SPECIAL ARTICLE

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

F. Cardoso1*, S. Paluch-Shimon2, E. Senkus3, G. Curigliano4, M. S. Aapro5, F. André6, C. H. Barrios7, J. Bergh8, G. S. Bhattacharyya9, L. Biganzoli10, F. Boyle11, M.-J. Cardoso1,12, L. A. Carey13, J. Cortés14,15, N. S. El Saghir16, M. Elzayat17, A. Eniu18, L. Fallowfield19, P. A. Francis20, K. Gelmon21, J. Gligorov22, R. Haidinger23, N. Harbeck24,X.Hu25, B. Kaufman26, R. Kaur27, B. E. Kiely28, S.-B. Kim29, N. U. Lin30, S. A. Mertz31, S. Neciosup32, B. V. Offersen33, S. Ohno34, O. Pagani35, A. Prat36,37,38, F. Penault-Llorca39,40, H. S. Rugo41, G. W. Sledge42, C. Thomssen43, D. A. Vorobiof44, T. Wiseman45,B.Xu46, L. Norton47, A. Costa48,49 & E. P. Winer30

1Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon, Portugal; 2Sharett Division of Oncology, Hadassah University Hospital, Jerusalem, Israel; 3Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; 4Department of Oncology and Hemato-Oncology, European Institute of Oncology, IRCCS, Division of Early Drug Development, University of Milan, Milan, Italy; 5Breast Center, Clinique de Genolier, Genolier, Switzerland; 6Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; 7Latin American Cooperative Oncology Group (LACOG), Grupo Oncoclínicas, Porto Alegre, Brazil; 8Department of Oncology-Pathology, Karolinska Institute & University Hospital, Stockholm, Sweden; 9Department of Medical Oncology, Salt Lake City Medical Centre, Kolkata, India; 10Department of Medical Oncology, Nuovo Ospedale di Prato e Istituto Toscano Tumori, Prato, Italy; 11The Pam McLean Centre, Royal North Shore Hospital, St Leonards, Australia; 12Nova Medical School, Lisbon, Portugal; 13Department of Hematology and Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, USA; 14IOB Institute of Oncology, Quiron Group, Madrid & Barcelona; 15Department of Oncology, Vall d’Hebron Institute of Oncology, Barcelona, Spain; 16Division of Hematology Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 17Europa Donna, The European Breast Cancer Coalition, Milan, Italy; 18Interdisciplinary Oncology Service (SIC), Riviera-Chablais Hospital, Rennaz, Switzerland; 19SHORE-C, Brighton & Sussex Medical School, University of Sussex, Brighton, UK; 20Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; 21Medical Oncology Department, BC Cancer Agency, Vancouver, Canada; 22Breast Cancer Expert Center, University Cancer Institute APHP, Sorbonne University, Paris, France; 23Brustkrebs Deutschland e.V., Munich, Germany; 24Breast Centre, Department of Obstetrics and Gynaecology, University of Munich (LMU), Munich, Germany; 25Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 26Department of Oncology, Sheba Medical Center, Ramat Gan, Israel; 27Breast Cancer Welfare Association Malaysia, Petaling Jaya, Malaysia; 28NHMRC Clinical Trials Centre, Sydney Medical School, Sydney, Australia; 29Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea; 30Susan Smith Center for Women’s Cancers e Breast Oncology Center, Dana-Farber Cancer Institute, Boston, USA; 31Metastatic Breast Cancer Network, Inverness, USA; 32Department of Medical Oncology, National Institute of Neoplastic Diseases, Lima, Peru; 33Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; 34Breast Oncology Centre, Cancer Institute Hospital, Tokyo, Japan; 35Medical School, Geneva University Hospital, Geneva, Switzerland; 36Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona; 37Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona; 38Department of Medicine, University of Barcelona, Barcelona, Spain; 39Department of Biopathology, Centre Jean Perrin, Clermont-Ferrand; 40University Clermont Auvergne/INSERM U1240, Clermont-Ferrand, France; 41Breast Oncology Clinical Trials Education, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA; 42Division of Oncology, Stanford School of Medicine, Stanford, USA; 43Department of Gynaecology, Martin Luther University Halle-Wittenburg, Halle, Germany; 44Oncology Research Unit, Belong.Life, Tel Aviv, Israel; 45Department of Applied Health Research in Cancer Care, The Royal Marsden Hospital NHS Foundation Trust, London, UK; 46Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China; 47Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, USA; 48European School of Oncology, Milan, Italy; 49European School of Oncology, Bellinzona, Switzerland

Available online 23 September 2020

Key words: ABC, advanced, breast cancer, ESO-ESMO, guidelines, metastatic

INTRODUCTION incurable disease, with a median overall survival (OS) of 3,4 For the purpose of advanced breast cancer (ABC) guidelines, about 3 years and a 5-year survival rate of around 25%, ABC comprises both inoperable locally advanced breast even in countries without major accessibility problems. cancer (LABC) and metastatic breast cancer (MBC).1,2 Survival is strongly related to breast cancer subtype, with Advanced/metastatic breast cancer remains a virtually the major advances seen in human epidermal growth factor receptor 2 (HER2)-positive ABC.5-9 ABC is a treatable disease with several available therapies and many others in devel-

*Correspondence to: Dr Fatima Cardoso, Breast Unit, Champalimaud Clinical opment. However, their impact on survival and quality of 3 Center, Av. De Brasília s/n, 1400-038 Lisbon, Portugal. life (QoL) of ABC patients has been slow and different for E-mail: [email protected] (F. Cardoso). de novo versus recurrent ABC, with the latter becoming much harder to treat in recent years.10 Outcomes are also 5 These Guidelines were developed by the European School of Oncology strongly related to access to the best available care, which (ESO) and European Society for Medical Oncology (ESMO). includes not only the most efficacious medicines, but also 0923-7534/© 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved. multidisciplinary, specialised care, implementation of

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 1 Annals of Oncology F. Cardoso et al. guidelines, high-quality pathology, imaging and radio- at the conference and supporting references. In addition, therapy (RT). Lack of any of these crucial pillars of modern the ESMO-MCBS version 1.113 (v1.1) was used to calculate oncological care inevitably results in substantially worse scores for new therapies/indications approved by the outcomes, as exemplified in the New Zealand report “Iam European Medicines Agency (EMA) since the last ABC still here”.11 While mortality rates have decreased in the guidelines, as well as a few new therapies that have been majority of developed countries, most deaths are currently scored but are still under EMA evaluation (https://www. seen in less developed societies, and access issues explain esmo.org/Guidelines/ESMO-MCBS). A table with these the majority of these inequalities.12 scores is included (see supplementary Table S1, available at The application of the ESMO-Magnitude of Clinical https://doi/org/10.1016/j.annonc.2020.09.010). Benefit Scale (ESMO-MCBS)13 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 METHODOLOGY therapies have been developed, providing hope that a Before the ABC 5 conference, preliminary recommendation substantial improvement in the median OS of ABC patients statements on the management of ABC were prepared might soon be seen. However, some clinically relevant based on available published data and following the questions are still unanswered and may be difficult to ESMO guidelines methodology (see http://www.esmo.org/ address through traditional clinical trials, such as the best Guidelines/ESMO-Guidelines-Methodology). These recom- sequence of therapies for each individual patient. The mendations were circulated to all 44 panel members by application of computer analytics to big data and real-world e-mail for comments and corrections on content and data is one of the potential ways forward. In-depth dis- wording. A final set of recommendations was presented, cussion must take place regarding the impact of this ‘new’ discussed and voted upon during the consensus session of level of evidence (LoE) in current treatment guidelines and ABC 5. All panel members were instructed to vote on all their integration with clinical trial data. questions, and any members with a potential conflict of The 5th International Consensus Conference for interest or who did not feel comfortable answering the Advanced Breast Cancer (ABC 5) took place in Lisbon, question (e.g. due to lack of expertise in a particular field) Portugal, on 14th-16th November 2019, bringing together were instructed to vote ‘abstain’. Additional changes in the 1500 participants from 94 countries worldwide, including wording of statements were made during the session. As health professionals, patient advocates and journalists. some important studies were presented a few weeks later Since its first edition in 2011, the main goal of the ABC at the 2019 San Antonio Breast Cancer Symposium, conference has been the development of high-quality in- particularly for new anti-HER2 therapies, three additional ternational consensus guidelines for the management of statements were developed after the ABC 5 conference, ABC. These guidelines are based on available evidence and circulated for revision and voted by all panel members. on expert opinion when evidence is lacking. They represent Statements related to the management of side-effects and the best management options for ABC patients globally, difficult symptoms, included under the supportive and assuming accessibility to all available therapies. Adaptation palliative care section, were not voted on during the of these guidelines is often needed in settings where access consensus session, but were discussed and unanimously to care is suboptimal. agreed by e-mail, and are therefore considered to have The ABC 5 guidelines are jointly developed by ESO and 100% consensus agreement. Previous ABC recommenda- ESMO, and have been endorsed by several international tions that did not require update or only minor changes oncology organisations, such as the European Society of were not re-voted but were reviewed by all panel members Breast Cancer Specialists (EUSOMA), European Society for by e-mail and remain valid. To provide a full overview of all Radiotherapy and Oncology (ESTRO), European Society of ABC guidelines currently approved, this manuscript includes Gynaecological Oncology (ESGO), Union for International a list of all recommendations per subject, highlighting those Cancer Control (UICC), Senologic International Society (SIS)/ that were discussed, voted and approved in ABC 5. How- International School of Senology (ISS), Federación Latino- ever, this manuscript only describes the evidence for newly Americana de Mastologia (FLAM), European Oncology developed or updated guidelines. We refer the reader to Nursing Society (EONS), European Society of Surgical the manuscripts of previous ABC guidelines for the detailed Oncology (ESSO), Arbeitsgemeinschaft Gynäkologische explanation of guidelines not updated/added during ABC 5. Onkologie e.V. (AGO) and the International Society of Supplementary Table S2, available https://doi/org/10. Geriatric Oncology (SIOG), and have official representation 1016/j.annonc.2020.09.010, describes the LoE and GoR from the American Society of Clinical Oncology (ASCO). The system used,14 as per ESMO guidelines methodology. ABC 5 conference was also organised under the auspices of Supplementary Figures, available at https://doi/org/10. the Organisation of European Cancer Institutes (OECI) and 1016/j.annonc.2020.09.010, feature updated ABC diag- with the support of the Breast Cancer Research Foundation nostic and treatment algorithms. (BCRF), Susan G. Komen and the ABC Global Alliance. Slides with all ABC guideline statements are available This manuscript summarises the guidelines developed at online at http://www.abc-lisbon.org/ and https://www. ABC 5, each of which are accompanied by the LoE, grade of esmo.org/guidelines/breast-cancer/consensus-recommend recommendation (GoR), percentage of consensus reached ations-advanced-breast-cancer-abc-5.

2 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

Section I. ABC definitions Section I. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus Visceral crisis is defined as severe Expert 97% frequent injections over a long period organ dysfunction, as assessed by opinion/n/a of time, risk of inadequate estrogen signs and symptoms, laboratory level suppression and cost. studies and rapid progression of disease. Visceral crisis is not the mere Maintenance therapy: in the context of Expert 100% presence of visceral metastases but ABC guidelines, maintenance therapy opinion/n/a implies important organ compromise refers to the continuation of leading to a clinical indication for the anti-HER2 therapy and/or ET after most rapidly efficacious therapy. discontinuation of ChT. Examples: Liver visceral crisis: rapidly increasing bilirubin >1.5 ULN in the Integrative medicine: complementary Expert 100% absence of Gilbert’s syndrome or and integrative medicine (CIM) opinion/n/a biliary tract obstruction. represents the use of complementary Lung visceral crisis: rapidly increasing treatments side by side with dyspnoea at rest, not alleviated by conventional approaches in a proper drainage of pleural effusion. therapeutic environment. In green, NEW/UPDATED ABC 5 statements. Primary endocrine resistance is Expert 67% ABC, advanced breast cancer; AI, aromatase inhibitor; consensus, percentage of panel fi fi de ned as relapse while on the rst 2 opinion/n/a members in agreement with the statement; ChT, chemotherapy; ET, endocrine therapy; years of adjuvant ET, or PD within the GoR, grade of recommendation; HER2, human epidermal growth factor receptor 2; fi fi rst 6 months of rst-line ET for ABC, LHRH, luteinising hormone-releasing hormone; LoE, level of evidence; n/a, not appli- while on ET. cable; OFA, ovarian function ablation; OFS, ovarian function suppression; PD, disease Secondary endocrine resistance is progression; q4w, every 4 weeks; RT, radiotherapy; ULN, upper limit of normal. defined as relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of Given the aim of standardising definitions and homogenis- completing adjuvant ET, or PD 6 months after initiating ET for ABC, ing the use of certain medical terms, ABC has provided while on ET. several definitions throughout the years. At ABC 5, the definition of visceral crisis was revisited, with some exam- Oligometastatic disease is defined as Expert 78% low-volume metastatic disease with opinion/n/a ples added (i.e. liver and lung visceral crisis) to better clarify limited number and size of metastatic the definition and avoid any misunderstanding between the lesions (up to five and not necessarily in the same organ), potentially mere existence of visceral metastases and the presence of amenable for local treatment aimed visceral crisis. This situation is estimated to occur in only at achieving a complete remission around 10%-15% of first-line ABC cases and requires the use status. of the most rapidly efficacious therapy, which is not Patients with multiple chronic Expert 100% necessarily chemotherapy (ChT) in all situations. conditions are defined as patients opinion/n/a A more subjective and difficult to define situation is with additional comorbidities ‘ ’ (e.g. cardiovascular, impaired renal or impending visceral crisis , where the criteria for visceral crisis liver function, autoimmune disease) are not yet met but, without rapidly efficacious measures, it is making it difficult to account for all of foreseen to happen. An example is a situation where more than the possible extrapolations to develop specific recommendations 70% of the liver is occupied by metastases, the liver enzymes for care. are substantially altered but bilirubin is still normal. In this type of situation, we also recommend the use of the most rapidly Adequate OFS in the context of ABC Adequate OFS for ABC premenopausal I/A 85% efficacious therapy. patients can be obtained through bilateral ovariectomy, continuous use Section II. General guidelines of LHRH agonists or OFA through pelvic RT (the latter is not always Guideline statement LoE/GoR Consensus effective and therefore is the least preferred option). The management of ABC is complex and, Expert 100% If an LHRH agonist is used in this age II/B 85% therefore, involvement of all appropriate opinion/A group, it should usually be given on a specialties in a multidisciplinary team q4w basis to optimise OFS. (including but not restricted to medical, Efficacy of OFS must be initially Expert 85% radiation and surgical oncologists, imaging confirmed analytically through serial opinion/B experts, pathologists, gynaecologists, evaluations of serum estradiol, even psycho-oncologists, social workers, nurses in the presence of amenorrhoea, and palliative care specialists) is crucial. especially if an AI is administered. As all endocrine interventions for From the time of diagnosis of ABC, patients Expert 100% premenopausal patients with should be offered appropriate psychosocial opinion/A endocrine-responsive ABC require care, supportive care and symptom-related indefinite OFS, choosing one method interventions as a routine part of their care. over the other requires a balance of The approach must be personalised to meet the patient’s wish for potentially the needs of the individual patient. preserving fertility, compliance with Continued Continued

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 3 Annals of Oncology F. Cardoso et al.

