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Review Breast cancer Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer Peter Schmid Barts Cancer Institute, London, UK E ndocrine treatment constitutes the therapeutic backbone for patients with oestrogen and/or progesterone receptor-positive breast cancer unless there is visceral crisis or suspected or known endocrine resistance. Whether all patients who are suitable for endocrine therapy should receive combination therapy or whether there remains a role for single-agent endocrine therapy is yet to be determined. Cancer biology (ESR1 mutational status) and disease pattern determine the choice of single-agent endocrine treatment. Possibly, patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for single-agent endocrine therapy, whereas patients with more aggressive disease including visceral metastases might benefit from combination therapy. Improved guidance on selection and sequencing of treatments should become available once overall survival (OS) and progression-free survival (PFS) data have been reported from the ongoing trials in breast cancer, principally, FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021), which include different patient groups and, probably, different endocrine sensitivity. Keywords Hormone receptor-positive advanced breast cancer, selective oestrogen receptor modulators, aromatase inhibitors, selective oestrogen receptor degrader, endocrine resistance, endocrine sensitivity Disclosure: Peter Schmid declares personal fees from Pfizer, Boehringer, Bayer, Puma, Eisai, Celgene and Roche/Genetech. Acknowledgements: Medical writing including preparation of the drafts under the guidance of the author, was provided by Catherine Amey and Janet Manson from Touch Medical Media, which was funded by AstraZeneca. This article was reviewed by the journal’s advisory board before publication. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 7 August 2017 Accepted: 20 September 2017 Citation: European Oncology & Haematology, 2017;13(2):127–33 Corresponding Author: Peter Schmid, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London Charterhouse Square, London EC1M 6BQ, UK. E: Support: The publication of this article was sponsored by AstraZeneca. The views and opinions expressed in the article are those of the authors and not necessarily those of AstraZeneca. TOU CH MED ICA L MEDIA The majority (60–75%) of all breast cancers have oestrogen and/or progesterone receptors. 1 Endocrine treatment constitutes the therapeutic backbone for patients with this cancer subtype unless there is a visceral crisis or concern/proof of endocrine resistance, 2 as recommended by the third European School of Oncology (ESO)/European Society for Medical Oncology (ESMO) international consensus guidelines for Advanced Breast Cancer (ABC 3) 3 and the National Comprehensive Cancer Network (NCCN) guidelines. 4 Current endocrine therapy includes: selective oestrogen receptor modulators, aromatase inhibitors, and selective oestrogen-receptor degraders (Table 1), and the modes of action of these therapies are outlined in Figure 1. Not all patients have a response to first-line endocrine therapy (primary or de novo resistance). Such resistance occurs in approximately 40% of patients with hormone receptor (HR)-positive breast cancer, and even patients who do respond eventually exhibit acquired resistance. 5 Cytotoxic chemotherapy is also considered a first-line treatment option in patients diagnosed with HR-positive breast cancer. The decision for chemotherapy or endocrine therapy depends on a number of factors, outlined below, and there is a wide variation in the use of these treatments. 6 Endocrine resistance Several molecular mechanisms have been proposed to underlie endocrine resistance, including: loss of oestrogen receptor expression; altered activity of oestrogen-receptor co-regulators; deregulation of apoptosis and cell cycle signalling; hyperactive receptor tyrosine kinase; and stress/cell kinase pathways. 7 The oestrogen receptor may be activated in a ligand-independent manner via intracellular signal transduction pathways mediated either by the phosphatidylinositol- 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, (Figure 1) or the mitogen-activated protein kinase (MAPK) pathway which promotes oestrogen receptor phosphorylation and subsequently, activation. 8,9 In addition, mutations in the ESR1 gene have recently attracted attention as an important mechanism for endocrine resistance in metastatic breast cancer (MBC). These mutations occur in approximately 20–40% of patients with metastatic oestrogen receptor-positive disease who received endocrine therapies, with the higher occurrence in more advanced patients. 10 Clustered in a ‘hotspot’ within the ligand-binding domain (LBD) of the oestrogen receptor, these mutations lead to ligand-independent oestrogen receptor activity that promotes tumour growth, and partial resistance to endocrine therapy, and potentially enhanced metastatic capacity. 10 The purpose of this article is to provide a concise overview of endocrine therapeutic strategies for MBC, including studies with cohorts in first-line therapy, second-line and beyond. 127