive (and PgR-positive), HER2-negative ABC can be considered as patients with triple-negative ABC for clinical trials.

## Iii/b 95%
If an ABC patient presents with a tumour with MSI-H/MMR-D, treatment with an anti-PD-1 agent is a possible consideration.
Expert opinion/C Yes: 41% Abstain: 10% Insufficient data: 49%
If an ABC patient presents with a tumour with an NTRK fusion, treatment with a TRKi is a possible consideration. Patients must be informed about the amount of data available for ABC specifically. Research on the best companion diagnosis tools and techniques is needed. Prospective registries should be created to collect data from all patients treated with these innovative approaches after proper consent.

## I/b
Yes: 29% Abstain: 24% Insufficient data: 47%
In green, NEW ABC 5 statements. ABC, advanced breast cancer; consensus, percentage of panel members in agreement with the statement; ctDNA, circulating tumour DNA; ER, estrogen receptor; ET, endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LoE, level of evidence; MMR-D, mismatch repair deficiency; MSI-H, microsatellite instability-high; NGS, nextgeneration sequencing; NTRK, neurotrophic receptor tyrosine kinase; PD, disease progression; PD-1, programmed cell death protein 1; PgR, progesterone receptor; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3kinase catalytic subunit alpha; TRKi, tropomyosin receptor kinase inhibitor.
Tumours with staining of ER <1% and progesterone receptor (PgR) <1% and with HER2-negative results by IHC and/ or in situ hybridisation are defined as TNBC. [bib_ref] College of American Pathologists Clinical Practice Guideline focused update, Wolff [/bib_ref] Patients with a low (1%-10%) expression of hormone receptors and HER2negative account for 2%-3% of breast cancers. They may share morphological (high grade, poor differentiation) [bib_ref] Low ER breast cancer: is this a distinct group?, Gloyeske [/bib_ref] and biological features [bib_ref] Effect of ASCO/CAP guidelines for determining ER status on molecular subtype, Deyarmin [/bib_ref] [bib_ref] Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that..., Iwamoto [/bib_ref] with TNBC and experience a similarly poor survival. [bib_ref] Survival outcomes in breast cancer patients with low estrogen/progesterone receptor expression, Balduzzi [/bib_ref] [bib_ref] Which threshold for ER positivity? a retrospective study based on 9639 patients, Yi [/bib_ref] A meta-analysis assessing the survival benefit of ET for ER-low (<10%) primary breast cancer showed lower endocrine responsiveness compared with ERpositive tumours [odds ratio (OR) 0.52, P 14 0.034]. [bib_ref] Borderline ER-positive primary breast cancer gains no significant survival benefit from endocrine..., Chen [/bib_ref] Recently, the ASCO-College of American Pathologists (CAP) guidelines acknowledged that patients with tumours between 1% and 10% of ER staining represent a new reporting category, stipulating the lack of data concerning benefit from ET and the proximity to ER-negative breast cancer of this patient group. [bib_ref] Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP Guideline update, Allison [/bib_ref] We recommend that this strategy is also adopted for ABC patients with a low ER-positive status.

## Section ix. specific sites of metastases

# Guideline statement
LoE/GoR Consensus

## Bone metastases
Radiological assessments are required in patients with persistent and localised pain due to bone metastases to determine whether there are impending or actual pathological fractures. If a fracture of a long bone or vertebrae is likely or has occurred, an orthopaedic assessment is required as the treatment of choice may be surgical stabilisation, which is generally followed by RT. In the absence of a clear fracture risk, RT is the treatment of choice.

## I/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 the 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/stabilisation is feasible or indicated, emergency RT is the treatment of choice and vertebroplasty is also an option.

## I/b 100%
Regarding the use of bone-targeted agents (bisphosphonate, denosumab), the ABC panel endorses the ESMO CPG 99 related to this subject.
n/a 100%

## Brain metastases
Patients with a single or a small number of potentially resectable brain metastases should be treated with surgery or radiosurgery. Radiosurgery is also an option for some unresectable brain metastases.

## I/b 92%
If surgery/radiosurgery is performed it may be followed by WBRT, but this should be discussed in detail with the patient, balancing the longer duration of intracranial disease control and the risk of neurocognitive effects.