Section II. Continued Section II. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus Following a thorough assessment and Expert 97% patients and their caregivers, should be confirmation of MBC, the potential opinion/A implemented by SBUs. treatment goals of care should be discussed. Patients should be told General statements: QoL that MBC is incurable but treatable, Strong consideration should be given to the I/C 87% and that some patients can live use of validated PROMs for patients to with MBC for extended periods of time record the symptoms of disease and side- (many years in some circumstances). effects of treatment experienced as a This conversation should be conducted in regular part of clinical care. These PROMs the accessible language, respecting patient should be simple and user-friendly to privacy and cultural differences, and facilitate their use in clinical practice and whenever possible, written information thought needs to be given to the easiest should be provided. collection platform e.g. tablets or smartphones. Systematic monitoring All ABC patients should be offered I/A 97% would facilitate communication between comprehensive, culturally sensitive, up-to- patients and their treatment teams by date and easy-to-understand information better characterising the toxicities of all about their disease and its management. anticancer therapies. This would permit early intervention of supportive care Patients (and their families, caregivers or Expert 100% services enhancing QoL. support network, if the patient agrees) opinion/A Specific tools for evaluation of QoL in ABC Expert 100% should be invited to participate in the patients should be developed. opinion/A decision-making process at all times. When Until then, trials evaluating QoL in this Expert 100% possible, patients should be encouraged to setting should use standardised PROs opinion/A be accompanied by persons who can support (instead of focusing exclusively on them and share treatment decisions CTCAEs) and incorporate site- and (e.g. family members, caregivers, support treatment-specific modules or subscales network). that exist both in the EORTC and FACT systems. Every ABC patient must have access to Expert 100% Additionally, attention needs to be paid to Expert 100% optimal cancer treatment and supportive opinion/A collection methods, timing of assessments opinion/A care according to the highest standards of and handling of missing data. More patient-centred care, as defined by: sophisticated statistics should also be Open communication between patients and employed to ensure that clinicians have their cancer care teams as a primary goal. better, reliable data to help patients Educating patients about treatment options when choosing between treatment and supportive care, through development options. and dissemination of evidence-based information in a clear, culturally appropriate General statements: clinical trials form. After appropriate informed consent, Expert 100% Encouraging patients to be proactive in their inclusion of patients in well-designed, opinion/A care and to share decision making with their prospective, independent trials must be a healthcare providers. priority whenever such trials are available Empowering patients to develop the capa- and the patient is willing to participate. bility of improving their own QoL within The ABC community strongly calls for Expert 100% their cancer experience. clinical trials addressing important opinion/A Always taking into account patient prefer- unanswered clinical questions in this ences, values and needs as essential to setting, and not just for regulatory optimal cancer care. purposes. Clinical trials should continue to Patients should have easy access to well- be performed, even after approval of a designed clinical studies since these are new treatment, to provide real-world data crucial for further improvement in the on its performance, efficacy and toxicity. management of ABC. General statements: affordability/cost Every ABC patient should: effectiveness Have access to the most Expert 100% The medical community is aware of the Expert 100% up-to-date treatments and innovative opinion/A problems raised by the cost of ABC opinion/A therapies at accessible breast units/centres. treatment. Balanced decisions should be Be treated in specialist breast I/A made in all instances; patients’ well-being, units/centres/services (SBUs) by a length of life and preferences should specialised multidisciplinary team including always guide decisions. specialised side-effects management and a We strongly recommend the use of Expert 88% nurse experienced in the treatment of ABC. objective scales, such as the opinion/A Survivorship issues and palliative care Expert ESMO-MCBS or the ASCO Value should be addressed and offered at an opinion/A Framework, to evaluate the real magnitude early stage. of benefit provided by a new treatment and A quality assurance programme covering Expert help prioritise funding, particularly in the entire breast cancer pathway from opinion/B countries with limited resources. screening and diagnosis to treatment, The ABC community strongly supports the I/A 90% rehabilitation, follow-up and palliative care, use of biosimilars both for treatment of including services and support for ABC breast cancer (i.e. trastuzumab) and for Continued Continued

4 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

Fortunately, these last few years have seen the develop- Section II. Continued ment and approval of several new therapies for ABC, Guideline statement LoE/GoR Consensus some with an impact on OS. Consequently, some ABC supportive care (i.e. growth factors). To be patients can live many years with their disease under used, the biosimilar must be approved control or in complete remission. Since the usual after passing the stringent development methods for systemic imaging of metastatic disease do and validation processes required by the EMA or the FDA or other similarly strict not provide good imaging of the breast, the panel be- authority. lieves that breast imaging is an option to consider in the

General statements: survivorship surveillance follow-up of these patients. Additionally, and As survival is improving in many patients with Expert 95% importantly, if at any time locoregional relapse or ABC, consideration of survivorship issues opinion/A progression is suspected, breast imaging must be should be part of the routine care of these patients. Health professionals should carried out. therefore be ready to change and adapt At ABC 5, several discussions took place regarding how treatment strategies to disease status, best to provide information regarding prognosis and treatment of adverse effects and QoL, patients’ priorities and life plans. length of life to ABC patients. Conversations about Attention to chronic needs for home and prognosis, priorities and end-of-life care are vitally family care, job and social requirements, important for those affected by advanced cancer and should be incorporated in the treatment 15 planning and periodically updated. should be part of routine care. Information about ABC patients who desire to work or need Expert 100% prognosis and likely survival time with and without fi to work for nancial reasons should opinion/A different anticancer treatments is important to enable have the opportunity to do so, with needed and reasonable flexibility in their fully informed and educated decision making by patients. working schedules to accommodate It also helps patients to plan for the future, arrange fi- continuous treatment and hospital visits. nances and work, maximise time with loved ones, plan ABC patients with stable disease being Expert 82% treated as a ‘chronic condition’ should opinion/B special events and prepare for death. Misunderstandings have the option to undergo breast about prognosis are common16-18 and are associated with reconstruction if clinically appropriate. 19-22 In ABC patients with long-standing stable Expert 83% increased exposure to futile treatments. Most pa- disease or complete remission, breast opinion/C tients want considerably more information than many imaging is an option. healthcare professionals expect, but the type and amount Breast imaging should also be performed I/A 100% fi 23 when there is a suspicion of locoregional of information sought should be clari ed. There are progression. some significant cultural variations, in particular the involvement of the family in filtering information, which Fertility preservation: the impact of the Expert 100% anticancer therapies on fertility should be opinion/B can make disclosure about prognosis and survival espe- discussed with all women with ABC of cially challenging.24 Although some physicians may avoid childbearing age, and their partners, discussing prognosis for fear of upsetting the patient or before the start of treatment. The discussion must also include appropriate destroying hope, there is no evidence that increased in- information about the prognosis of the formation about prognosis with sensitive communication disease and the potential consequences of pregnancy (e.g. stopping ongoing is harmful to patients, or that it increases anxiety or 25-30 treatment). distress. For patients wanting quantitative informa- tion on life expectancy, providing ranges for worst-case, General statements: other Specialised oncology nurses (if possible Expert 92% typical and best-case scenarios is more helpful and con- specialised breast nurses) should be part opinion/A veys more hope than providing a single point estimate of of the multidisciplinary team managing median survival.31 Ranges for survival scenarios are also ABC patients. In some countries, this role may be played by a physician assistant or more accurate than a single point estimate of expected another trained and specialised healthcare survival.16,32,33 Oncologists should offer prognostic infor- practitioner. mation to all patients with ABC, allowing patients to The use of telemedicine in oncology to help Expert 93% management of patients with ABC living in opinion/B determine the type and extent of information required. remote places is an important option to The patient’s needs for prognostic information are likely consider when geographic distances are a to fluctuate over time, and as their disease progresses, so problem and provided that issues of connectivity are solved. it is important for oncologists to repeatedly determine In green, NEW/UPDATED ABC 5 statements. the information required throughout the illness from ABC, advanced breast cancer; ASCO, American Society of Clinical Oncology; diagnosis to death. Oncologists also need guidance and consensus, percentage of panel members in agreement with the statement; CTCAE, Common Terminology Criteria for Adverse Events; EMA, European Medicines communication skills training on how to handle these Agency; EORTC, European Organisation for Research and Treatment of Cancer; difficult discussions, as there is evidence that some on- ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit fi Scale; FACT, Functional Assessment of Cancer Therapy; FDA, Food and Drug cologists are overly optimistic about survival bene ts Administration; GoR, grade of recommendation; LoE, level of evidence; MBC, met- from anticancer treatments while others are unduly astatic breast cancer; PRO, patient-reported outcome; PROM, patient-reported nihilistic about the benefits of good quality supportive outcome measure; QoL, quality of life. care.34

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 5 Annals of Oncology F. Cardoso et al.

Section III. Assessment and treatment general guidelines Section III. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus Image and disease assessment guidelines attention to detail (e.g. complete removal Minimal staging work-up for ABC includes a II/A 67% of the disease) as in patients with early- history and physical examination, stage disease. haematology and biochemistry tests and Additional prospective clinical trials imaging of the chest, abdomen and bones. evaluating the value of this approach, Brain imaging should not be routinely II/D 94% the best candidates and best timing are performed in asymptomatic patients. This currently ongoing. approach is applicable to all patients with A small but very important subset of patients Expert 91% ABC, including those with HER2-positive with ABC, for example those with opinion/B and/or triple-negative ABC. oligometastatic disease or low-volume The clinical value of tumour markers is not II/C 89% metastatic disease that is highly sensitive well established for diagnosis or follow-up to systemic therapy, can achieve complete after adjuvant therapy, but their use (if remission and a long survival. A elevated) as an aid to evaluate response multimodal approach, including to treatment, particularly in patients with locoregional treatments with curative non-measurable metastatic disease, is intent, should be considered for these reasonable. An increase in tumour selected patients. A prospective clinical markers alone should not be used to trial addressing this specific situation is initiate a change in treatment. needed. Evaluation of response to therapy should Expert 81% generally occur every 2-4 months for ET or opinion/B Systemic treatment general guidelines after 2-4 cycles for ChT, depending on the Treatment choice should take at least these Expert 95% dynamics of the disease, the location and factors into account: opinion/A extent of metastatic involvement and type HR and HER2 status and germline BRCA of treatment. Imaging of a target lesion status, PIK3CA in HR-positive and PD-L1 in may be sufficient in many patients. In TNBC, if targeted therapies are accessible. certain patients, such as those with Previous therapies and their toxicities, DFI, indolent disease, less frequent monitoring tumour burden (defined as number and is acceptable. Additional testing should be site of metastases), biological age, PS, performed in a timely manner, irrespective comorbidities (including organ of the planned intervals, if PD is suspected dysfunctions), menopausal status (for ET), or new symptoms appear. A thorough the need for rapid disease/symptom history and physical examination must control, socio-economic and psychological always be performed. factors, available therapies in the patient’s country and patient’s preference. Biopsy guidelines The age of the patient should not be the sole I/E 100% A biopsy (preferably providing histology) of a I/B 98% reason to withhold effective therapy (in metastatic lesion should be performed, if elderly patients) nor to overtreat (in easily accessible, to confirm diagnosis, young patients). Age alone should not particularly when metastasis is diagnosed determine the intensity of treatment. for the first time. Biological markers (especially HR and HER2) I/B 98% ChT general guidelines should be reassessed at least once in the Both combination and sequential, single- I/A 96% metastatic setting, if clinically feasible. agent ChT are reasonable options. Based Depending on the metastatic site (e.g. on the available data, we recommend bone tissue), technical considerations sequential monotherapy as the preferred need to be discussed with the pathologist. choice for ABC. Combination ChT If the results of tumour biology in the Expert 87% should be reserved for patients with metastatic lesion differ from the primary opinion/B rapid clinical progression, tumour, it is currently unknown which life-threatening visceral metastases or result should be used for treatment the need for rapid symptom and/or decision making. Since a clinical trial disease control. addressing this issue is difficult to In the absence of medical contraindications I/A 71% undertake, we recommend considering or patient concerns, anthracycline- or the use of targeted therapy (ET and/or taxane-based regimens, preferably as anti-HER2 therapy) when receptors are single agents, would usually be considered positive in at least one biopsy, regardless as first-line ChT for HER2-negative ABC in of timing. those patients who have not received these regimens as (neo)adjuvant Locoregional treatment general guidelines treatment and for whom ChT is To date, the removal of the primary tumour I/C 70% appropriate. Other options are, however, in patients with de novo stage IV breast available and effective, such as cancer has not been associated with capecitabine and vinorelbine, particularly prolongation of survival, with the possible if avoiding alopecia is a priority for the exception of the subset of patients with patient. bone-only disease. However, it can be In patients with taxane-naive and I/A 59% considered in selected patients with anthracycline-resistant ABC or with controlled systemic disease, particularly to anthracycline maximum cumulative dose improve QoL, always taking into account or toxicity (i.e. cardiac) who are being the patient’s preferences. considered for further ChT, taxane-based Of note, some studies suggest that surgery is II/B 70% therapy, preferably as single agent, would only valuable if performed with the same usually be considered as the treatment of Continued Continued

6 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

factors to take into consideration when making treatment Section III. Continued decisions. Details about how to evaluate these factors and Guideline statement LoE/GoR Consensus their clinical implications are discussed in the respective choice. Other options are, however, sections of the guidelines. available and effective, such as The statement about the use of bevacizumab was capecitabine and vinorelbine, particularly rewritten but consensus was still not achieved. In the dis- if avoiding alopecia is a priority for the patient. cussion, it became clear that the main reasons for this lack In patients pretreated (in the adjuvant and/or I/A 77% of consensus were the withdrawal of approval by the Food metastatic setting) with an anthracycline and a taxane, single-agent capecitabine, and Drug Administration (FDA), rendering it an unavailable vinorelbine or eribulin are the preferred option in the United States, and the fact that for many choices. Additional choices include panellists, bevacizumab should not be considered a treat- gemcitabine, platinum agents, a different taxane and liposomal anthracyclines. The ment option. The available data show that bevacizumab decision should be individualised and take combined with ChT as first-line therapy for ABC provides a into account different toxicity profiles, moderate benefit in progression-free survival (PFS) and no previous exposure, patient preferences and country availability. benefit in OS. The ESMO-MCBS v1.1 score for bevacizumab If given in the adjuvant setting, a taxane can I/B 92% is two.35 Some experts believe it can be a good option for be re-used as first-line therapy, situations of extensive cutaneous inflammatory disease due particularly if there has been at least 1 year of DFI. to its potential antiangiogenic effect. If given in the adjuvant setting, provided that I/B 93% maximum cumulative dose has not been achieved and there are no cardiac Section IV. ER-positive/HER2-negative (luminal-like) ABC contraindications, anthracyclines can be re-used in ABC, particularly if there has Guideline statement LoE/GoR Consensus been at least 1 year of DFI. ET is the preferred option for HR-positive I/A 93% Metronomic ChT is a treatment option for I/B 98% disease, even in the presence of visceral patients not requiring rapid tumour disease, unless there is visceral crisis, for response. Available regimens are CM (low- pre- and perimenopausal women with OFS/ dose oral cyclophosphamide and OFA, men (preferably with an LHRH agonist) methotrexate), capecitabine or oral and postmenopausal women. vinorelbine-based regimens. Randomised trials are needed and underway to Many trials in ER-positive ABC have not Expert 95% accurately compare metronomic ChT with included premenopausal women. Despite opinion/A standard dosing regimens. this, we recommend that young women with Duration of each regimen and the number of Expert 96% ER-positive ABC should have adequate OFS/ regimens should be tailored to each opinion/A OFA and then be treated in the same way as individual patient. postmenopausal women, with endocrine Usually, each regimen (except anthracyclines) I/B 72% agents with or without targeted therapies. should be given until PD or unacceptable toxicity. Future trials exploring new endocrine-based Expert 92% What is considered unacceptable should strategies should be designed to allow for opinion/A be defined together with the patient. enrolment of both pre- and postmenopausal women, and men. Other agents Bevacizumab combined with ChT as first-line I/C Yes: 42% For premenopausal women, for whom ET was I/A 93% therapy for ABC provides a moderate No: 53% decided, OFS/OFA combined with additional benefit in PFS and no benefit in OS. The endocrine-based therapy is the preferred absence of known predictive factors for choice. bevacizumab efficacy renders recommendations on its use difficult. OFA by laparoscopic bilateral oophorectomy Expert 91% Bevacizumab can only therefore be ensures definitive estrogen suppression and opinion/C considered as an option in selected cases contraception, avoids the potential initial and only in the first-line setting. tumour flare seen with an LHRH agonist and ESMO-MCBS v1.1 score: 2 may increase eligibility for clinical trials. In green, NEW/UPDATED ABC 5 statements. Patients should be informed of the options ABC, advanced breast cancer; ChT, chemotherapy; CM, cyclophosphamide/metho- for OFS/OFA and decisions should be made trexate; consensus, percentage of panel members in agreement with the statement; on a case-by-case basis. DFI, disease-free interval; ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; ET, endocrine therapy; GoR, grade of recom- Single-agent tamoxifen is the only available I/D 92% mendation; HER2, human epidermal growth factor 2; HR, hormone receptor; LoE, endocrine option for premenopausal women level of evidence; MBC, metastatic breast cancer; OS, overall survival; PD, disease who decline OFS/OFA, but the panel believes progression; PD-L1, programmed death-ligand 1; PFS, progression-free survival; it is a less effective option. PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PS, performance status; QoL, quality of life; TNBC, triple-negative breast cancer. The preferred first-line agent depends on the I/A 84% type and duration of adjuvant ET as well as the time elapsed from the end of adjuvant ET; it can be an AI, tamoxifen or fulvestrant Germline BRCA status, phosphatidylinositol-4,5-bisphos- for pre- and perimenopausal women with OFS/OFA, men (preferably with an LHRH phate 3-kinase catalytic subunit alpha (PIK3CA) for estrogen agonist) and postmenopausal women. receptor (ER)-positive ABC and programmed death-ligand 1 (PD-L1) for triple-negative ABC were included as important Continued

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 7 Annals of Oncology F. Cardoso et al.

Section IV. Continued Section IV. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus A CDK4/6 inhibitor combined with ET is the I/A 97% significant OS benefit, cost and availability. standard of care for patients with ER- Tamoxifen or fulvestrant can also be combined II/B 80% positive/HER2-negative ABC, since it achieves with everolimus. a substantial PFS benefit, significantly Adequate prevention, close monitoring and I/B 97% increases OS and either maintains or proactive treatment of AEs is needed, improves QoL. particularly in older patients treated with The CDK4/6 inhibitor can be combined with an everolimus due to the increased incidence of AI or with fulvestrant, in de novo or recurrent toxic deaths reported in the BOLERO-2 trial. ABC, in first or second line and in cases of primary or secondary resistance (defined as Everolimus and CDK4/6 inhibitors should not n/a/E 74% per ABC guidelines). be used after PD on that specific agent (i.e. This recommendation applies to beyond progression), outside a clinical trial. postmenopausal women, to premenopausal women in combination with an LHRH agonist Alpelisib with fulvestrant is a treatment option I/B 88% and to men preferably in combination with for patients with PIK3CA-mutated tumours an LHRH agonist. (in exons 9 or 20), previously exposed to an AI and with appropriate HbA1c levels, since it The ESMO-MCBS scores for the use of a I/A 100% provided about 5 months of benefitin CDK4/6 inhibitor combined with ET for ABC median PFS. patients vary according to the setting and The decision to give alpelisib should take into drug. consideration the inclusion/exclusion criteria They are the following, with the current in the SOLAR-1 study (i.e. pre-existing available data and follow-up: diabetes and baseline HbA1c), as well as the Palbociclib þ AI first line: efficacy score: 3 toxicity profile of alpelisib. (PFS); no improved QoL; ESMO-MCBS v1.1 Its efficacy after exposure to CDK4/6 inhibitors score: 3 is unknown, since only 6% of patients in the Abemaciclib þ AI first line: efficacy score: SOLAR-1 trial had been previously treated 3 (PFS); no QoL reported; ESMO-MCBS with those agents. ESMO-MCBS v1.1 score: 3 v1.1 score: 3 Ribociclib þ AI first line postmenopausal: Patients receiving alpelisib in combination with I/B 93% efficacy score: 3 (PFS); no improved QoL; ET for PIK3CA-mutated ABC should be ESMO-MCBS v1.1 score: 3 instructed to take non-sedating Ribociclib þ ET first line premenopausal: antihistamines to prevent rash at the start of efficacy score: 4 (PFS & OS); QoL therapy. Antihistamines can be discontinued improved; ESMO-MCBS v1.1 score: 5 after 4 weeks as the risk for rash is primarily Palbociclib þ fulvestrant second line: effi- in the first 2 weeks of therapy. cacy score: 3 (PFS & OS); improved QoL; ESMO-MCBS v1.1 score: 4 At present, no validated predictive biomarkers I/E 95% Ribociclib þ fulvestrant first, second line: other than hormone receptor status exist to efficacy score: 4 (PFS & OS); no improve- identify patients who will/will not benefit ment in QoL; ESMO-MCBS v1.1 score: 4 from the addition of a CDK4/6 inhibitor or an Abemaciclib þ fulvestrant second line: ef- mTOR inhibitor to ET and none of the studied ficacy score: 4 (PFS & OS); no QoL biomarkers is ready for use in clinical benefit; ESMO-MCBS v1.1 score: 4 practice. Research efforts must continue. Of note, the three CDK4/6 inhibitors have not Alpelisib should only be used in cases of II/A 95% been compared head-to-head within a PIK3CA-mutated tumours. clinical trial. The combination of a non-steroidal AI and II/D Yes: 38% It remains unclear if CDK4/6 inhibitors should Expert 100% fulvestrant as first-line therapy for No: 60% be preferably administered in the first- or opinion/n/a postmenopausal patients resulted in Abstain: 2% second-line setting. However, the majority of significant improvement in both PFS and OS panellists preferred giving a CDK4/6 inhibitor compared with AI alone in one phase III trial in the first-line setting for the majority of and no benefit in a second trial with a similar their patients. design. Notably, a suboptimal dose of fulvestrant was used in the study that There are no data supporting the use of a n/a/D 66% demonstrated benefit. combination of CDK4/6 inhibitor and ET as Subset analysis suggested that the benefitwas maintenance therapy after ChT. limited to patients without prior exposure to Maintenance therapy, in this situation, should adjuvant ET (tamoxifen). Based on these be carried out with ET alone. data, combination ET may be offered to some patients with ABC without prior exposure to The addition of everolimus to an AI is a valid I/B 88% adjuvant ET in cases where a CDK4/6 option for some patients [for pre- and inhibitor will not be given. ESMO-MCBS v1.1 perimenopausal women with OFS/OFA, men score: 2 (preferably with an LHRH agonist) and Comparative data between this combination postmenopausal women] previously exposed and a CDK4/6 inhibitor with ET are not to or naive of (in case CDK4/6 inhibitors are available. not available) ET, since it significantly prolongs PFS, albeit without evidence of an The optimal sequence of endocrine-based I/A 100% OS benefit. ESMO-MCBS v1.1 score: 2 therapy is uncertain. It depends on which The decision to treat must take into account agents were previously used [in the (neo) the toxicities associated with this adjuvant or advanced settings], duration of combination, the lack of a statistically response to those agents, burden of the Continued Continued

8 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

ledtoincreasedcardiotoxicity(arrhythmia)andshouldbe Section IV. Continued avoided.36 Notwithstanding these results, the panel acknowl- Guideline statement LoE/GoR Consensus edgesthatthere is a small group of patients who can be treated disease, patients’ preference and availability. with ET alone; although clear identification of these patients is Available options for first and second line not possible at this time, factors such as limited burden of include AI/fulvestrant þ CDK4/6 inhibitor, metastatic disease and features of less aggressive biology [i.e. AI/tamoxifen/fulvestrant þ everolimus, fulvestrant þ alpelisib (for PIK3CA-mutated very long disease-free interval (DFI)] can help with this iden- tumours), AI, tamoxifen, fulvestrant. This tification.There are currently no biomarkers to enable accurate applies to pre- and perimenopausal women fi with OFS/OFA, men (preferably with an LHRH identi cation of these patients. The ESMO-MCBS scores pro- agonist) and postmenopausal women. vided are based on available data at the time of publication of this manuscript. These scores may change in the future, with Options for treatment of ER-positive disease II/B 98% beyond second line include single agents not new data being published, and updates will be provided on the previously used (NSAI, SAI, tamoxifen, ESMO website. fulvestrant, megestrol acetate, low-dose The SOLAR-1 phase III, randomised, placebo-controlled trial estrogen). Single-agent abemaciclib is also a potential option. evaluated the role of alpelisib, an oral inhibitor of the phos- Challenging a patient with an agent on which Expert 98% phoinositide 3-kinase alpha (PI3Ka) isoform, in combination the disease previously progressed after an opinion/B with fulvestrant, for postmenopausal women and men who had initial response is occasionally considered, 58 but there are no robust data to support this previously been treated with an AI. In the PIK3CA-mutated approach. This applies to pre- and cohort, alpelisib provided a PFS benefitof11.0monthsversus perimenopausal women with OFS/OFA, men (preferably with an LHRH agonist) and 5.7 months [hazard ratio (HR) for progression or death: 0.65; postmenopausal women. 95% confidence interval (CI) 0.50-0.85, P < 0.001]. OS data are not yet available. Toxicity was substantially increased in the Trials comparing the different combinations of II/B Not voted endocrine þ targeted agents with single- alpelisib arm, especially hyperglycaemia, rash, gastrointestinal agent ChT are ongoing. (GI) complaints (nausea, vomiting, loss of appetite, mucositis, Initial results from phase II and III randomised diarrhoea) and fatigue, which lead to dose reductions/in- trials comparing combinations of endocrine þ targeted agents to single-agent terruptions in around 70% of patients and discontinuations in ChT do not show significant differences in 25%. Alpelisib, in combination with fulvestrant, was EMA- terms of efficacy, and the former compares favourably in terms of safety. approved for use in this setting in July 2020. The ESMO-MCBS for alpelisib in combination with fulvestrant was established at Concomitant ChT and ET has not shown a II/D 100% three because this scoring system does not consider the per- survival benefit and should not be performed outside a clinical trial. centages of dose alterations and/or discontinuations as a marker of important toxicity, which in the opinion of the ABC Endocrine treatment after ChT (maintenance III/B 88% panel, is a shortcoming of the v1.1 of the scale (scheduled to be ET) to maintain benefit is a reasonable option, though it has not been properly changed in the upcoming version 1.2 of the ESMO-MCBS). In assessed in randomised trials. view of the balance between efficacy and toxicity, it is crucial to In green, NEW/UPDATED ABC 5 statements. carefully select patients who may be candidates for this treat- ABC, advanced breast cancer; AE, adverse event; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; ChT, chemotherapy; consensus, percentage of panel ment, considering the inclusion/exclusion criteria in SOLAR-1 members in agreement with the statement; ER, estrogen receptor; ESMO-MBCS, and comorbidities, especially pre-existing diabetes and base- European Society for Medical Oncology Magnitude of Clinical Benefit Scale; ET, line HbA1c levels. It is also recommended that patients take non- endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; LHRH, luteinising hormone-releasing sedating antihistamines to prevent rash at the start of ther- hormone; LoE, level of evidence; mTOR, mammalian target of rapamycin; n/a, not apy59,60; these can be discontinued after 4 weeks as the risk of applicable; NSAI, non-steroidal aromatase inhibitor; OFS, ovarian function suppres- fi sion; OFA, ovarian function ablation; OS, overall survival; PD, progressive disease; rash is primarily in the rst 2 weeks of therapy. The ABC panel PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PFS, considers alpelisib a treatment option for patients with ER- progression-free survival; QoL, quality of life; SAI, steroidal aromatase inhibitor. positive/HER2-negative PIK3CA-mutated ABC, but in view of the higher benefit provided by CDK4/6 inhibitors, alpelisib plus ET The last 2 years have seen the establishment of cyclin- should be used after CDK4/6 plus ET. Only 20 patients (6%) in dependent kinase (CDK)4/6 inhibitors combined with endo- SOLAR-1 had been previously exposed to a CDK4/6 inhibitor. crine therapy (ET) as the standard of care for However,this is a common issue in oncology, where standards of ER-positive/HER2-negative ABC in view of the OS benefitseen care might change during the course of a trial. Furthermore, the in several trials,36-42 both in the first- and second-line settings, large phase II BYLieve trial has shown efficacy of alpelisib after substantial PFS benefit and good toxicity profile.36-57 These CDK4/6 inhibitor use.60 Based on all of the available data, the agents can be combined with an aromatase inhibitor (AI) or ABC panel acknowledges that no data exist to determine the fulvestrant, and are effective in de novo or recurrent ABC, in best sequence of therapies for this ABC subtype but believes first or second line, in cases of primary or secondary resistance, that the most adequate sequence, in settings where availability in postmenopausal and premenopausal women (the latter of all drugs exist, is the use of a CDK4/6 inhibitor plus ET as first with ovarian function suppression/ablation), and in men line, followed by alpelisib plus ET in patients with PIK3CA- (preferably with a luteinising hormone-releasing hormone mutated tumours or everolimus plus ET in patients with PIK3CA- agonist). Of note, the combination of tamoxifen and ribociclib wild type or unknown tumours.

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 9 Annals of Oncology F. Cardoso et al.

Section V. HER2-positive ABC Section V. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus Anti-HER2 therapy should be offered early (as I/A 98% The standard first-line therapy for patients I/A 86% first line) to all patients with HER2-positive previously untreated with anti-HER2 therapy ABC, except in the presence of is the combination of ChT þ trastuzumab and contraindications to the use of such therapy. pertuzumab because it has proven to be superior to ChT þ trastuzumab in terms of Patients progressing on an anti-HER2 therapy I/A 91% OS in this population. ESMO-MCBS combined with a cytotoxic or endocrine v1.1 score: 4 agent should be offered additional anti-HER2 therapy with subsequent treatment, except For patients previously treated [in the (neo) I/A 76% in the presence of contraindications, since it adjuvant setting] with anti-HER2 therapy, the is beneficial to continue suppression of the combination of ChT þ trastuzumab and HER2 pathway. pertuzumab is an important option for The choice of the anti-HER2 agent will depend first-line therapy. on country-specific availability, the specific Few (88) of these patients were treated in the anti-HER2 therapy previously administered CLEOPATRA trial and all with a trastuzumab- and the relapse-free interval. The optimal free interval >12 months. sequence of all available anti-HER2 therapies is currently unknown. There are currently no data supporting the use I/E 86% The optimal duration of anti-HER2 therapy for of dual blockade with trastuzumab þ MBC (i.e. when to stop these agents) is pertuzumab and ChT beyond progression currently unknown. (i.e. continuing dual blockade beyond progression) and therefore dual blockade In patients achieving a complete remission, the Expert 93% should not be given beyond progression optimal duration of maintenance anti-HER2 opinion/C outside clinical trials. therapy is unknown and needs to be balanced against treatment toxicity, logistical In a HER2-positive ABC patient previously II/B 76% burden and cost. Stopping anti-HER2 therapy untreated with the combination of ChT þ after several years of sustained complete trastuzumab þ pertuzumab, it is acceptable remission may be considered in some to use this treatment after first line. patients, particularly if treatment rechallenge is available in case of progression. After first-line trastuzumab-based therapy, T- I/A 88% DM1 provides superior efficacy relative to Patients who have received any type of (neo) I/B 100% other HER2-based therapies in the adjuvant anti-HER2 therapy should not be second line (versus lapatinib þ capecitabine) excluded from clinical trials for HER2-positive and beyond (versus treatment of physician’s ABC. These patients remain candidates for choice). anti-HER2 therapies. T-DM1 should be preferred in patients who have progressed through at least one line of For highly selected patientsa with ER-positive/ I/B 80% trastuzumab-based therapy, because it HER2-positive ABC, for whom ET þ anti-HER2 provides an OS benefit. ESMO-MCBS v1.1 therapy was chosen as first-line therapy, dual score: 4 anti-HER2 blockade (with either pertuzumab þ trastuzumab or lapatinib þ In case of progression on trastuzumab-based I/B 84% trastuzumab) can be used since it provides a therapy, the combination trastuzumab þ benefit in PFS. This decision must be lapatinib is a reasonable treatment option for balanced against the higher side-effects, some patients. ESMO-MCBS v1.1 score: 4 higher costs and lack of OS benefit so far, as There are, however, no data on the use of this compared with ET þ anti-HER2 monotherapy. combination after progression on pertuzumab or T-DM1. For patients with ER-positive/HER2-positive n/a/B 80% ABC, for whom ChT þ anti-HER2 therapy was The combination of neratinib þ capecitabine I/D 90% chosen as first-line therapy and provided a was compared with lapatinib þ capecitabine benefit, it is reasonable to use ET þ anti- as third line or beyond therapy for HER2- HER2 therapy as maintenance therapy after positive ABC, showing a marginal benefitin stopping ChT, although this strategy has not PFS, and with no significant difference in the been studied in randomised trials. co-primary end point of OS. There was no Duration of maintenance therapy should be comparator arm with trastuzumab þ until progression, unacceptable toxicity or capecitabine, which had previously been patient request, and needs to be evaluated in demonstrated to give superior OS to clinical trials. lapatinib þ capecitabine. Therefore, the There are no data to decide between single- combination of neratinib þ capecitabine is agent anti-HER2 or dual blockade to combine not recommended for routine clinical with maintenance ET after stopping ChT in practice. ER-positive/HER2-positive ABC. ESMO-MCBS: No manuscript publication; precludes scoring. In the first-line setting, for HER2-positive ABC I/A 95% Additional studies are needed to clearly I/D 90% previously treated (in the adjuvant setting establish the potential role of this with DFI >12 months) or untreated with combination in the treatment of brain trastuzumab, combinations of ChT þ metastases, as well as the role of neratinib trastuzumab are superior to combinations of for ABC. ChT þ lapatinib in terms of PFS and OS. II/B 98% Continued Continued

10 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

After years of relatively limited progress in the management Section V. Continued of advanced HER2-positive breast cancer, the last year has Guideline statement LoE/GoR Consensus enriched our armamentarium of drugs effective in this ABC Trastuzumab deruxtecan (DS-8201) showed subtype. A number of new representatives of the most important activity in a phase II study in relevant classes of drugsdmonoclonal antibodies, heavily pretreated patients with HER2- antibody-drug conjugates (ADCs) and tyrosine kinase in- positive ABC (median lines of therapy: 6), and is a treatment option in this setting, where hibitors (TKIs)dhave demonstrated activity superior to approved. Pulmonary toxicity (interstitial previously-available options in patients pretreated with lung disease/pneumonitis) can be fatal and fi requires active surveillance and proper standard rst- and second-line treatments. management. ESMO-MCBS v1.1 score: 2. Tucatinib, a highly selective inhibitor of the HER2 tyrosine kinase, used in combination with capecitabine and trastu- Dual blockade with tucatinib þ trastuzumab þ II/B 98% capecitabine showed a small benefitin zumab in a population of ABC patients pretreated with median PFS (2 months) and median OS (4 trastuzumab, pertuzumab and trastuzumab emtansine months) over trastuzumab þ capecitabine in (T-DM1), demonstrated improvement of PFS (median 7.8 patients previously treated with trastuzumab, < pertuzumab and T-DM1, including patients months versus 5.6 months, HR 0.54; 95% CI 0.42-0.71, P with brain metastases, at the expense of 0.001) and OS (median 21.9 months versus 17.4 months, HR higher toxicity (i.e. diarrhoea). If approved, it 0.66; 95% CI 0.50-0.88; P ¼ 0.005) compared with patients can be considered a treatment option in this 62 setting. ESMO-MCBS v1.1 score: 3. treated with capecitabine/trastuzumab/placebo. This was achieved at the expense of increased toxicity, mostly diar- þ Margetuximab ChT showed only a small PFS I/D 95% rhoea and elevated aminotransferase levels of grade 3, benefit (1 month) when compared with trastuzumab þ ChT for patients pretreated but did not lead to frequent treatment discontinuation. with pertuzumab and T-DM1, and cannot Importantly, a reduction in the risk of CNS progression or therefore be recommended for routine clinical practice. ESMO-MCBS: No death by 69% was observed in patients with stable brain manuscript publication; precludes scoring. metastases, while a confirmed objective response rate of The role of CD16A genotype as a predictor of 47% and a reduced risk of death by 51% were observed in anti-HER2 antibody efficacy and selection 63 of anti-HER2 agent should be further patients with active brain metastases. explored. Trastuzumab deruxtecan (DS-8201), an ADC composed of trastuzumab, a cleavable tetrapeptide-based linker and a Regarding the ChT component of HER2-positive I/A 88% ABC treatment: cytotoxic topoisomerase I inhibitor, demonstrated a When pertuzumab is not given, first-line response rate of 60.6% (95% CI 53.4-68.0) and an unprec- regimens for HER2-positive ABC can include d trastuzumab combined with vinorelbine or a edented median PFS of 16.4 months (95% CI 12.7 not taxane. Differences in toxicity between these reached) in a phase II study of heavily pretreated patients regimens should be considered and discussed (median six lines, range 2-27 lines, including trastuzumab with the patient in making a final decision. 64 Other ChT agents can be administered with and T-DM1). Trastuzumab deruxtecan was associated with trastuzumab but are not as well studied and a 13.6% risk of interstitial lung disease (ILD)/pneumonitis, are not preferred. fatal in 2.2% of cases, which needed appropriate and rapid For later lines of therapy, trastuzumab can be II/A 91% diagnosis and treatment. For the safe utilisation of this administered with several ChT agents, compound in clinical practice (i.e. outside clinical trials), including but not limited to, vinorelbine (if active surveillance and education regarding the signs and not given in first line), taxanes (if not given in first line), capecitabine, eribulin, liposomal symptoms, for both patients and healthcare professionals, anthracyclines, platinums, gemcitabine or are crucial to enable rapid diagnosis and management. metronomic CM. The decision should be fi individualised and take into account different Con rmatory results from phase III studies are eagerly toxicity profiles, previous exposure, awaited and needed to accurately determine the role of this patient preferences and country very promising drug in the HER2-positive ABC setting. availability. Both tucatinib and trastuzumab deruxtecan are FDA- ChT agents to combine with a dual blockade of See in 86% approved and await evaluation by the EMA. trastuzumab þ pertuzumab are docetaxel statement Another two agents which demonstrated formally positive [I/A] or paclitaxel [I/B]. Also possible are vinorelbine [II/A], nab-paclitaxel [II/B], (although clinically of questionable value) trial results in capecitabine [I/A] and metronomic ChT for pretreated HER2-positive ABC patients are margetuximab (a older patients [II/B]. monoclonal antibody) and neratinib. Margetuximab resulted In green, NEW/UPDATED ABC 5 statements. ABC, advanced breast cancer; ChT, chemotherapy; CM, cyclophosphamide and in only a 0.9-month PFS prolongation (HR 0.76; 95% CI 0.59- methotrexate; consensus, percentage of panel members in agreement with 0.98, P ¼ 0.033) compared with trastuzumab (both com- the statement; DFI, disease-free interval; ESMO-MCBS, European Society for ’ fi fi bined with ChT of physician s choice), no OS bene t and a Medical Oncology Magnitude of Clinical Bene t Scale; ET, endocrine therapy; 65 GoR, grade of recommendation; HER2, human epidermal growth factor re- good toxicity profile. The potential role of CD16A genotype ceptor 2; LoE, level of evidence; MBC, metastatic breast cancer; n/a, not as a predictor of anti-HER2 antibody efficacy was explored applicable; OS, overall survival; PFS, progression-free survival; T-DM1, trastu- zumab emtansine. and initial results were encouraging and deserve further a See definition in ABC 4.61 evaluation. Margetuximab is currently under evaluation by the FDA and EMA and is not yet approved for use in ABC.