## I/c 72%
HER2-positive ABC and brain metastases Because patients with HER2-positive ABC and brain metastases can live for several years,
[formula] I/A 89% [/formula]

## Continued

## Section ix. continued
Guideline statement LoE/GoR Consensus consideration of long-term toxicity is important and less toxic local therapy options (e.g. stereotactic RT) should be preferred to WBRT, when available and appropriate (e.g. in the setting of a limited number of brain metastases). In patients with HER2-positive ABC who develop brain metastases with stable extracranial disease, systemic therapy should not be changed.

## I/d 95%
For patients with HER2-positive ABC where brain metastases are the only site of recurrence, the addition of ChT to local therapy is not known to alter the course of the disease and is not recommended. It is recommended to re-start the anti-HER2 therapy (trastuzumab) if this had been stopped.
[formula] I/D I/B 83% 83% [/formula]
For patients with HER2-positive ABC with progressive brain metastases as the predominant site of disease burden, if no further relevant local therapy options are available, a change in systemic therapy is a reasonable option, preferably in clinical trials.

## Iii/a 85%
Radionecrosis after stereotactic RT for brain metastases is an uncommon complication that may occur, especially with longer survival and follow-up, and in particular in cases of re-irradiation. Differential diagnosis with tumour progression is often difficult. Treatment of symptomatic patients with a course of high-dose steroids is the first treatment of choice. If no response, bevacizumab may be used, as an option to decrease the surrounding oedema, usually at a dose of 7.5 mg/kg every 2 weeks for a median of 4 cycles. Prospective randomised trials are needed to further validate this option.

## Iii/b 61%

## Lmd
There is no accepted standard of care for breast cancer LMD. The choice of treatment (RT, intra-CSF therapy, systemic therapy, supportive care) should consider prognostic evaluation and multidisciplinary discussion.

## Annals of oncology
The ABC panel decided to endorse the ESMO Clinical Practice Guideline (CPG) related to the use of bone-targeted agents (bisphosphonate, denosumab), which replace all previous statements regarding this subject. [bib_ref] Bone health in cancer: ESMO Clinical Practice Guidelines, Coleman [/bib_ref] Leptomeningeal disease (LMD) is a rare complication of breast cancer with a 5% incidence rate. LMD carries a poor prognosis, with a median OS of approximately 4 weeks which can be prolonged to a few months in some patients with aggressive multimodal treatment. [bib_ref] Leptomeningeal carcinomatosis in patients with breast cancer, Franzoi [/bib_ref] Its diagnosis is based on clinical evaluation, cerebrospinal magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. The European Association of Neuro-Oncology (EANO) and ESMO have proposed classifying LMD using two major criteria: presence (type I) or not (type II) of positive CSF and neuroimaging findings. [bib_ref] EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with..., Le Rhun [/bib_ref] The same authors have proposed defining the therapeutic plan based on the presentation of the disease [nodular (A) or linear (B) or mixed (C) meningeal involvement, positive CSF cytology, presence or not of extracerebral disease, etc.] and taking into account the patient's life expectancy. [bib_ref] How we treat patients with leptomeningeal metastases, Le Rhun [/bib_ref] Available active treatment options are RT, intra-CSF therapy and systemic therapy. The choice of treatment should always involve multidisciplinary discussion. Currently, there is no accepted standard of care for breast cancer LMD and recommendations are essentially expert opinion-based. The EANO-ESMO CPG recommends considering focal RT for circumscribed, notably symptomatic lesions, and whole-brain RT (WBRT) for extensive nodular or symptomatic linear LMD. [bib_ref] EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with..., Le Rhun [/bib_ref] The use of intrathecal therapy is controversial. It is recommended in cases where tumour cells are present in the CSF; it is optional in cases of linear metastatic meningeal disease. [bib_ref] Leptomeningeal carcinomatosis in patients with breast cancer, Franzoi [/bib_ref] [bib_ref] EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with..., Le Rhun [/bib_ref] [bib_ref] How we treat patients with leptomeningeal metastases, Le Rhun [/bib_ref] This strategy is not recommended in patients with obstructive hydrocephalus (RT can be used to restore CSF flow and successful restoration should be checked before the use of any intrathecal treatment) or in patients with nodular meningeal metastases only. Three agents are commonly used for intrathecal treatment of LMD: methotrexate, cytarabine (including liposomal cytarabine) or thioTEPA. [bib_ref] Leptomeningeal carcinomatosis in patients with breast cancer, Franzoi [/bib_ref] [bib_ref] EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with..., Le Rhun [/bib_ref] [bib_ref] How we treat patients with leptomeningeal metastases, Le Rhun [/bib_ref] Their use can cause a spectrum of toxicities ranging from myelosuppression to neurotoxicity. Methotrexate is the most commonly used agent. Neurotoxicity is increased with the use of methotrexate and RT and this combination is not recommended. Other agents, such as trastuzumab for HER2-positive disease, are under evaluation. Intrathecal therapy can be considered in cases where systemic disease is stable. However, two prospective trials have shown that the addition of intrathecal to systemic therapy has no OS or QoL advantage. [bib_ref] How we treat patients with leptomeningeal metastases, Le Rhun [/bib_ref] Retrospective data suggest some activity of different agents used systemically. [bib_ref] Leptomeningeal carcinomatosis in patients with breast cancer, Franzoi [/bib_ref] 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/a 100%
Chest wall and regional recurrences should be treated with surgical excision when feasible with limited risk of morbidity.