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 11 Annals of Oncology F. Cardoso et al.

Neratinib provided a small reduction in the risk of disease Section VI. Continued progression of 24% (95% CI 0.63-0.93; P ¼ 0.006, medians not provided), a marginal difference in PFS and no impact Guideline statement LoE/GoR Consensus on OS (co-primary end point) compared with lapatinib (both Immunotherapy, with a checkpoint inhibitor, for III/D 85% in combination with capecitabine), at the cost of increased any biological subtype of ABC should not be used toxicity.66 Furthermore, the NALA study has a severe limi- in routine clinical practice outside clinical trials. Several ongoing trials are evaluating the role of tation of not having a comparator arm with trastuzumab this type of treatment in all ABC subtypes. plus capecitabine, which was previously shown to provide In green, NEW ABC 5 statements. superior OS to lapatinib plus capecitabine in the first- and ABC, advanced breast cancer; AR, androgen receptor; ChT, chemotherapy; 67 consensus, percentage of panel members in agreement with the statement; ESMO- second-line settings. As of October 2020, neratinib in MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; combination with capecitabine is FDA-approved for pre- GoR, grade of recommendation; HER2, human epidermal growth factor receptor 2; LoE, level of evidence; n/a, not applicable; PD-L1, programmed death-ligand 1; T- treated metastatic HER2-positive breast cancer, but is still DM1, trastuzumab emtansine; TNBC, triple-negative breast cancer. under evaluation by the EMA in this setting. a For PD-L1 testing, see precision medicine statements. 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 Recent years have brought about the beginning of a sig- fi currently unknown. ni cant 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 Section VI. Triple-negative ABC option for non-BRCA-mutated triple-negative ABC, with no specific recommendations regarding types of agents, with Guideline statement LoE/GoR Consensus the possible exception of platinum compounds for patients In triple-negative ABC patients (regardless of BRCA I/A 91% status) previously treated with anthracyclines with BRCA-mutated triple-negative ABC. However, immu- with or without taxanes in the (neo)adjuvant notherapy has emerged as an option in the first-line setting setting, carboplatin demonstrated comparable for those with PD-L1 1% in immune cells. IMpassion-130 is efficacy and a more favourable toxicity profile compared with docetaxel and is, therefore, an a phase III randomised, placebo-controlled trial that important treatment option. compared atezolizumab and nab-paclitaxel with nab- paclitaxel alone.68 The study had co-primary end points of For non-BRCA-associated triple-negative ABC, I/A 98% there PFS and OS in the intention-to-treat (ITT) population and are no data supporting different or specificChT had a hierarchal design that allowed for evaluation of OS in recommendations, besides platinum. Therefore, the PD-L1-positive population if the OS in the ITT population all ChT recommendations for HER2-negative disease also apply for triple-negative ABC. was significantly improved from the addition of atezolizu- mab. In the ITT population, atezolizumab provided a benefit The AR is a potential target in triple-negative ABC. II/D 85% in PFS of 7.2 versus 5.5 months with a HR of 0.8 (95% CI There are, however, no standardised methods to assay AR. Limited data suggest a low level of 0.69-0.92, P ¼ 0.002). In the PD-L1 positive group, atezo- efficacy for AR antagonist agents such as lizumab provided a PFS benefit of 7.5 versus 5 months with bicalutamide and enzalutamide. At this time, < these agents should not be used in routine a HR of 0.62 (95% CI 0.49-0.78, P 0.001). In the ITT clinical practice. population, there was no significant benefit in OS with the More definitive trials are needed, and research addition of atezolizumab; median OS was 21.3 months efforts must continue to optimise and standardise the determination of AR. versus 17.6 months (HR 0.84; 95% CI 0.69-1.02, P ¼ 0.08). However, despite the hierarchal statistical design that pre- Atezolizumab þ nab-paclitaxel is an option for I/B 95% cluded an OS analysis in the PD-L1-positive population if the first-line therapy for PD-L1-positivea triple-negative ABC, either de novo or at least 12 OS in the ITT population was not significant, an analysis was months since (neo)adjuvant ChT. ESMO-MCBS conducted and presented, and showed an OS of 25 months v1.1 score: 3 versus 15.1 months favouring the atezolizumab arm. Based Checkpoint inhibitor monotherapy in later lines for I/E 89% on these data, atezolizumab in combination with nab- triple-negative ABC is not recommended due to paclitaxel was approved and may be considered an option low response rates. in the first-line setting for de novo advanced/metastatic Several ongoing trials are evaluating the role of n/a/E 98% disease or disease that has developed at least 12 months immunotherapy in other ABC subtypes (non- after completion of (neo)adjuvant ChT in tumours that have TNBC) and, for the moment, it is not recommended outside clinical trials. PD-L1 expression 1% based on staining of the immune cells using the companion test of SP142 PD-L1 immuno- 68 Continued histochemical assay (Ventana Medical Systems). Recently,

12 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology these data were updated showing a PFS difference of 2.5 Section VII. Continued months and an OS difference of 7 months in the PD-L1- 69 positive population. More recently, at ASCO 2020 virtual Guideline statement LoE/GoR Consensus meeting, data from the KEYNOTE-355 trial was presented. family members. However, it must be KEYNOTE-355 was a randomised double-blind, phase III trial clarified to the patient that at present, a evaluating the role of pembrolizumab plus ChT for previ- mutation in another moderate-/high- penetrance gene has no direct clinical ously untreated triple-negative ABC, which showed an implications for the patients themselves in improvement in PFS with the addition of pembrolizumab the setting of ABC. ¼ The therapeutic implications of somatic n/a/E 83% (9.7 versus 5.6 months; HR 0.65; CI 0.49-0.86, P 0.0012) BRCA1/2 mutations in breast tumours for PD-L1-positive (combined positive score 10), triple- need to be further explored within a negative ABC.70 research setting and should not be used for decision making in routine clinical Checkpoint inhibitor monotherapy in later lines for triple- practice. negative ABC is not recommended due to low response rates, as seen in the KEYNOTE-199 trial.71 In patients with BRCA-associated ABC In patients with gBRCA-associated triple- I/A 86% triple-negative ABC and a germline BRCA mutation, a poly- negative ABC or endocrine-resistant ABC adenosine diphosphate ribose polymerase (PARP) inhibitor previously treated with an anthracycline is a preferred treatment option (please refer to section on with or without a taxane (in the adjuvant and/or metastatic setting), a platinum hereditary ABC). In the small proportion of patients with regimen is the preferred ChT option, if not both PD-L1-positive disease and BRCA1/2 mutations, the previously administered. selection of immunotherapy or a PARP inhibitor for first-line All other ChT recommendations are similar to those for sporadic ABC. treatment remains an area of debate. For patients with a gBRCA mutation, single- I/A 78% No further data to support antiandrogen therapy for agent PARPi (olaparib or talazoparib) is a preferred treatment option for those with triple-negative ABC with expression of the androgen re- triple-negative ABC. ceptor has been published since ABC 4 and therefore it In ER-positive gBRCA-associated ABC, the Expert 78% cannot be recommended for routine clinical use outside a optimal sequence between a PARPi and ET opinion/B with or without a CDK4/6 inhibitor is clinical trial. unknown. Given the OS benefit seen with Sacituzumab govitecan-hziy has demonstrated promising CDK4/6 inhibitors, the panel recommends activity in advanced lines for triple-negative ABC in a phase their use before a PARPi. Single-agent PARPis (olaparib or talazoparib) Expert 78% I/II study of 108 patients who had received a range of 2-10 are associated with a PFS benefit, opinion/B prior treatments for metastatic disease.72 The overall improvement in QoL and a favourable toxicity profile. Results suggest that any response rate was 33.3% (95% CI 24.6-43.1), with a median benefit in OS may be limited to the first- duration of response of 7.7 months (95% CI 4.9-10.8). Of line setting. the patients with a response to sacituzumab govitecan-hziy, ESMO-MCBS v1.1 score: 4 It is unknown how PARPis (olaparib or Expert 90% 55.6% maintained their response for 6 months and 16.7% talazoparib) compare with platinum opinion/n/a maintained their response for 12 months. Based on these compounds in this setting, the optimal use preliminary results, the FDA has granted accelerated with platinum (combined or sequential) fi and their efficacy in tumours progressing approval. However, phase III results are needed to con rm after platinum. efficacy and establish the role of this agent in the man- More research is needed to answer questions agement of triple-negative ABC. related to treatment sequencing. BROCADE3 was the first phase III trial testing I/D 98% a PARPi (veliparib) in gBRCA-mutated MBC Section VII. Hereditary ABC that included a platinum. Initial presentation of results showed a small fi Guideline statement LoE/GoR Consensus bene t in PFS (1.9 months). However, durable PFS at 3 years was seen in a Genetic testing significant minority (one in four patients) For ABC patients, results from germline I/A 88% during veliparib maintenance, which could genetic testing have therapeutic provide patients lacking other implications and should therefore be maintenance treatment options with ChT- performed as early as possible. free time. Mature OS data are needed Appropriate counselling should be provided before this regimen can be recommended to patients and their families if a for routine clinical practice. pathogenic germline mutation is found. ESMO-MCBS: No manuscript publication; At present, only germline mutations in I/A 100% precludes scoring. BRCA1/2 have proven clinical utility and In green, NEW ABC 5 statements. therapeutic impact. ABC, advanced breast cancer; CDK, cyclin-dependent kinase; ChT, chemotherapy; Testing for other additional moderate- to Expert 100% consensus, percentage of panel members in agreement with the statement; ESMO- high-penetrance genes may be opinion/C MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; considered, if deemed appropriate by the ET, endocrine therapy; GoR, grade of recommendation; HER2, human epidermal geneticist/genetic counsellor, in particular growth factor receptor 2; LoE, level of evidence; MBC, metastatic breast cancer; n/a, because they may have implications for not applicable; OS, overall survival; PARPi, poly-adenosine diphosphate ribose po- lymerase inhibitor; PFS, progression-free survival; QoL, quality of life. Continued

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 13 Annals of Oncology F. Cardoso et al.

For ABC patients, results from germline genetic testing for Section VIII. Precision medicine amutationinBRCA1/2 have therapeutic implications and should therefore be discussed with the patient and car- Guideline statement LoE/GoR Consensus ried out as early as possible. Genetic testing should Multigene panels, such as those I/D 83% be guided by national/international guidelines,73 should obtained using NGS or other technology on tumour DNA, have be proposed to all male breast cancer patients and may not yet proven beneficial in also be considered for all patients with triple-negative clinical trials for ABC; their disease. Genes to be tested depend on personal and impact on outcome remains undefined and family history. However, at present, only germline muta- should not be used in routine tions in BRCA1/2 have any clinical utility and therapeutic clinical practice. impact. Although BRCA1/2 are the most frequently For patients who are suitable to participate in clinical trials of mutated genes, testing for other additional moderate- to novel therapies and are readily high-penetrance genes may be considered, if deemed able/motivated to attend a centre with relevant clinical trials, appropriate by the geneticist/genetic counsellor, but it NGS testing may be used in the must be clarified to the patient that, at present, a mu- context of prospective molecular tation in another moderate- to high-penetrance gene has triage programmes to select d patients for therapeutic trials. limited clinical implications in the setting of ABC this is Specific tests (as distinguished from an area of research with several ongoing clinical trials and broad mutation profiles) are emerging phase II data suggesting a benefitofPARPin- useful and discussed in separate statements; others may play a hibitors (PARPis) in patients with germline PALB2 role in the future as the mutations.74 medicines they are linked with Since ABC 4, further data from the OlympiAD study achieve regulatory approval. suggested an OS benefit for olaparib when given in the first- ctDNA assessment is not I/D 97% line setting, with a median OS of 22.6 versus 14.7 months recommended for demonstration (HR 0.51; 95% CI 0.29-0.90, P ¼ 0.02) in a subgroup analysis of disease progression. 75 of predefined stratification subgroups, lending further ctDNA assessment is an option for II/A 93% support to existing data for a PFS benefit with olaparib in the detection of PIK3CA 76 mutations for a selection of the ITT population of the study. patients eligible for alpelisib. The EMBRACA study77 hadasimilardesigntothe OlympiAD study, comparing talazoparib with ChT mon- If treatment with the PI3K inhibitor, I/B 100% alpelisib, is available, patients otherapy per physician’s choice (capecitabine, eribulin, should be tested for PIK3CA vinorelbine or gemcitabine). Most patients had not mutation (in exon 9 and 20) in a received prior platinum-based therapy. At a median tissue (metastasis or primary) and/or by ctDNA testing in blood. follow-up of 11.2 months, PFS was longer in the tala- Patientswhodonothavean zoparib arm (8.6 versus 5.6 months, HR 0.54; 95% CI available archival tissue sample < and have an uninformative result 0.41-0.71, P 0.0001). Recently, at the American As- using a liquid biopsy test could sociation for Cancer Research (AACR) 2020 virtual consider undergoing a tumour meeting, an update was presented and no benefitwas biopsy for PIK3CA mutation testing. demonstrated in OS.78 However, it is worth noting that nearly 60% of patients in the control arm went on to ESR1 mutation status assessment is I/D 90% receive a PARP inhibitor or platinum agent. At the not ready for routine clinical practice use and is ESMO 2019 annual meeting, data was presented from not recommended, either for the BROCADE3 studydthe first phase III study in ABC demonstration of disease comparing the addition of a PARPi (veliparib) to a progression or selection of ET (such as a switch from AI to platinum-containing regimen (paclitaxel and carboplatin) fulvestrant). for germline BRCA-mutated ABC.79 The study demon- fi PD-L1 status should be tested in I/A 97% strated a PFS bene t favouring the veliparib arm, with a cases of first-line triple-negative median PFS of 14.5 versus 12.6 months (HR 0.71; 95% ABC if treatment with immune CI 0.57-0.88, P ¼ 0.002) and a suggestion of sustained checkpoint inhibitors is available. response at 2 and 3 years favouring the arm that was PD-L1 status is the companion test I/A 97% receiving maintenance veliparib but at the expense of for the use of the combination of significant toxicity. Peer-reviewed publication of the data atezolizumab and taxane as first- line therapy for triple-negative is awaited, and further data are needed before this ABC, using IHC with the SP142 combination can be recommended for germline BRCA- antibody (Ventana) and a cut-off mutated ABC. of 1% of positive staining on immune cells. Further studies are also needed to clarify the value of PARPis in platinum-resistant disease, as well as their value Continued compared with platinum compounds.

14 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

deleterious BRCA 1 and 2 mutations and PIK3CA mutations Section VIII. Continued are all classified as tier IA. The majority of PIK3CA mutations Guideline statement LoE/GoR Consensus affect hot spots i.e. the three most frequent in exons 9 and Patients with low (1%-10%) ER- III/B 95% 20 (exon 9: E542K, E545K, helicase domain; exon 20: positive (and PgR-positive), H1047R, kinase domain). They are present in up to 40% of HER2-negative ABC should not be metastatic luminal breast cancer. The mutations activate the considered for ET exclusively. Patients with low (1%-10%) ER- alpha isoform of PI3K and drive oncogenicity. There were positive (and PgR-positive), three sub-analyses of the SOLAR-1 trial58 which showed HER2-negative ABC can be fi considered as patients with that the bene t seen with alpelisib was independent of the triple-negative ABC for clinical type of PIK3CA test, i.e. tissue biopsy from the primary or trials. the metastasis, liquid or tissue biopsy, NGS or targeted PCR 84-86 If an ABC patient presents with a Expert Yes: 41% test. If treatment with the PI3K inhibitor, alpelisib, is tumour with MSI-H/MMR-D, opinion/C Abstain: 10% available, patients should be tested for PIK3CA mutation (in treatment with an anti-PD-1 Insufficient data: 49% exons 9 and 20) in tissue (metastasis or primary) and/or by agent is a possible consideration. ctDNA testing in blood. Patients who do not have an If an ABC patient presents with a I/B Yes: 29% available archival tissue sample and have an uninformative tumour with an NTRK fusion, Abstain: 24% result using the liquid biopsy test could consider undergoing treatment with a TRKi is a Insufficient data: 47% possible consideration. a new biopsy for PIK3CA mutation testing. Patients must be informed about Acquisition of ESR1 mutations, frequent in ABC patients the amount of data available for ABC specifically. Research on previously treated by AIs (20%-40%), is one of the mecha- the best companion diagnosis nisms of resistance to hormonal therapies. The conse- tools and techniques is needed. quence is a ligand-independent, constitutive activity of ER. Prospective registries should be created to collect data from all To assess the impact of the presence of ESR1 mutations in patients treated with these plasma samples of ABC patients, the post hoc prospective- innovative approaches after retrospective analysis of the SOFEA trial failed to demon- proper consent. fi In green, NEW ABC 5 statements. strate a statistically signi cant impact of ESR1 mutations on ABC, advanced breast cancer; consensus, percentage of panel members in agree- response to AI versus fulvestrant (interaction test between ment with the statement; ctDNA, circulating tumour DNA; ER, estrogen receptor; ET, the two regimens P ¼ 0.07). The analysis of the PALOMA-3 endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LoE, level of evidence; MMR-D, trial showed that the presence of plasma ESR1 mutations mismatch repair deficiency; MSI-H, microsatellite instability-high; NGS, next- had no impact on response to palbociclib (interaction test generation sequencing; NTRK, neurotrophic receptor tyrosine kinase; PD, disease ¼ 87 progression; PD-1, programmed cell death protein 1; PgR, progesterone receptor; between the two regimens P 0.74). Despite promising PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3- preclinical data and statistical trends, the ESCAT scale for kinase catalytic subunit alpha; TRKi, tropomyosin receptor kinase inhibitor. ESR1 mutations is tier II.83 Therefore, ESR1 mutation status assessment is not ready for routine clinical use and is not recommended, either for demonstration of disease pro- Circulating DNA assays assess cell-free tumour DNA qualita- gression or selection of hormonal treatment (such as a tively and quantitatively for molecular alterations in a non- switch from AI to fulvestrant). invasive fashion from a simple blood sample. Different Increased counts of tumour-infiltrating lymphocytes technologies are available from single-gene assay by quan- (TILs) are prognostic for survival in triple-negative breast titative polymerase chain reaction (qPCR) to whole genome cancer (TNBC), making this disease a potential target for sequencing by next-generation sequencing (NGS).80,81 immunotherapy.88 Based on the results of the IMpassion- Standardisation is a critical point, especially for NGS-based 130 trial,68 atezolizumab was approved with the Ventana analysis. There is insufficient evidence of clinical validity PD-L1 (SP142) assay as a companion diagnostic immuno- and utility for the majority of circulating tumour DNA (ctDNA) histochemistry (IHC) assay. Therefore, PD-L1 status should assays in advanced cancer.82 Thus, ctDNA assessment is not be tested in cases of first-line triple-negative ABC if treat- recommended for demonstration of disease progression in ment with immune checkpoint inhibitors is available. ABC. However, for single biomarkers using targeted assays, Several IHC assays are available to assess PD-L1 status.89 ctDNA assessment is an option for the detection of PIK3CA SP263 (Ventana) and 22-C3 (Dako), both of which are mutations for selection of patients eligible for alpelisib. widely used in pathology laboratories for other tumour The progress of precision medicine has helped to types, have been evaluated for their clinical validity in the describe around 40 recurrent driver alterations in breast context of the IMpassion-130 trial but failed to reproduce cancer. ESMO has recently developed a scale for clinical SP142 clinical validity.90 Thus, PD-L1 status by SP142 is the actionability of molecular targets (ESCAT) to interpret the companion test for the use of atezolizumab in combination targetability of genomic alterations in the context of clinical with a taxane for first-line therapy in triple-negative ABC, practice.83 The aim is to help clinicians to prioritise treat- with a cut-off of 1% positive staining on immune cells. It is ment after NGS results. The tool ranks genomic alterations critical for medical oncologists and pathologists to know the in tiers, based on the strength of their clinical validation available assays and their relevance to the therapeutic op- (from I to V and X). ERBB2 amplification, germline tions in order to develop a workflow for IHC testing.

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 15 Annals of Oncology F. Cardoso et al.

Tumours with staining of ER <1% and progesterone re- Section IX. Continued ceptor (PgR) <1% and with HER2-negative results by IHC and/ 91 or in situ hybridisation are defined as TNBC. Patients with a Guideline statement LoE/GoR Consensus low (1%-10%) expression of hormone receptors and HER2- consideration of long-term toxicity is negative account for 2%-3% of breast cancers. They may important and less toxic local therapy share morphological (high grade, poor differentiation)92 and options (e.g. stereotactic RT) should be 93,94 preferred to WBRT, when available and biological features with TNBC and experience a similarly appropriate (e.g. in the setting of a limited poor survival.95,96 A meta-analysis assessing the survival number of brain metastases). fi < In patients with HER2-positive ABC who I/D 95% bene t of ET for ER-low ( 10%) primary breast cancer develop brain metastases with stable showed lower endocrine responsiveness compared with ER- extracranial disease, systemic therapy positive tumours [odds ratio (OR) 0.52, P ¼ 0.034].97 should not be changed. For patients with HER2-positive ABC where I/D 83% Recently, the ASCO-College of American Pathologists (CAP) brain metastases are the only site of guidelines acknowledged that patients with tumours be- recurrence, the addition of ChT to local tween 1% and 10% of ER staining represent a new reporting therapy is not known to alter the course of fi the disease and is not recommended. category, stipulating the lack of data concerning bene t from It is recommended to re-start the anti-HER2 I/B 83% ET and the proximity to ER-negative breast cancer of this therapy (trastuzumab) if this had been patient group.98 We recommend that this strategy is also stopped. For patients with HER2-positive ABC with III/A 85% adopted for ABC patients with a low ER-positive status. progressive brain metastases as the predominant site of disease burden, if no Section IX. Specific sites of metastases further relevant local therapy options are available, a change in systemic therapy is a Guideline statement LoE/GoR Consensus reasonable option, preferably in clinical trials. Bone metastases Radionecrosis after stereotactic RT for brain III/B 61% Radiological assessments are required in I/A 96% metastases is an uncommon complication patients with persistent and localised pain that may occur, especially with due to bone metastases to determine longer survival and follow-up, and in whether there are impending or actual particular in cases of re-irradiation. pathological fractures. If a fracture of a Differential diagnosis with tumour long bone or vertebrae is likely or has progression is often difficult. Treatment occurred, an orthopaedic assessment is of symptomatic patients with a course required as the treatment of choice may be of high-dose steroids is the first surgical stabilisation, which is generally treatment of choice. If no response, followed by RT. In the absence of a clear bevacizumab may be used, as an fracture risk, RT is the treatment of choice. option to decrease the surrounding Neurological symptoms and signs which I/B 100% oedema, usually at a dose of 7.5 mg/kg suggest the possibility of spinal cord every 2 weeks for a median of 4 cycles. compression must be investigated as a Prospective randomised trials are needed matter of urgency. This requires a full to further validate this option. radiological assessment of the potentially affected area as well as adjacent areas of LMD the spine. MRI is the method of choice. An There is no accepted standard of care for Expert 95% emergency surgical opinion (neurosurgical breast cancer LMD. The choice of opinion or orthopaedic) may be required for treatment (RT, intra-CSF therapy, systemic surgical decompression. If no therapy, supportive care) should consider decompression/stabilisation is feasible or prognostic evaluation and indicated, emergency RT is the treatment multidisciplinary discussion. of choice and vertebroplasty is also an option. Focal RT should be considered for Expert 95% circumscribed, notably symptomatic opinion Regarding the use of bone-targeted agents n/a 100% lesions. (bisphosphonate, denosumab), the ABC panel endorses the ESMO CPG99 related to WBRT can be considered for extensive Expert 95% this subject. nodular or symptomatic linear LMD. opinion Addition of intrathecal to systemic therapy II/D 95% Brain metastases has no OS or QoL advantage and no clinically meaningful effect on CSF Patients with a single or a small number of I/B 92% progression. potentially resectable brain metastases should be treated with surgery or Intrathecal therapy can be considered if Expert 95% radiosurgery. Radiosurgery is also an systemic disease is stable and there is opinion fl option for some unresectable brain normal CSF ow, when there is evidence metastases. of malignant cells in the CSF (type I LMD). Significant toxicity may occur. If surgery/radiosurgery is performed it may I/C 72% be followed by WBRT, but this should be discussed in detail with the patient, Liver metastases balancing the longer duration of Prospective RCTs of local therapy for breast Expert 83% intracranial disease control and the risk of cancer liver metastases are urgently opinion/C neurocognitive effects. needed since available evidence comes only from series in highly selected patients. HER2-positive ABC and brain metastases Since there are no randomised data supporting the effect of local therapy on Because patients with HER2-positive ABC and I/A 89% survival, every patient must be informed of brain metastases can live for several years, Continued Continued

16 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

The ABC panel decided to endorse the ESMO Clinical Section IX. Continued Practice Guideline (CPG) related to the use of bone-targeted Guideline statement LoE/GoR Consensus agents (bisphosphonate, denosumab), which replace all 99 this when discussing a potential local previous statements regarding this subject. therapy technique. Local therapy should Leptomeningeal disease (LMD) is a rare complication of only be proposed in very selected cases of breast cancer with a 5% incidence rate. LMD carries a poor good PS, with limited liver involvement and no extrahepatic lesions, after adequate prognosis, with a median OS of approximately 4 weeks which systemic therapy has demonstrated control can be prolonged to a few months in some patients with of the disease. Currently, there are no data 100 to select the best technique for the aggressive multimodal treatment. Its diagnosis is based on individual patient (surgery, stereotactic RT, clinical evaluation, cerebrospinal magnetic resonance imaging intrahepatic ChT, etc.). (MRI) and cerebrospinal fluid (CSF) analysis. The European Malignant pleural effusions Association of Neuro-Oncology (EANO) and ESMO have pro- Malignant pleural effusions require systemic III/A 86% posed classifying LMD using two major criteria: presence (type treatment with/without local I) or not (type II) of positive CSF and neuroimaging findings.101 management. fi Thoracentesis for diagnosis should be III/B The same authors have proposed de ning the therapeutic plan performed if it is likely that this will based on the presentation of the disease [nodular (A) or linear change clinical management. False (B) or mixed (C) meningeal involvement, positive CSF cytology, negative results are common. Drainage is recommended in patients with III/A presence or not of extracerebral disease, etc.] and taking into symptomatic, clinically significant pleural account the patient’slifeexpectancy.102 Available active effusion. Use of an intrapleural catheter or intrapleural III/B treatment options are RT, intra-CSF therapy and systemic administration of talc or drugs therapy. The choice of treatment should always involve (e.g. bleomycin, biological response multidisciplinary discussion. Currently, there is no accepted modifiers) can be helpful. Clinical trials evaluating the best technique standard of care for breast cancer LMD and recommendations are needed. are essentially expert opinion-based. The EANO-ESMO CPG recommends considering focal RT for circumscribed, notably Chest wall and regional (nodal) recurrences Due to the high risk of concomitant distant Expert 100% symptomatic lesions, and whole-brain RT (WBRT) for extensive metastases, patients with chest wall or opinion/A nodular or symptomatic linear LMD.101 The use of intrathecal regional (nodal) recurrence should therapy is controversial. It is recommended in cases where undergo full restaging, including assessment of chest, abdomen and bone. tumour cells are present in the CSF; it is optional in cases of Chest wall and regional recurrences should be II/A 97% linear metastatic meningeal disease.100-102 This strategy is not treated with surgical excision when feasible recommended in patients with obstructive hydrocephalus (RT with limited risk of morbidity. Locoregional RT is indicated for patients not II/A 97% can be used to restore CSF flow and successful restoration previously irradiated. should be checked before the use of any intrathecal treatment) For patients previously irradiated, re- Expert 97% or in patients with nodular meningeal metastases only. Three irradiation of all or part of the chest wall opinion/C may be considered in selected cases. agents are commonly used for intrathecal treatment of LMD: In addition to local therapy (surgery and/or I/B 95% methotrexate, cytarabine (including liposomal cytarabine) or RT), in the absence of distant metastases, 100-102 the use of systemic therapy (ChT, ET and/ thioTEPA. Their use can cause a spectrum of toxicities or anti-HER2 therapy) should be ranging from myelosuppression to neurotoxicity. Metho- considered. trexate is the most commonly used agent. Neurotoxicity is ChT after first local or regional recurrence I/B 95% improves long-term outcomes in ER- increased with the use of methotrexate and RT and this negative disease and can be used. combination is not recommended. Other agents, such as ET in this setting improves long-term I/B 95% trastuzumab for HER2-positive disease, are under evaluation. outcomes for ER-positive disease and should be used. Intrathecal therapy can be considered in cases where systemic The choice of systemic treatment depends on Expert 95% disease is stable. However, two prospective trials have shown tumour biology, previous treatments, opinion/A that the addition of intrathecal to systemic therapy has no OS length of DFI and patient-related factors 102 (comorbidities, preferences, etc.). or QoL advantage. Retrospective data suggest some activity 100-102 In patients with disease not amenable to Expert 97% of different agents used systemically. Since its onset, radical local treatment, the choice of opinion/B palliative systemic therapy should be made according to principles previously defined for metastatic disease. These patients may still be considered for Section X. Specific populations palliative local therapy. In green, NEW ABC 5 statements. Guideline statement LoE/GoR Consensus ABC, advanced breast cancer; ChT, chemotherapy; consensus, percentage of panel members in agreement with the statement; CPG, Clinical Practice Guideline; CSF, Advanced male breast cancer cerebrospinal fluid; DFI, disease-free interval; ER, estrogen receptor; ESMO, Euro- For ER-positive male ABC, which represents III/A 100% pean Society for Medical Oncology; ET, endocrine therapy; GoR, grade of recom- the majority of cases, ET is the preferred mendation; HER2, human epidermal growth factor receptor 2; LMD, leptomeningeal option unless there is visceral crisis or disease; LoE, level of evidence; MRI, magnetic resonance imaging; OS, overall sur- rapidly progressive disease needing a fast vival; PS, performance status; QoL, quality of life; RCT, randomised controlled trial; response. RT, radiotherapy; WBRT, whole-brain radiotherapy. Continued

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 17 Annals of Oncology F. Cardoso et al.

Section X. Continued Section XI. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus For ER-positive male ABC, tamoxifen is the IV/B 83% When an anthracycline is given, it should be I/A 87% preferred option. administered sequentially with the anti-HER2 For male patients with ABC who need to IV/B 86% therapy. receive an AI, a concomitant LHRH agonist or orchidectomy is the preferred option. For patients with HER2-positive LABC I/A 85% AI monotherapy may also be considered (inflammatory or non-inflammatory), without with close monitoring of response. distant metastases, who are in complete Clinical trials are needed in this patient remission after appropriate preoperative population. systemic therapy and appropriate locoregional No new statements for this section were developed at ABC 5. therapy, and being treated with a potential ABC, advanced breast cancer; AI, aromatase inhibitor; consensus, percentage of curative intent, the approved adjuvant duration panel members in agreement with the statement; ER, estrogen receptor; ET, of 1 year of anti-HER2 therapy should be used. endocrine therapy; GoR, grade of recommendation; LHRH, luteinising hormone- releasing hormone; LoE, level of evidence. Following effective preoperative systemic II/A 98% 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. Section XI. LABCa In patients with axillary low burden of disease at III/B 62% Guideline statement LoE/GoR Consensus presentation (previously cN0-cN1) with complete response after systemic treatment Before starting any therapy, a core biopsy I/A 97% (ycN0), SLNB can be an option, provided all the providing histology and biomarker expression recommendations for sentinel node after (ER, PgR, HER2, proliferation/grade) is primary systemic treatment are followed (i.e. indispensable to guide treatment decisions. dual tracer, clipping/marking positive nodes, minimum of three sentinel nodes). Since LABC patients have a significant risk of I/A 100% metastatic disease, a full staging work-up, Inflammatory LABC including a complete history, physical For inflammatory LABC, overall treatment I/A 93% examination, laboratory tests and imaging of recommendations are similar to those for non- the chest and abdomen (preferably with a CT inflammatory LABC, with systemic therapy as scan) and bone before initiation of systemic first treatment. therapy is highly recommended. Mastectomy with axillary dissection is I/A 95% recommended in almost all cases, even when PET-CT, if available, may be used (instead of and II/B 100% there is a good response to primary systemic not in addition to CT scans and a bone scan). therapy. Immediate reconstruction is generally not IV/E 95% Systemic therapy (not surgery or RT) should be III/A 100% recommended in patients with the initial treatment. inflammatory LABC. If LABC remains inoperable after systemic Expert Locoregional RT (chest wall and lymph nodes) I/A 98% therapy and eventual RT, ‘palliative’ opinion/D is required, even when a pCR is achieved with mastectomy should not be done unless the systemic therapy. surgery is likely to result in an overall No new statements for this section were developed at ABC 5. improvement in QoL. ABC, advanced breast cancer; BCS, breast-conserving surgery; ChT, chemotherapy; consensus, percentage of panel members in agreement with the statement; ChT, A combined treatment modality based on a I/A 100% chemotherapy; CT, computed tomography; ER, estrogen receptor; ET, endocrine multidisciplinary approach (systemic therapy, therapy; GoR, grade of recommendation; HER2, human epidermal growth factor surgery and RT) is strongly indicated in the vast receptor 2; HR, hormone receptor; LABC, locally advanced breast cancer; LoE, level majority of cases. of evidence; pCR, pathological complete response; PET, positron emission tomog- raphy; PgR, progesterone receptor; PS, performance status; QoL, quality of life; RT, Options for HR-positive LABC include an I/A 85% radiotherapy; SLNB, sentinel lymph node biopsy. anthracycline- and taxane-based ChT regimen, a For the purpose of these recommendations, LABC means inoperable, non- or ET. metastatic locally advanced breast cancer. The choice of ChT versus ET as initial treatment Expert 85% will depend on tumour (grade, biomarker opinion/A expression) and patient (menopausal status, PS, comorbidities, preference) considerations. Section XII. Supportive and palliative care