## Ii/a 97%
Locoregional RT is indicated for patients not previously irradiated.

## Ii/a 97%
For patients previously irradiated, reirradiation of all or part of the chest wall may be considered in selected cases.
Expert opinion/C 97% In addition to local therapy (surgery and/or RT), in the absence of distant metastases, the use of systemic therapy (ChT, ET and/ or anti-HER2 therapy) should be considered.

## I/b 95%
ChT after first local or regional recurrence improves long-term outcomes in ERnegative disease and can be used.

## I/b 95%
ET in this setting improves long-term outcomes for ER-positive disease and should be used. For triple-negative LABC, anthracycline-and taxane-based ChT is recommended as initial treatment. A platinum can be combined with the taxane.
[formula] I/B 95% [/formula]

## I/a 85%
For HER2-positive LABC, concurrent taxane and anti-HER2 therapy is recommended since it increases the rate of pCR.

## I/a 92%
For HER2-positive LABC, anthracycline-based ChT should be incorporated into the treatment regimen.

## I/a 72%
Continued Section XI. Continued

## Guideline statement loe/gor consensus
When an anthracycline is given, it should be administered sequentially with the anti-HER2 therapy.

## I/a 87%
For patients with HER2-positive LABC (inflammatory or non-inflammatory), without distant metastases, who are in complete remission after appropriate preoperative systemic therapy and appropriate locoregional therapy, and being treated with a potential curative intent, the approved adjuvant duration of 1 year of anti-HER2 therapy should be used.

## I/a 85%
Following effective preoperative systemic therapy with or without RT, surgery will be possible in many patients. This will consist of mastectomy with axillary dissection in the majority of cases, but in selected patients with a good response, BCS may be possible.