For triple-negative LABC, anthracycline- and I/A 85% Guideline statement LoE/GoR Consensus taxane-based ChT is recommended as initial treatment. Supportive care allowing safer and more I/A 100% A platinum can be combined with the taxane. tolerable delivery of appropriate treatments should always be part of the For HER2-positive LABC, concurrent taxane and I/A 92% treatment plan. anti-HER2 therapy is recommended since it increases the rate of pCR. Early introduction of expert palliative care, I/A 100% including effective control of pain and For HER2-positive LABC, anthracycline-based ChT I/A 72% other symptoms, should be a priority. should be incorporated into the treatment regimen. Access to effective pain treatment I/A 100% (including morphine, which is Continued Continued

18 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

Section XII. Continued Section XII. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus inexpensive) is necessary for all patients Management of dyspnoea in need of pain relief. Treatable causes like pleural effusion, 100% pulmonary emboli, cardiac The ABC community is aware of the Expert 100% insufficiency, anaemia or drug toxicity limitations that are being imposed opinion/n/a must be ruled out. Patient support is worldwide, as a consequence of the essential. Oxygen is of no use in non- opioid use disorders in certain areas of hypoxic patients. the world. The ABC community is united Opioids are the drugs of choice in the I/A in insisting that cancer patients should palliation of dyspnoea. not have restrictions placed that will limit Benzodiazepines can be used in patients II/A their access to adequate pain control. experiencing anxiety. Steroids can be effective in dyspnoea Expert The panel encourages research on the I/C 97% caused by lymphangitis opinion/B potential role of cannabis to assist with carcinomatosis, RT or drug-induced pain and symptom control but strongly pneumonitis, superior vena cava stresses that it cannot replace proven syndrome, an inflammatory medicines such as morphine for component or in (cancer-induced) adequate pain control. obstruction of the airways (in which case laser/stent is to be Optimally, discussions about patient Expert 96% considered). preferences at the end of life should opinion/A begin early in the course of metastatic Management of nausea and vomiting disease. However, when active treatment ESMO/MASCC guidelines103 are available 100% is no longer able to control widespread for the management of ChT-induced and life-threatening disease, and the and morphine-induced nausea and toxicities of remaining options outweigh vomiting, and these are endorsed by the benefits, physicians and other the ABC community. members of the healthcare team should There is a need to study nausea and Expert initiate discussions with the patient (and vomiting related to chronic use of opinion/A family members/friends, if the patient anticancer drugs. agrees) about end-of-life care. Management of endocrine toxicities from Management of cancer-related fatigue mTOR or PIK3CA inhibition Cancer-related fatigue is frequently 100% Hyperglycaemia and hyperlipidaemia are II/A 100% experienced by patients with ABC, common, sub-acute complications of exerts a deleterious impact on QoL mTOR or PIK3CA inhibition. Evaluation and limits physical, functional, of pre-existing diabetes or psychological and social well-being. hyperglycaemia at baseline is The aetiology of this fatigue is essential. Regular, careful monitoring complex; therefore, effective of glycaemia and lipid panel is needed management needs to be to identify these toxicities. multidimensional. Management of grade 1 and 2 It is important to assess cancer-related hyperglycaemia includes treatment fatigue using appropriate PROMs with oral antidiabetics and basal before implementing various non- insulin, in accordance with pharmacological (such as exercise international recommendations for [I, A]), and, if needed, pharmacological I/A diabetes mellitus treatment. Statins interventions [II, B]. II/B are indicated to treat grade 2 and 3 hypercholesterolaemia, and fibrates Management of CDK inhibitor-induced should be introduced if the neutropaenia triglyceride level is >500 mg/dl (with Neutropaenia is the most common II/A 100% attention to possible drugedrug toxicity associated with CDK4/6 interaction between everolimus and inhibition and is not generally fibrates). Treatment interruption and associated with febrile neutropaenia, dose reduction are generally effective although an increase in infections has for grade 2 and 3 toxicity. Treatment been reported. Treatment should be should be discontinued for grade 4 delayed until neutrophils have toxicity. recovered to at least 1000/ml; dose reduction can also be considered. Management of mucositis/stomatitis Steroid mouthwash should be used for I/B 100% Management of NIP the prevention of stomatitis induced NIP is an uncommon complication of II/A 100% by mTOR inhibitors (suggested mTOR inhibition or CDK4/6 inhibition. schedule: 0.5 mg/5 ml Patient education is critical to ensure dexamethasone, 10 ml to swish 2 early reporting of respiratory min, then spit out; q.i.d.). symptoms. Treatment interruption Early intervention is Expert and dose reduction are generally recommended. opinion/A effective for grade 2 symptomatic NIP For grade >2 stomatitis, delaying Expert with the use of systemic steroids and treatment until the toxicity resolves opinion/A treatment discontinuation for grade 3 and considering lowering the dose of or greater toxicity. the targeted agent are also recommended. Continued Continued

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 19 Annals of Oncology F. Cardoso et al.

Section XII. Continued Section XII. Continued

Guideline statement LoE/GoR Consensus Guideline statement LoE/GoR Consensus Mild toothpaste and gentle hygiene are Expert 100% Sexual health recommended for the treatment of opinion/B Sexuality is an experience on many levels Expert 100% stomatitis. and is not confined to the act of opinion/n/a Consider adding steroid dental paste to Expert intercourse. Sexuality remains treat developing ulcerations. opinion/B important for many ABC patients. ABC patients frequently experience Management of CIPN impaired sexual health and need CIPN is frequent and potentially dose- specific attention. Openly addressing limiting. Risk factors for neuropathy misconceptions and sexual challenges and pre-existing neuropathy need to after treatment, as well as educating be identified. patients, have been shown to improve No medical prevention can currently be II/C QoL. When life expectancy is limited, recommended. physical contact, affection, emotional Drug-related factors (dosing, timing, communication and comfort are route) can lower the risk of CIPN. particularly important. Standardised The use of tight gloves and socks during I/C instruments (questionnaires) may help ChT may help reduce the incidence to assess the grade of impairment. and severity of CIPN. There are limited evidence-based II/B Dyspareunia treatments for CIPN, with tricyclic Dyspareunia is often caused by vaginal antidepressants, serotonin- dryness. noradrenaline reuptake inhibitors, The first choice for treating vaginal II/B 100% duloxetine, pregabalin and gabapentin dryness and soreness are hormone- being most often used. free lubricants and moisturisers (e.g. High-quality studies are needed to water-based gel, hyaluronic acid gel). evaluate strategies for the prevention If hormone-free measures are not II/B 100% and management of CIPN. effective, low-dose estrogen- containing vaginal medication may be Management of HFS used. HFS is also described as palmar-plantar 100% The value of local testosterone erythrodysesthaesia syndrome. Most application and of invasive measures frequent causes are capecitabine, like vaginal laser or hyaluronic acid pegylated liposomal doxorubicin and injections is still unclear. multikinase inhibitors. In green, NEW ABC 5 statements. Patients should be instructed about early ABC, advanced breast cancer; CBT, cognitive behavioural therapy; CDK, cyclin- recognition of HFS. dependent kinase; ChT, chemotherapy; CIPN, chemotherapy-induced peripheral Drug-related factors (dosing, timing, neuropathy; consensus, percentage of panel members in agreement with the route) can lower the risk of HFS. statement; ER, estrogen receptor; ESMO, European Society for Medical Oncology; Treatment of hyperkeratosis/fungal Expert GoR, grade of recommendation; HFS, hand and foot syndrome; LoE, level of evi- infections, comfortable shoes and opinion/A dence; MASCC, Multinational Association of Supportive Care in Cancer; mTOR, avoidance of friction and heat are mammalian target of rapamycin; n/a, not applicable; NIP, non-infectious pneumo- recommended. nitis; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; Intensive skin care of hands and feet II/A PROM, patient-reported outcome measure; q.i.d., four times a day; QoL, quality of (urea cream/ointment) is life; RT, radiotherapy. recommended. High-quality studies are needed to ABC meetings and guidelines have highlighted and fought evaluate strategies for the prevention and management of HFS. for early and equal access to effective pain treatment (including morphine, which is inexpensive) for all patients in Management of postmenopausal 104 symptoms need of pain relief. Yet, in Europe and all over the world, Systemic hormone therapy is generally I/D 100% there is inadequate and very unequal access to pain con- not recommended to treat trol,105 and the recent ESMO guidelines106 are difficult to postmenopausal symptoms in ABC patients, particularly not in ER-positive follow in those countries where the majority of patients disease. experiencing cancer pain live. Recent years have seen a Valid alternatives are: drawback in adequate cancer pain management, even in For postmenopausal symptoms in I/B general: mind-body interventions, wealthy countries, due to what is known as the opioid physical training and CBT are effective epidemic, which has a myriad of causes and will not be non-pharmacological treatment solved by any simple solution.107 Consequent to a staggering options. For hot flushes: venlafaxine, oxybuty- I/B increase in opioid-related deaths in the United States, nin, gabapentin, clonidine and various governmental inputs and stakeholder strategies have acupuncture are available options. For sleep disturbances: melatonin. II/C been proposed and implemented with varying success. There is no convincing evidence that I/D Recent trends in opioid-related data demonstrate an almost phytotherapeutic drugs improve fourfold increase in overdose deaths from 1999 to 2008. postmenopausal symptoms. Possible drug interactions must be Stricter prescribing practices and prescription monitoring considered. programmes have been instituted but unfortunately these have raised obstacles for cancer patients. Several organisa- Continued tions, such as ASCO,108 have been calling for measures to

20 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology ensure adequate protection of cancer patients. The ABC expectancy is limited, physical contact, affection, panel strongly supports this position and states that no re- emotional communication and comfort are particularly strictions should be in place that limit cancer patients’ ac- important. Standardised instruments (questionnaires) may cess to adequate pain control. help to assess the grade of impairment.136-140 At first Recent data on cannabidiol for medical use has not yet recurrence, one out of four patients is younger than 50 substantiated claims indicating that it is effective in cancer years old and premenopausal. Therefore, issues of pain management to the same level as morphine109 and fertility and contraception must be discussed, and for more research is needed.110 the latter, only hormone-free contraceptives can be Many therapies for ABC are associated with estrogen recommended.141 deprivation and patients often suffer from menopausal symptoms such as hot flushes, night sweats, sleep distur- bances, fatigue, arthralgia, cognitive impairment, depression and vaginal dryness, as well as impaired sexual functioning (e.g. loss of sexual desire, dyspareunia). Hormone replace- Section XIII. Integrative medicine ment therapy is contraindicated due to the endocrine char- Guideline statement LoE/GoR Consensus acter of the disease and should not be used to treat Alternative therapies (i.e. therapies used n/a/E 100% complaints. Nevertheless, the final decision belongs to the instead of scientifically-based medicines) patient, after adequate information, since in some cases are not recommended in any phase or stage of cancer treatment. these symptoms are impacting significantly on QoL.111,112 For menopausal symptoms in general, mind-body interventions, Breast cancer centres/units/departments Expert 100% should be aware that the majority of opinion/C physical training and cognitive behavioural therapy should be their patients would like to be informed recommended as effective non-pharmacological treatment about CIM and that many of them are options.113-117 To control hot flushes, valid alternatives are using it. Physicians should actively ask for 118-121 information about its use in view of the venlafaxine, oxybutynin, gabapentin and clonidine. potential deleterious interactions with Sleep disturbances may be treated with melatonin.122,123 specific anticancer therapies. If There is no convincing evidence that phytotherapeutic complementary therapies are not available at the centre, certified contacts drugs may improve menopausal symptoms. Possible drug should be available to promote referral interactions must be considered. to practitioners qualified in the therapies Sexuality is an experience on many levels and is not people are interested in receiving. confined to the act of intercourse. ABC patients frequently Some complementary therapies have the Expert 100% experience impaired sexual health and need specific potential to reduce disease symptom opinion/C burden and/or side-effects of anticancer attention. A recent retrospective study showed that breast therapies, and therefore improve the QoL cancer patients are more affected than patients with of ABC patients. ovarian cancer or healthy controls: decreased or no interest fi Evidence suggests beneficial effects of the I/B 100% in sexual activity was frequently reported with a signi cant following methods, which can therefore association to less satisfaction and more discomfort (dys- be used: pareunia); however, the lack of desire was not associated Physical exercise/sport (equivalent to 3-5 hours of moderate walking per week) with global health status, QoL or the ability to experience improves QoL, cardiorespiratory fitness, orgasms; estrogen deprivation (gonadotropin-releasing physical performance and fatigue, and it may also improve DFS and OS. hormone agonists, AIs) seemed to have more impact than 124 MBSR programmes, hypnosis and yoga tamoxifen. may improve QoL and fatigue, and help Dyspareunia is often caused by vaginal dryness. The first reduce anxiety, distress and some side- effects of anticancer therapies. choice for treating vaginal dryness and soreness are Acupuncture may help against ChT- hormone-free lubricants (e.g. water-based gel, hyaluronic induced nausea and vomiting, fatigue acid gel).125-127 If hormone-free measures are not effec- and hot flushes. tive, low-dose estriol-containing vaginal medication may Methods with no or unfavourable effects II/E 100% be used.128-132 The value of local testosterone application The following methods of alternative and of invasive measures like vaginal laser or hyaluronic medicine are not recommended in ABC 133-135 since available evidence shows no effect acid injections is still unclear. In summary, gynae- at best, or even association with worse cological and sexual symptoms are important challenges outcome: Antioxidant supplements for most ABC patients. In particular, even in an anony- Drugs outside the approved indication mous setting, patients are often too shy to report their (e.g. methadone) problems regarding impaired sexual life. Therefore, active Herbs including Chinese herbal medicine Orthomolecular substances verbalisation of gynaecological and sexual symptoms in an (selenium, zinc, etc.) adequate and trustful atmosphere is a mandatory part of Oxygen and ozone therapy follow-up visits. Openly addressing misconceptions and Proteolytic enzymes, thymic peptides Phytoestrogens (soy food, isoflavones) sexual challenges after treatment, as well as educating Continued patients, have been shown to improve QoL. When life

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 21 Annals of Oncology F. Cardoso et al.

Hospira, JnJ, Novartis, Merck, Merck Serono, Mundipharma, Section XIII. Continued Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro, Tevam Vifor, G1 Guideline statement LoE/GoR Consensus Therapeutics and Lilly; receipt of honoraria for symposia High-dose vitamins (vitamin C, D, E, lectures from Amgen, Bayer, Schering, Cephalon, Chugai, carotenoids, etc.) Eisai, Genomic Health, GSK, Helsinn, Hospira, Ipsen, JnJ L-carnitine, laetrile Ortho Biotech, Kyowa Hakko Kirin, Merck, Merck Serono, No new statements for this section were developed at ABC 5. fi ABC, advanced breast cancer; ChT, chemotherapy; CIM, complementary and inte- Mundipharma, Novartis, P zer, Pierre Fabre, Roche, Sandoz, grative medicine; consensus, percentage of panel members in agreement with the Sanofi, Tesaro, Taiho, Tevam Vifor, G1 Therapeutics and Lilly. statement; DFS, disease-free survival; GoR, grade of recommendation; LoE, level of CHB reports receipt of honoraria or consultation fees from evidence; MBSR, mindfulness-based stress reduction; n/a, not applicable; OS, overall survival; QoL, quality of life. Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Gen- entech, Eisai, MSD, AstraZeneca and Bayer; receipt of CONCLUSIONS AND FUTURE DIRECTIONS grants/research support to the institution from AbbVie, ABC guidelines provide a useful tool for the management of Amgen, Astellas Pharma, AstraZeneca, BMS, Celgene, ABC in clinical practice. Each guideline has an associated LoE, Covance, Lilly, Medivation, Merck Serono, MSD, Novartis, fi GoR and percentage of consensus. Additionally, v1.1 of the P zer, PharmaMar and Roche/Genentech. JB reports receipt ESMO-MCBS13 was applied to drugs approved by the EMA of grants/research support grants to Karolinska Institute and after 2016. As usual, if additional new agents are approved by University Hospital from Amgen, AstraZeneca, Bayer, Merck, fi fi the EMA before the next ABC Consensus Conference, the P zer, Roche, Sano -Aventis; no personal payments; pay- ESMO-MCBS will be applied and the result will be made ment from UpToDate to Asklepios Medicine HB for a available as an e-update to the present guidelines. chapter on breast cancer prediction. LB reports receipt of We acknowledge that in many areas of the world, some grants/research support from Celgene, Genomic Health and of these guidelines may not be implemented due to the Novartis; receipt of honoraria or consultation fees from existence of disparities in access. It is the mission of the ABC AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Genomic fi Global Alliance142 to fight for better outcomes for all ABC Health, Ipsen, Lilly, Novartis, P zer, Pierre Fabre and Roche. patients around the world. For this goal to be achieved, FC reports receipt of honoraria or consultation fees from efforts must continue not only in research but also in public Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi policy to ensure equal access to multidisciplinary, speci- Sankyo, Eisai, GE Oncology, Genentech, GSK, MacroGenics, alised care, including anticancer, palliative and end-of-life Medscape, MSD, Merus BV, Mylan, Mundipharma, Novartis, fi fi care, and full implementation of these guidelines. We P zer, Pierre Fabre, prIME Oncology, Roche, Sano , Seattle emphasise again that reimbursement rules in all countries Genetics and Teva. JC reports acting as a consultant/advisor should be patient-centred and be an incentive to, not work for Roche, Celgene, Cellestia, AstraZeneca, Biothera Phar- against, the clinical implementation of high-quality inter- maceutical, Merus, Seattle Genetics, Daiichi Sankyo, Ery- national guidelines. Clinical trials and consequent approval tech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko, and reimbursement must not continue to exclude certain Bioasis, Clovis Oncology, Boehringer Ingelheim and Kyowa groups of patients, such as premenopausal women and Kirin; received honoraria from Roche, Novartis, Celgene, fi men, which keep seeing their treatment options reduced in Eisai, P zer, Samsung Bioepis, Lilly, MSD and Daiichi Sankyo; many countries. received research funding to the institution from Roche, At a time when the world is facing the COVID-19 Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier pandemic, the ABC community must unite to maintain or Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, fi increase the resources needed to face the ever-rising cancer Guardant Health, MSD, P zer, PIQUR Therapeutics, Puma C ‘epidemic’, which is responsible for 18.1 million new cases and Queen Mary University of London; holds stock, patents and 9.6 million deaths annually worldwide, with half a and intellectual property for MEDSIR; received travel, ac- million deaths annually due to ABC.12 commodation and expenses from Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. GC reports receipt of honoraria or ACKNOWLEDGEMENTS consultation fees from Roche, Pfizer, Lilly, Novartis and SeaGen; participation in a sponsored speakers’ bureau for Manuscript editing support was provided by Angela Cor- SeaGen, Pfizer, Lilly and Novartis. NSES reports receipt of storphine of Kstorfin Medical Communications Ltd; this grants/research support to institution from Novartis; receipt support was funded by ESMO. of honoraria or consultation fees from Novartis, Roche, fi FUNDING P zer, Lilly and AstraZeneca. ME reports acting in an advi- sory role for Novartis and Roche. AE reports receipt of No external funding has been received for the preparation grants/research support from AstraZeneca, Roche, Celltrion, of these guidelines. Production costs have been covered by Pfizer and Novartis. LF reports receipt of grants/research ESMO from central funds. support from BMS, GSK, Myriad and Novartis; receipt of honoraria or consultation fees from BMS, AstraZeneca, DISCLOSURE Teva, Novartis, Eisai, Takeda, Pfizer, Lilly, Genomic Health MSA reports receipt of consultation fees from Amgen, BMS, and Myriad. PAF reports receipt of honoraria or consulta- Celgene, Clinigen, Eisai, Genomic Health, GSK, Helsinn, tion fees from AstraZeneca and Novartis; travel for lecture

22 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology for Pfizer and Ipsen. KG reports receipt of grants/research Genentech, OBI, Odonate, Daiichi Sankyo, Eisai, Seattle support from AstraZeneca, Pfizer and BMS; receipt of hon- Genetics, MacroGenics and Immunomedics. ES reports oraria or consultation fees from Pfizer, AstraZeneca, receipt of honoraria or consultation fees from Amgen, Novartis, Nanostring, Merck, Mylan, Genomic Health, Roche AstraZeneca, Clinigen, Egis, Eli Lilly, Genomic Health, and BMS. JG reports receipt of grants/research support Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and TLC Bio- from Amgen, Eisai, Genomic Health, Novartis, Pfizer and pharmaceuticals; travel support from Amgen, AstraZeneca, Roche/Genentech; receipt of honoraria or consultation fees Egis, Novartis, Pfizer and Roche; contracted research for from Daiichi, Eisai, Genomic Health, Ipsen, MacroGenics, Amgen, AstraZeneca, Boehringer, Eli Lilly, Merck, Novartis, MSD, Mylan, Novartis, Onxeo, Pfizer and Roche/Genentech; Pfizer, Roche and Samsung; holds stock in Eli Lilly. EPW re- participation in a sponsored speakers’ bureau for Eisai, ports receipt of grants/research support from Merck and Genomic Health, Ipsen, Novartis, Pfizer and Roche/Gen- Genentech/Roche; receipt of honoraria or consultation fees entech. NH reports receipt of honoraria or consultation fees from Carrick Therapeutics, Genentech/Roche, Genomic from Amgen, AstraZeneca, Celgene, Daiichi Sakyo, Lilly, Health, GSK, Jounce, Leap, Lilly, Merck and Seattle Genetics; MSD, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal and research fees to institute from Genentech/Roche and Seattle Genetics. RK reports receipt of grants/research Merck; participation in a scientific advisory board for Leap. support from Pfizer Malaysia. BEK reports receipt of grants/ BX reports receipt of advisory fees from Novartis and research support to institution from Roche; receipt of Roche; fees for serving on a speakers’ bureau from Astra- honoraria for advisory boards and educational pre- Zeneca, Pfizer, Roche and Eisai. FA, FB, BK, FEL, GWS, CT and sentations as well as travel and meeting expenses from TW have not reported any potential conflict of interest. Roche; receipt of honoraria for advisory boards and GSB, MJC, LAC, AC, RH, XH, BVO and DAV have declared no educational presentations from Novartis. SBK reports significant conflict of interest. receipt of grants/research support to institution from Novartis, Sanofi-Aventis, Kyowa Kirin Inc. and DongKook REFERENCES Pharm Co.; receipt of consultancy fees from Novartis, AstraZeneca, Lilly, Enzychem, Daehwa Pharmaceutical Co. 1. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast. Ltd, ISU ABXIS and Daiichi Sankyo. NUL reports receipt of 2014;23(5):489-502. grants/research support from Genentech and Seattle Ge- 2. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international netics; receipt of honoraria or consultation fees from consensus guidelines for advanced breast cancer (ABC2). Ann Oncol. Seattle Genetics, Daiichi Sankyo and Puma. SAM reports 2014;25(10):1871-1888. receipt of honoraria from Pfizer and Lilly; SN reports receipt 3. Cardoso F, Spence D, Mertz S, et al. Global analysis of advanced/ fi metastatic breast cancer: decade report (2005-2015). Breast. of grants/research support from Roche, P zer, BMS and 2018;39:131-138. Novartis; participation in a sponsored speakers’ bureau for 4. Howlader N, Noone AM, Krapcho M, et al., eds. SEER Cancer Statistics Roche, Pfizer, BMS, Merck and Novartis. LN reports receipt Review, 1975-2013, National Cancer Institute. Based on November 2015 of honoraria from Sermonix Oncology Ad Board, Prime SEER Data Submission. Bethesda, MD: SEER; 2016. Available at https:// Oncology, Sarah Lawrence Lecture, Context advisory board, seer.cancer.gov/archive/csr/1975_2013/. Accessed July 10, 2020. 5. Sundquist M, Brudin L, Tejler G. Improved survival in metastatic Oncology Pioneers Science Lecture Series, BCRF program- breast cancer 1985-2016. Breast. 2017;31:46-50. matic review meeting and CSHL external advisory board 6. Kobayashi K, Ito Y, Matsuura M, et al. Impact of immunohistological meeting. SO reports receipt of grants/research support subtypes on the long-term prognosis of patients with metastatic from Chugai, Eisai, Taiho, Daiichi Sankyo; participation in a breast cancer. Surg Today. 2016;46(7):821-826. sponsored speakers’ bureau for Chugai, AstraZeneca, Eisai, 7. Fietz T, Tesch H, Rauh J, et al. Palliative systemic therapy and overall d fi survival of 1,395 patients with advanced breast cancer results from Taiho, P zer and Lilly. OP reports participation in a spon- the prospective German TMK cohort study. Breast. 2017;34:122-130. sored speakers’ bureau for Takeda, Roche, Pfizer, Novartis 8. Gobbini E, Ezzalfani M, Dieras V, et al. Time trends of overall survival and Lilly. SPS has participated in a speakers’ bureau and among metastatic breast cancer patients in the real-life ESME cohort. received honoraria from Roche, AstraZeneca, Novartis, Eur J Cancer. 2018;96:17-24. Pfizer, Nanostring and Teva; reports consultancy for Roche, 9. Deluche E, Antoine A, Bachelot T, et al. Contemporary outcomes of fi metastatic breast cancer among 22,000 women from the multicentre AstraZeneca, Novartis and P zer. FPL reports receipt of ESME cohort 2008-2016. Eur J Cancer. 2020;129:60-70. grants/research support from Roche; receipt of honoraria 10. Malmgren JA, Mayer M, Atwood MK, et al. Differential presentation or consultation fees from Roche, Puma, Pierre Fabre and survival of de novo and recurrent metastatic breast cancer over and AstraZeneca. AP reports personal financial interests and time: 1990-2010. Breast Cancer Res Treat. 2018;167(2):579-590. lecture fees for Roche, Pfizer, Novartis, Amgen, BMS and 11. Breast Cancer Foundation NZ. “I’m still here”. Insights into livingdand dyingewith advanced breast cancer in New Zealand. Breast Cancer Daiichi Sankyo; participation in an advisory role/consultancy Foundation NZ. Available at https://www.breastcancerfound for Roche, Pfizer, Novartis, Amgen, BMS, Puma and Onco- ation.org.nz/what-we-do/advocacy/abcinnz. Accessed July 10, 2020. lytics Biotech; institutional financial interests include con- 12. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: tracted research for Novartis, Nanostring, Roche and GLOBOCAN estimates of incidence and mortality worldwide for 36 Boehringer; lecture fees from Nanostring technologies; cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. 13. Cherny NI, Dafni U, Bogaerts J, et al. ESMO-magnitude of clinical clinical trials for Novartis, Roche, Boehringer, Daiichi Sankyo, benefit scale version 1.1. Ann Oncol. 2017;28(10):2340-2366. Pfizer, Lilly and Amgen. HSR reports receipt of grants/ 14. Dykewicz CA. Summary of the guidelines for preventing opportunistic research support from Pfizer, Merck, Novartis, Lilly, infections among hematopoietic stem cell transplant recipients. Clin

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 23 Annals of Oncology F. Cardoso et al.

Infect Dis. 2001;33(2):139-144 (adapted from: Gross PA, Barrett TL, 35. Hey SP, Gyawali B, D’Andrea E, et al. A systematic review and meta- Dellinger EP, et al. Purpose of quality standards for infectious dis- analysis of bevacizumab in first-line metastatic breast cancer: lessons eases. Clin Infect Dis. 1994;1918:1421). for research and regulatory enterprises. J Natl Cancer Inst. 15. Mack JW, Weeks JC, Wright AA, et al. End-of-life discussions, goal 2020;112(4):335-342. attainment, and distress at the end of life: predictors and outcomes 36. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus of receipt of care consistent with preferences. J Clin Oncol. endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307- 2010;28(7):1203-1208. 316. 16. Smith-Uffen MES, Johnson SB, Martin AJ, et al. Estimating survival in 37. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus advanced cancer: a comparison of estimates made by oncologists and fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514- patients. Support Care Cancer. 2020;28(7):3399-3407. 524. 17. Hagerty RG, Butow PN, Ellis PM, et al. Communicating prognosis in 38. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of cancer care: a systematic review of the literature. Ann Oncol. ribociclib and fulvestrant in hormone receptor-positive, human 2005;16(7):1005-1053. epidermal growth factor receptor 2-negative advanced breast cancer: 18. Fried TR, Bradley EH, O’Leary J. Prognosis communication in serious MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. illness: perceptions of older patients, caregivers, and clinicians. JAm 39. Sledge Jr GW, Toi M, Neven P, et al. The effect of abemaciclib plus Geriatr Soc. 2003;51(10):1398-1403. fulvestrant on overall survival in hormone receptor-positive, erbb2- 19. Mack JW, Cronin A, Keating NL, et al. Associations between end-of-life negative breast cancer that progressed on endocrine therapy- discussion characteristics and care received near death: a prospective MONARCH 2: a randomized clinical trial. JAMA Oncol. 2019;6(1): cohort study. J Clin Oncol. 2012;30(35):4387-4395. 116-124. 20. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life 40. Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in discussions, patient mental health, medical care near death, combination with fulvestrant in women with HRþ/HER2- advanced and caregiver bereavement adjustment. JAMA. 2008;300(14): breast cancer who had progressed while receiving endocrine therapy. 1665-1673. J Clin Oncol. 2017;35(25):2875-2884. 21. Weeks JC, Cook EF, O’Day SJ, et al. Relationship between cancer 41. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy patients’ predictions of prognosis and their treatment preferences. for premenopausal women with hormone-receptor-positive, JAMA. 1998;279(21):1709-1714. advanced breast cancer (MONALEESA-7): a randomised phase 3 22. Pronzato P, Bertelli G, Losardo P, et al. What do advanced cancer trial. Lancet Oncol. 2018;19(7):904-915. patients know of their disease? A report from Italy. Support Care 42. Tripathy D, Sohn J, Im S-A, et al. Abstract GS2-05: first-line ribociclib vs Cancer. 1994;2(4):242-244. placebo with goserelin and tamoxifen or a non-steroidal aromatase in- 23. Jenkins V, Fallowfield L, Saul J. Information needs of patients with hibitor in premenopausal women with hormone receptor-positive, HER2- cancer: results from a large study in UK cancer centres. Br J Cancer. negative advanced breast cancer: results from the randomized phase III 2001;84(1):48-51. MONALEESA-7 trial. Cancer Res. 2018;78(4 Supplement). GS2-05. 24. Arraras JI, Greimel E, Chie WC, et al. Cross-cultural differences in 43. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in information disclosure evaluated through the EORTC questionnaires. advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. Psychooncology. 2013;22(2):268-275. 44. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line 25. Fallowfield LJ, Jenkins VA, Beveridge HA. Truth may hurt but deceit therapy for HR-positive, advanced breast cancer. N Engl J Med. hurts more: communication in palliative care. Palliat Med. 2016;375(18):1738-1748. 2002;16(4):297-303. 45. Rugo HS, Finn RS, Diéras V, et al. Palbociclib plus letrozole as first-line 26. Barnett MM. Does it hurt to know the worst?epsychological therapy in estrogen receptor-positive/human epidermal growth fac- morbidity, information preferences and understanding of prognosis tor receptor 2-negative advanced breast cancer with extended follow- in patients with advanced cancer. Psychooncology. 2006;15(1): up. Breast Cancer Res Treat. 2019;174(3):719-729. 44-55. 46. di Leo A, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial 27. Enzinger AC, Zhang B, Schrag D, et al. Outcomes of prognostic therapy for patients with HRþ/HER2- advanced breast cancer. Ann disclosure: associations with prognostic understanding, distress, and Oncol. 2017;28(suppl 5):v605-v649. relationship with physician among patients with advanced cancer. 47. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results J Clin Oncol. 2015;33(32):3809-3816. from MONALEESA-2, a phase 3 trial of first-line ribociclib þ 28. Gattellari M, Voigt KJ, Butow PN, et al. When the treatment goal is letrozole in hormone receptor-positive (HRþ), HER2-negative not cure: are cancer patients equipped to make informed decisions? (HER2e), advanced breast cancer (ABC). JClinOncol. 2017;35 J Clin Oncol. 2002;20(2):503-513. (15_suppl):1038. 29. Hagerty RG, Butow PN, Ellis PM, et al. Communicating with realism 48. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus pal- and hope: incurable cancer patients’ views on the disclosure of bociclib versus fulvestrant plus placebo for treatment of hormone- prognosis. J Clin Oncol. 2005;23(6):1278-1288. receptor-positive, HER2-negative metastatic breast cancer that 30. Smith TJ, Dow LA, Virago E, et al. Giving honest information to pa- progressed on previous endocrine therapy (PALOMA-3): final analysis tients with advanced cancer maintains hope. Oncology (Williston of the multicentre, double-blind, phase 3 randomised controlled trial. Park). 2010;24(6):521-525. Lancet Oncol. 2016;17(4):425-439. 31. Kiely BE, McCaughan G, Christodoulou S, et al. Using scenarios to 49. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as explain life expectancy in advanced cancer: attitudes of people with a initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32): cancer experience. Support Care Cancer. 2013;21(2):369-376. 3638-3646. 32. Stockler MR, Tattersall MH, Boyer MJ, et al. Disarming the guarded 50. Harbeck N, Iyer S, Bhattacharyya H, et al. Impact of disease prognosis: predicting survival in newly referred patients with incur- progression status on time to deterioration of patient reported able cancer. Br J Cancer. 2006;94(2):208-212. health related quality of life in first line ERþ HER2- advanced/ 33. Kiely BE, Martin AJ, Tattersall MH, et al. The median informs metastatic breast cancer patients in the PALOMA-2 study. Breast. the message: accuracy of individualized scenarios for survival 2017;36:S43. time based on oncologists’ estimates. J Clin Oncol. 2013;31(28):3565- 51. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a ran- 3571. domized study of abemaciclib as initial therapy for advanced breast 34. Fallowfield LJ, Catt SL, May SF, et al. Therapeutic aims of drugs of- cancer. NPJ Breast Cancer. 2019;5:5. fering only progression-free survival are misunderstood by patients, 52. Rugo HS, Diéras V, Gelmon KA, et al. Impact of palbociclib plus and oncologists may be overly optimistic about likely benefits. Sup- letrozole on patient-reported health-related quality of life: results port Care Cancer. 2017;25(1):237-244. from the PALOMA-2 trial. Ann Oncol. 2018;29(4):888-894.