## Ii/a 98%
In patients with axillary low burden of disease at presentation (previously cN0-cN1) with complete response after systemic treatment (ycN0), SLNB can be an option, provided all the recommendations for sentinel node after primary systemic treatment are followed (i.e. dual tracer, clipping/marking positive nodes, minimum of three sentinel nodes). Annals of Oncology ensure adequate protection of cancer patients. The ABC panel strongly supports this position and states that no restrictions should be in place that limit cancer patients' access to adequate pain control. Recent data on cannabidiol for medical use has not yet substantiated claims indicating that it is effective in cancer pain management to the same level as morphineand more research is needed. [bib_ref] Cannabis sativa: much more beyond D(9)-tetrahydrocannabinol, Alves [/bib_ref] Many therapies for ABC are associated with estrogen deprivation and patients often suffer from menopausal symptoms such as hot flushes, night sweats, sleep disturbances, fatigue, arthralgia, cognitive impairment, depression and vaginal dryness, as well as impaired sexual functioning (e.g. loss of sexual desire, dyspareunia). Hormone replacement therapy is contraindicated due to the endocrine character of the disease and should not be used to treat complaints. Nevertheless, the final decision belongs to the patient, after adequate information, since in some cases these symptoms are impacting significantly on QoL. [bib_ref] Increased risk of recurrence after hormone replacement therapy in breast cancer survivors, Holmberg [/bib_ref] [bib_ref] Hormone replacement therapy after breast cancer: 10 year follow up of the..., Fahlen [/bib_ref] For menopausal symptoms in general, mind-body interventions, physical training and cognitive behavioural therapy should be recommended as effective non-pharmacological treatment options. [bib_ref] Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatmentinduced menopausal..., Duijts [/bib_ref] [bib_ref] Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer..., Mann [/bib_ref] [bib_ref] Mind-body interventions for vasomotor symptoms in healthy menopausal women and breast cancer..., Stefanopoulou [/bib_ref] [bib_ref] Physical activity for women with breast cancer after adjuvant therapy, Lahart [/bib_ref] [bib_ref] Randomized controlled trial of increasing physical activity on objectively measured and self-reported..., Hartman [/bib_ref] To control hot flushes, valid alternatives are venlafaxine, oxybutynin, gabapentin and clonidine. [bib_ref] Venlafaxine in management of hot flashes in women with breast cancer: a..., Ramaswami [/bib_ref] [bib_ref] Informing hot flash treatment decisions for breast cancer survivors: a systematic review..., Johns [/bib_ref] [bib_ref] Efficacy and safety of gabapentin and pregabalin in patients with vasomotor symptoms:..., Shan [/bib_ref] [bib_ref] Oxybutynin vs placebo for hot flashes in women with or without breast..., Leon-Ferre [/bib_ref] Sleep disturbances may be treated with melatonin. [bib_ref] A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on..., Chen [/bib_ref] [bib_ref] The effect of melatonin on sleep and quality of life in patients..., Innominato [/bib_ref] There is no convincing evidence that phytotherapeutic drugs may improve menopausal symptoms. Possible drug interactions must be considered.

## Iii/b 62%
Sexuality is an experience on many levels and is not confined to the act of intercourse. ABC patients frequently experience impaired sexual health and need specific attention. A recent retrospective study showed that breast cancer patients are more affected than patients with ovarian cancer or healthy controls: decreased or no interest in sexual activity was frequently reported with a significant association to less satisfaction and more discomfort (dyspareunia); however, the lack of desire was not associated with global health status, QoL or the ability to experience orgasms; estrogen deprivation (gonadotropin-releasing hormone agonists, AIs) seemed to have more impact than tamoxifen. [bib_ref] Sexual activity and quality of life in patients after treatment for breast..., Mayer [/bib_ref] Dyspareunia is often caused by vaginal dryness. The first choice for treating vaginal dryness and soreness are hormone-free lubricants (e.g. water-based gel, hyaluronic acid gel). [bib_ref] Is vaginal hyaluronic acid as effective as vaginal estriol for vaginal dryness..., Stute [/bib_ref] [bib_ref] A comparison between vaginal estrogen and vaginal hyaluronic for the treatment of..., Serati [/bib_ref] [bib_ref] Postmenopausal vulvovaginal atrophy (VVA) is positively improved by topical hyaluronic acid application...., Origoni [/bib_ref] If hormone-free measures are not effective, low-dose estriol-containing vaginal medication may be used. [bib_ref] Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor) on inflammatory and..., Donders [/bib_ref] [bib_ref] Vaginal estriol-lactobacilli combination and quality of life in endocrine-treated breast cancer, Buchholz [/bib_ref] [bib_ref] Management of urogenital atrophy in breast cancer patients: a systematic review of..., Mazzarello [/bib_ref] [bib_ref] Quality of life and sexual function of naturally postmenopausal women on an..., Caruso [/bib_ref] The value of local testosterone application and of invasive measures like vaginal laser or hyaluronic acid injections is still unclear. [bib_ref] Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased..., Melisko [/bib_ref] [bib_ref] Efficacy of injecting platelet concentrate combined with hyaluronic acid for the treatment..., Hersant [/bib_ref] [bib_ref] Laser-based devices for female genitourinary indications: position statements from the European Society..., Romero-Otero [/bib_ref] In summary, gynaecological and sexual symptoms are important challenges for most ABC patients. In particular, even in an anonymous setting, patients are often too shy to report their problems regarding impaired sexual life. Therefore, active verbalisation of gynaecological and sexual symptoms in an adequate and trustful atmosphere is a mandatory part of follow-up visits. Openly addressing misconceptions and sexual challenges after treatment, as well as educating patients, have been shown to improve QoL. When life expectancy is limited, physical contact, affection, emotional communication and comfort are particularly important. Standardised instruments (questionnaires) may help to assess the grade of impairment. [bib_ref] The Female Sexual Functioning Index (FSFI): evaluation of acceptability, reliability, and validity..., Bartula [/bib_ref] [bib_ref] Development and validation of a sexual relations satisfaction scale in patients with..., Mancha [/bib_ref] [bib_ref] Communication about sexual health in breast cancer: what can we learn from..., Reese [/bib_ref] [bib_ref] Patient-reported barriers and facilitators to seeking and accessing support in gynecologic and..., Dai [/bib_ref] [bib_ref] Fallowfield's sexual activity questionnaire in women with without and at risk of..., Atkins [/bib_ref] At first recurrence, one out of four patients is younger than 50 years old and premenopausal. Therefore, issues of fertility and contraception must be discussed, and for the latter, only hormone-free contraceptives can be recommended. [bib_ref] Contraception in cancer survivors -an expert review Part I. Breast and gynaecological..., Gompel [/bib_ref] Section XIII. Integrative medicine