24 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

53. Verma S, O’Shaughnessy J, Burris HA, et al. Health-related quality of 70. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, life (HRQoL) of postmenopausal women with hormone receptor- double-blind, phase III study of pembrolizumab þ chemotherapy positive (HRþ), human epidermal growth factor receptor 2- versus placebo þ chemotherapy for previously untreated locally negative (HER2-) advanced breast cancer (ABC) treated with recurrent inoperable or metastatic triple-negative breast cancer. J Clin ribociclib þ letrozole: results from MONALEESA-2. J Clin Oncol. Oncol. 2020;38(15_suppl):1000. 2017;35(15_suppl):1020. 71. Cortés J, Lipatov O, Im S, et al. KEYNOTE-119: phase 3 study of 54. Harbeck N, Iyer S, Turner N, et al. Quality of life with palbociclib plus pembrolizumab (pembro) versus single-agent chemotherapy (chemo) fulvestrant in previously treated hormone receptor-positive, HER2- for metastatic triple-negative breast cancer (mTNBC). Ann Oncol. negative metastatic breast cancer: patient-reported outcomes from 2019;30(suppl 5):v851-v934. the PALOMA-3 trial. Ann Oncol. 2016;27(6):1047-1054. 72. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in 55. Kaufman PA, Toi M, Neven P, et al. Health-related quality of life in refractory metastatic triple-negative breast cancer. N Engl J Med. MONARCH 2: abemaciclib plus fulvestrant in hormone receptor- 2019;380(8):741-751. positive, HER2-negative advanced breast cancer after endocrine 73. Paluch-Shimon S, Cardoso F, Sessa C, et al. Prevention and screening therapy. Oncologist. 2020;25(2):e243-e251. in BRCA mutation carriers and other breast/ovarian hereditary cancer 56. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and syndromes: ESMO Clinical Practice Guidelines for cancer prevention fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20): and screening. Ann Oncol. 2016;27(suppl 5):v103-v110. 1926-1936. 74. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: a phase II study 57. Verma S, Bartlett CH, Schnell P, et al. Palbociclib in combination with of olaparib monotherapy in metastatic breast cancer patients fulvestrant in women with hormone receptor-positive/HER2-negative with germline or somatic mutations in DNA damage response (DDR) advanced metastatic breast cancer: detailed safety analysis from a pathway genes (olaparib expanded). J Clin Oncol. 2020;38(15_suppl): multicenter, randomized, placebo-controlled, phase III study (PAL- 1002. OMA-3). Oncologist. 2016;21(10):1165-1175. 75. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and 58. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, tolerability results: olaparib versus chemotherapy treatment of phy- hormone receptor-positive advanced breast cancer. N Engl J Med. sician’s choice in patients with a germline BRCA mutation and 2019;380(20):1929-1940. HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4): 59. Nunnery SE, Mayer IA. Management of toxicity to isoform a-specific 558-566. PI3K inhibitors. Ann Oncol. 2019;30(suppl 10):x21-x26. 76. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast 60. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib (ALP) þ fulvestrant cancer in patients with a germline BRCA mutation. N Engl J Med. (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor- 2017;377(6):523-533. positive (HRþ), human epidermal growth factor receptor 2-negative 77. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced (HER2e) advanced breast cancer (ABC) previously treated with cyclin- breast cancer and a germline BRCA mutation. N Engl J Med. dependent kinase 4/6 inhibitor (CDKi) þ aromatase inhibitor (AI): 2018;379(8):753-763. BYLieve study results. J Clin Oncol. 2020;38(15_suppl):1006. 78. Litton JK, Hurvitz SA, Mina LA, et al. Talazoparib in germline BRCA1/2- 61. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International mutated HER2-negative advanced breast cancer: final overall survival Consensus Guidelines for advanced breast cancer (ABC 4). Ann Oncol. results from randomized phase 3 EMBRACA trial. AACR virtual annual 2018;29(8):1634-1657. meeting. 27-28 April 2020. Abstract CT071. 62. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and cape- 79. Dieras VC, Han HS, Kaufman B, et al. Phase 3 study of veliparib with citabine for HER2-positive metastatic breast cancer. N Engl J Med. carboplatin and paclitaxel in HER2-negative advanced/metastatic 2020;382(7):597-609. gBRCA-associated breast cancer. Ann Oncol. 2019;30(suppl 5):v851- 63. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival v934. with tucatinib plus trastuzumab and capecitabine for previously 80. Diaz Jr LA, Bardelli A. Liquid biopsies: genotyping circulating tumor treated HER2-positive breast cancer with brain metastases in the DNA. J Clin Oncol. 2014;32(6):579-586. HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. 81. Alimirzaie S, Bagherzadeh M, Akbari MR. Liquid biopsy in breast 64. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in pre- cancer: a comprehensive review. Clin Genet. 2019;95(6):643-660. viously treated HER2-positive breast cancer. N Engl J Med. 82. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA 2020;382(7):610-621. analysis in patients with cancer: American Society of Clinical 65. Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: a phase Oncology and College of American Pathologists joint review. J Clin 3 (P3) study of margetuximab (M) þ chemotherapy (C) versus tras- Oncol. 2018;36(16):1631-1641. tuzumab (T) þ C in patients (pts) with HER2þ metastatic (met) breast 83. Condorelli R, Mosele F, Verret B, et al. Genomic alterations in breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. cancer: level of evidence for actionability according to ESMO Scale for 2019;37(15_suppl):1000. Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 66. Saura C, Oliveira M, Feng Y-H, et al. Neratinib þ capecitabine versus 2019;30(3):365-373. lapatinib þ capecitabine in patients with HER2þ metastatic breast 84. Rugo HS, Mayer I, Conte P, et al. Abstract CT142: prevalence of cancer previously treated with 2 HER2-directed regimens: findings PIK3CA mutations in patients with hormone receptor-positive, human from the multinational, randomized, phase III NALA trial. J Clin Oncol. epidermal growth factor-2-negative advanced breast cancer from the 2019;37(15_suppl):1002. SOLAR-1 trial. Cancer Res. 2019;79(13 Supplement):CT142. 67. Pivot X, Manikhas A, Zurawski_ B, et al. CEREBEL (EGF111438): a phase 85. Juric D, Ciruelos E, Rubovszky G, et al. Abstract GS3-08: Alpelisib þ III, randomized, open-label study of lapatinib plus capecitabine versus fulvestrant for advanced breast cancer: subgroup analyses from trastuzumab plus capecitabine in patients with human epidermal the phase III SOLAR-1 trial. Cancer Res. 2019;79(4 Supplement). GS3- growth factor receptor 2-positive metastatic breast cancer. J Clin 08. Oncol. 2015;33(14):1564-1573. 86. Juric D, Andre F, Singer CF, et al. Abstract P4-10-04: clinical outcomes 68. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in of alpelisib in hormone receptor-positive, human epidermal growth advanced triple-negative breast cancer. N Engl J Med. 2018;379(22): factor receptor-2-negative advanced breast cancer by next- 2108-2121. generation sequencing-detected PIK3CA alteration status and 69. Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel phosphatase and tensin homolog loss: biomarker analysis from the as first-line treatment for unresectable, locally advanced or meta- SOLAR-1 study. Cancer Res. 2020;80(4 Supplement). P4-10-04. static triple-negative breast cancer (IMpassion130): updated efficacy 87. Fribbens C, O’Leary B, Kilburn L, et al. Plasma ESR1 mutations and the results from a randomised, double-blind, placebo-controlled, phase 3 treatment of estrogen receptor-positive advanced breast cancer. trial. Lancet Oncol. 2020;21(1):44-59. J Clin Oncol. 2016;34(25):2961-2968.

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 25 Annals of Oncology F. Cardoso et al.

88. Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis 111. Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of Primers. 2019;5(1):66. recurrence after hormone replacement therapy in breast cancer 89. Adam J, Le Stang N, Rouquette I, et al. Multicenter harmonization survivors. J Natl Cancer Inst. 2008;100(7):475-482. study for PD-L1 IHC testing in non-small-cell lung cancer. Ann Oncol. 112. Fahlén M, Fornander T, Johansson H, et al. Hormone replacement 2018;29(4):953-958. therapy after breast cancer: 10 year follow up of the Stockholm 90. Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohisto- randomised trial. Eur J Cancer. 2013;49(1):52-59. chemistry (IHC) assays in unresectable locally advanced or metastatic 113. Duijts SF, van Beurden M, Oldenburg HS, et al. Efficacy of cognitive triple-negative breast cancer (mTNBC): post-hoc analysis of IMpas- behavioral therapy and physical exercise in alleviating treatment- sion130. Ann Oncol. 2019;30(suppl 5):v851-v934. induced menopausal symptoms in patients with breast cancer: re- 91. Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth sults of a randomized, controlled, multicenter trial. J Clin Oncol. factor receptor 2 testing in breast cancer: American Society of Clinical 2012;30(33):4124-4133. Oncology/College of American Pathologists Clinical Practice Guideline 114. Mann E, Smith MJ, Hellier J, et al. Cognitive behavioural treatment for focused update. J Clin Oncol. 2018;36(20):2105-2122. women who have menopausal symptoms after breast cancer treat- 92. Gloyeske NC, Dabbs DJ, Bhargava R. Low ERþ breast cancer: is this a ment (MENOS 1): a randomised controlled trial. Lancet Oncol. distinct group? Am J Clin Pathol. 2014;141(5):697-701. 2012;13(3):309-318. 93. Deyarmin B, Kane JL, Valente AL, et al. Effect of ASCO/CAP guidelines 115. Stefanopoulou E, Grunfeld EA. Mind-body interventions for vaso- for determining ER status on molecular subtype. Ann Surg Oncol. motor symptoms in healthy menopausal women and breast cancer 2013;20(1):87-93. survivors. A systematic review. J Psychosom Obstet Gynaecol. 94. Iwamoto T, Booser D, Valero V, et al. Estrogen receptor (ER) mRNA and 2017;38(3):210-225. ER-related gene expression in breast cancers that are 1% to 10% ER- 116. Lahart IM, Metsios GS, Nevill AM, et al. Physical activity for women positive by immunohistochemistry. J Clin Oncol. 2012;30(7):729-734. with breast cancer after adjuvant therapy. Cochrane Database Syst 95. Balduzzi A, Bagnardi V, Rotmensz N, et al. Survival outcomes in breast Rev. 2018;1(1):Cd011292. cancer patients with low estrogen/progesterone receptor expression. 117. Hartman SJ, Nelson SH, Myers E, et al. Randomized controlled trial of Clin Breast Cancer. 2014;14(4):258-264. increasing physical activity on objectively measured and self-reported 96. Yi M, Huo L, Koenig KB, et al. Which threshold for ER positivity? a cognitive functioning among breast cancer survivors: the memory & retrospective study based on 9639 patients. Ann Oncol. 2014;25(5): motion study. Cancer. 2018;124(1):192-202. 1004-1011. 118. Ramaswami R, Villarreal MD, Pitta DM, et al. Venlafaxine in manage- 97. Chen T, Zhang N, Moran MS, et al. Borderline ER-positive primary ment of hot flashes in women with breast cancer: a systematic review breast cancer gains no significant survival benefit from endocrine and meta-analysis. Breast Cancer Res Treat. 2015;152(2):231-237. therapy: a systematic review and meta-analysis. Clin Breast Cancer. 119. Johns C, Seav SM, Dominick SA, et al. Informing hot flash treatment 2018;18(1):1-8. decisions for breast cancer survivors: a systematic review of ran- 98. Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and proges- domized trials comparing active interventions. Breast Cancer Res terone receptor testing in breast cancer: ASCO/CAP Guideline update. Treat. 2016;156(3):415-426. J Clin Oncol. 2020;38(12):1346-1366. 120. Shan D, Zou L, Liu X, et al. Efficacy and safety of gabapentin and 99. Coleman R, Hadji P, Body JJ, et al. Bone health in cancer: ESMO pregabalin in patients with vasomotor symptoms: a systematic review Clinical Practice Guidelines. Ann Oncol. 2020. https://doi.org/10. and meta-analysis. Am J Obstet Gynecol. 2020;222(6):564-579.e12. 1016/j.annonc.2020.07.019. Online ahead of print. 121. Leon-Ferre RA, Novotny PJ, Wolfe EG, et al. Oxybutynin vs placebo for 100. Franzoi MA, Hortobagyi GN. Leptomeningeal carcinomatosis in hot flashes in women with or without breast cancer: a randomized, patients with breast cancer. Crit Rev Oncol Hematol. 2019;135:85-94. double-blind clinical trial (ACCRU SC-1603). JNCI Cancer Spectr. 101. Le Rhun E, Weller M, Brandsma D, et al. EANO-ESMO Clinical Practice 2020;4(1):pkz088. Guidelines for diagnosis, treatment and follow-up of patients with 122. Chen WY, Giobbie-Hurder A, Gantman K, et al. A randomized, leptomeningeal metastasis from solid tumours. Ann Oncol. placebo-controlled trial of melatonin on breast cancer survivors: 2017;28(suppl 4):iv84-iv99. impact on sleep, mood, and hot flashes. Breast Cancer Res Treat. 102. Le Rhun E, Preusser M, van den Bent M, et al. How we treat patients 2014;145(2):381-388. with leptomeningeal metastases. ESMO Open. 2019;4(suppl 2): 123. Innominato PF, Lim AS, Palesh O, et al. The effect of melatonin on e000507. sleep and quality of life in patients with advanced breast cancer. 103. Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO Support Care Cancer. 2016;24(3):1097-1105. guideline update for the prevention of chemotherapy- and 124. Mayer S, Iborra S, Grimm D, et al. Sexual activity and quality of life in radiotherapy-induced nausea and vomiting and of nausea and vomiting patients after treatment for breast and ovarian cancer. Arch Gynecol in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-v133. Obstet. 2019;299(1):191-201. 104. Cardoso F, Costa A, Norton L, et al. 1st International consensus 125. Stute P. Is vaginal hyaluronic acid as effective as vaginal estriol guidelines for advanced breast cancer (ABC 1). Breast. 2012;21(3): for vaginal dryness relief? Arch Gynecol Obstet. 2013;288(6):1199- 242-252. 1201. 105. Knaul FM, Farmer PE, Krakauer EL, et al. Alleviating the access abyss 126. Serati M, Bogani G, Di Dedda MC, et al. A comparison between in palliative care and pain reliefdan imperative of universal health vaginal estrogen and vaginal hyaluronic for the treatment of dys- coverage: the Lancet Commission report. Lancet. 2018;391(10128): pareunia in women using hormonal contraceptive. Eur J Obstet 1391-1454. Gynecol Reprod Biol. 2015;191:48-50. 106. Fallon M, Giusti R, Aielli F, et al. Management of cancer pain in adult 127. Origoni M, Cimmino C, Carminati G, et al. Postmenopausal vulvova- patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(suppl ginal atrophy (VVA) is positively improved by topical hyaluronic acid 4):iv166-iv191. application. A prospective, observational study. Eur Rev Med Phar- 107. Jones MR, Viswanath O, Peck J, et al. A brief history of the opioid macol Sci. 2016;20(20):4190-4195. epidemic and strategies for pain medicine. Pain Ther. 2018;7(1):13-21. 128. Donders G, Bellen G, Neven P, et al. Effect of ultra-low-dose estriol 108. Page R, Blanchard E. Opioids and cancer pain: patients’ needs and and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and in- access challenges. J Oncol Pract. 2019;15(5):229-231. fectious markers of the vaginal ecosystem in postmenopausal women 109. Cannabis and cannabinoids. Med Lett Drugs Ther. 2019;61(1585):179- with breast cancer on aromatase inhibitors. Eur J Clin Microbiol Infect 182. Dis. 2015;34(10):2023-2028. 110. Alves P, Amaral C, Teixeira N, et al. Cannabis sativa: much more 129. Buchholz S, Mögele M, Lintermans A, et al. Vaginal estriol-lactobacilli beyond D(9)-tetrahydrocannabinol. Pharmacol Res. 2020;157: combination and quality of life in endocrine-treated breast cancer. 104822. Climacteric. 2015;18(2):252-259.

26 https://doi.org/10.1016/j.annonc.2020.09.010 Volume 31 - Issue 12 - 2020 F. Cardoso et al. Annals of Oncology

130. Mazzarello S, Hutton B, Ibrahim MFK, et al. Management of uro- 136. Bartula I, Sherman KA. The Female Sexual Functioning Index (FSFI): genital atrophy in breast cancer patients: a systematic review of evaluation of acceptability, reliability, and validity in women with available evidence from randomized trials. Breast Cancer Res Treat. breast cancer. Support Care Cancer. 2015;23(9):2633-2641. 2015;152(1):1-8. 137. Mancha RG, Muñoz M, de la Cruz-Merino L, et al. Development and 131. Caruso S, Cianci S, Amore FF, et al. Quality of life and sexual function validation of a sexual relations satisfaction scale in patients with breast of naturally postmenopausal women on an ultralow-concentration cancer - “SEXSAT-Q”. Health Qual Life Outcomes. 2019;17(1):143. estriol vaginal gel. Menopause. 2016;23(1):47-54. 138. Reese JB, Sorice KA, Zimmaro LA, et al. Communication about 132. American College of Obstetricians and Gynecologists’ Committee on sexual health in breast cancer: what can we learn from patients’ Gynecologic Practice, Farrell R. ACOG Committee opinion no. 659: the self-report and clinic dialogue? Patient Educ Couns. 2020;103(9): use of vaginal estrogen in women with a history of estrogen- 1821-1829. dependent breast cancer. Obstet Gynecol. 2016;127(3):e93-e96. 139. Dai Y, Cook OY, Yeganeh L, et al. Patient-reported barriers and facili- 133. Melisko ME, Goldman ME, Hwang J, et al. Vaginal testosterone tators to seeking and accessing support in gynecologic and breast cream vs estradiol vaginal ring for vaginal dryness or decreased cancer survivors with sexual problems: a systematic review of libido in women receiving aromatase inhibitors for early-stage qualitative and quantitative studies. J Sex Med. 2020;17(7): breast cancer: a randomized clinical trial. JAMA Oncol. 2017;3(3): 1326-1358. 313-319. 140. Atkins L, Fallowfield LJ. Fallowfield’s sexual activity questionnaire in 134. Hersant B, SidAhmed-Mezi M, Belkacemi Y, et al. Efficacy of injecting women with without and at risk of cancer. Menopause Int. platelet concentrate combined with hyaluronic acid for the treatment 2007;13(3):103-109. of vulvovaginal atrophy in postmenopausal women with history of 141. Gompel A, Ramirez I, Bitzer J. Contraception in cancer survivors - an breast cancer: a phase 2 pilot study. Menopause. 2018;25(10):1124- expert review Part I. Breast and gynaecological cancers. Eur J Con- 1130. tracept Reprod Health Care. 2019;24(3):167-174. 135. Romero-Otero J, Lauterbach R, Aversa A, et al. Laser-based devices for 142. ABC Global Alliance. ABC Global Charter 2018. ABC Global Alliance. female genitourinary indications: position statements from the Available at https://www.abcglobalalliance.org/wp-content/uploads/ European Society for Sexual Medicine (ESSM). JSexMed. 2020;17(5): 2018/06/ABC-Global-Charter-Booklet-June-2018-Final.pdf. Accessed 841-848. July 15, 2020.

Volume 31 - Issue 12 - 2020 https://doi.org/10.1016/j.annonc.2020.09.010 27