## Guideline statement loe/gor consensus
Alternative therapies (i.e. therapies used instead of scientifically-based medicines) are not recommended in any phase or stage of cancer treatment.
n/a/E 100% Breast cancer centres/units/departments should be aware that the majority of their patients would like to be informed about CIM and that many of them are using it. Physicians should actively ask for information about its use in view of the potential deleterious interactions with specific anticancer therapies. If complementary therapies are not available at the centre, certified contacts should be available to promote referral to practitioners qualified in the therapies people are interested in receiving.
Expert opinion/C 100% Some complementary therapies have the potential to reduce disease symptom burden and/or side-effects of anticancer therapies, and therefore improve the QoL of ABC patients.
Expert opinion/C 100% Evidence suggests beneficial effects of the following methods, which can therefore be used: Physical exercise/sport (equivalent to 3-5 hours of moderate walking per week) improves QoL, cardiorespiratory fitness, physical performance and fatigue, and it may also improve DFS and OS. MBSR programmes, hypnosis and yoga may improve QoL and fatigue, and help reduce anxiety, distress and some sideeffects of anticancer therapies. Acupuncture may help against ChTinduced nausea and vomiting, fatigue and hot flushes.

## I/b 100%
Methods with no or unfavourable effects The following methods of alternative medicine are not recommended in ABC since available evidence shows no effect at best, or even association with worse outcome: Antioxidant supplements Drugs outside the approved indication (e.g. methadone) Herbs including Chinese herbal medicine Orthomolecular substances (selenium, zinc, etc.) Oxygen and ozone therapy Proteolytic enzymes, thymic peptides Phytoestrogens (soy food, isoflavones)

## Conclusions and future directions
ABC guidelines provide a useful tool for the management of ABC in clinical practice. Each guideline has an associated LoE, GoR and percentage of consensus. Additionally, v1.1 of the ESMO-MCBS 13 was applied to drugs approved by the EMA after 2016. As usual, if additional new agents are approved by the EMA before the next ABC Consensus Conference, the ESMO-MCBS will be applied and the result will be made available as an e-update to the present guidelines. We acknowledge that in many areas of the world, some of these guidelines may not be implemented due to the existence of disparities in access. It is the mission of the ABC Global Alliance 142 to fight for better outcomes for all ABC patients around the world. For this goal to be achieved, efforts must continue not only in research but also in public policy to ensure equal access to multidisciplinary, specialised care, including anticancer, palliative and end-of-life care, and full implementation of these guidelines. We emphasise again that reimbursement rules in all countries should be patient-centred and be an incentive to, not work against, the clinical implementation of high-quality international guidelines. Clinical trials and consequent approval and reimbursement must not continue to exclude certain groups of patients, such as premenopausal women and men, which keep seeing their treatment options reduced in many countries.
At a time when the world is facing the COVID-19 pandemic, the ABC community must unite to maintain or increase the resources needed to face the ever-rising cancer 'epidemic', which is responsible for 18.1 million new cases and 9.6 million deaths annually worldwide, with half a million deaths annually due to ABC. [bib_ref] Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for..., Bray [/bib_ref]