Hormone receptor positive breast cancer has an evolving therapeutic scenario.

Estrogen receptor is the main driver of tumor growth for this breast cancer subtype.

The mainstay of the treatment is represented by endocrine therapy.

The development of endocrine resistance represents a critical challenge.

Novel estrogen receptor signalling inhibitors are currently under development.

Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in hormone receptor positive (HR+) breast cancer (BC). Thus, endocrine therapy (ET) alone or in combination with targeted agents constitutes the mainstay of the treatment for this BC subtype. Despite its efficacy, intrinsic or acquired resistance to ET occurs in a large proportion of cases, mainly due to aberrant activation of ER signaling (i.e. through ligand-independent ER activation, in the presence of estrogen receptor 1 (ESR1) gene aberration or ER protein phosphorylation) and/or the upregulation of escape pathways, such as the PI3K/AKT/mTOR pathway.

Therefore, the development of new ER pathway targeting agents remains essential to delay and overcome ET resistance, enhance treatment efficacy and tolerability, and ultimately prolong patient survival and improve their quality of life.

Several novel ER targeting agents are currently under investigation. Among these, the oral selective ER degraders (SERDs) represent the pharmacological class at the most advanced stage of development and promise to enrich the therapeutic armamentarium of HR+ BC in the next few years, as they showed promising results in several clinical trials, either as single ET agents or in combination with targeted therapies.

In this manuscript, we aim to provide a comprehensive overview on the clinical development of novel ER targeting agents, reporting the most up-to-date evidence on oral SERDs and other compounds, including new selective ER modulators (SERMs), ER proteolysis targeting chimera (PROTACs), selective ER covalent antagonists (SERCAs), complete ER antagonists (CERANs), selective human ER partial agonists (ShERPAs). Furthermore, we discuss the potential implications of introducing these novel treatment strategies in the evolving and complex therapeutic scenario of HR+ BC.

ER signaling

Endocrine resistance

SERDs

PROTACs

SERCAs

Martina Pagliuca, MD, PhD student. Currently completing her residency in Medical Oncology at University Federico II of Naples (Italy) and conducting research activities at Gustave Roussy (Villejuif, Paris; France). Her areas of focus interest are breast cancer and translational research.

Marco Donato, MD. Graduated from University of Messina (Italy), currently completing his residency in Medical Oncology at Campus Bio-medico University of Rome. His areas of interest are breast cancer and clinical research.

Agostina Lagodin D’Amato, MD. Resident in Medical Oncology at Ospedale Policlinico San Martino, Università di Genova, Italy. Interested in skin cancer and Immuno-Oncology.

Mario Rosanova, MD. Currently working as a physician in the Oncology Unit of Ospedale del Mare (Naples, Italy), he completed his medical oncology residency at University Federico II of Naples (Italy) in 2018. Since february 2020, he's member of the multidisciplinary team for breast cancer care of Azienda Sanitaria Locale Napoli 1 Centro (Naples, Italy). His areas of focus interest are breast cancer and gastrointestinal cancers. He's also active in the field of clinical research.

Anna Orsola Maria Russo, MD. Medical oncologist at Oncology Division Ospedale delle Murge "Fabio Perinei" Altamura (BA). Previously resident in Medical Oncology at University Federico II of Naples. Her areas of focus interest are breast cancer and clinical trials.

Roberta Scafetta, MD. Graduated from La Sapienza University in Rome, currently completing her residency in Medical Oncology at Campus Bio-medico University of Rome. Her areas of interest are breast cancer and clinical research.

Carmine De Angelis, MD, PhD. Assistant Professor of Medical Oncology at the Department of Clinical Medicine and Surgery of University of Naples Federico II and Adjunct Professor at the Lester and Sue Smith Breast Center of Baylor College of Medicine. His research focus on understanding mechanisms of endocrine and anti-HER2 resistance and on the development and optimization of innovative therapies for women with breast cancer.

Meghna Trivedi, PharmD, PhD. Currently is a Director of Clinical and Translational Research and an Associate Professor of Pharmacy Practice and Translational Research and of Pharmacology at the University of Houston College of Pharmacy. Her areas of interest are discovery of novel biomarkers, targets, and drugs in breast cancer.

Fabrice André, MD, PhD. He is a past recipient of Young Investigator and Career Development awards from the American Society of Clinical Oncology (ASCO) and is currently Head of Research and Professor in the Department of Medical Oncology, Institut Gustave Roussy, Villejuif (France). His research work in the field of biomarkers and personalised therapies focuses on biomarker discovery, development of targeted agents and implementation of personalised medicine. He is also leading phase I-III trials testing targeted agents in the field of breast cancer and large national trials testing implementation of high throughput technologies in the health care system. Professor André is chairman of the biomarker group at UNICANCER (French cooperative group) and Editor-in-Chief of Annals of Oncology. Professor André is currently chair of the ESMO Translational Research and Precision Medicine Working Group and member of the ESMO Breast Cancer Faculty. He is ESMO elected President 2025–2026.

Grazia Arpino, MD, PhD. Currently she is professor in Oncology at the University of Naples Federico II, she works in the University Hospital Federico II where she is the head of the unit developing novel predictive and prognostic molecular markers in breast cancer. Her research interests mainly focus on mechanisms of endocrine and anti-HER2 resistance development and optimization of adjuvant therapies strategies in pre- and post-menopausal women with breast cancer.

Lucia Del Mastro, MD, is Director of the clinical Oncology Unit at Ospedale Policlinico San Martino, Genova (Italy) and full professor of oncology at University of Genova, Italy. Her areas of focus interest are breast cancer, translational research and supportive care.

Michelino De Laurentiis, MD, PhD. Between 2002 and 2010 he held the position of Assistant Professor of Medical Oncology in the Department of Endocrinology and Molecular and Clinical Oncology, University ‘Federico II’, Naples. In 2015 he was appointed as Affiliate Professor at the Temple University of Philadelphia, PA, USA. He currently heads the Department of Breast and Thoracic Oncology at the National Cancer Institute “Fondazione Pascale” in Naples, Italy. He is a founding member of the main Italian group for clinical research in breast cancer (Gruppo Italiano Mammella GIM). He also sits as a member in the Scientific Committee and the Translational Research Committee of the GIM and he is directly responsible for the coordination of clinical breast cancer trials and translational studies. His main research interests are breast cancer treatment and prognostic and predictive factors.

Fabio Puglisi, MD, PhD. He is Full Professor of medical oncology and head of the school of medical oncology at the University of Udine, Italy. He is the Chief of the Department of Medical Oncology and the Director of the Unit of Medical Oncology and Cancer Prevention at the National Cancer Institute, IRCCS Centro di Riferimento Oncologico, Aviano (PN), Italy. He is author of several publications in scientific peer-reviewed journals, focused on clinical and translational studies on breast cancer.

Mario Giuliano, MD, PhD. Associate Professor of Medical Oncology at the Department of Clinical Medicine and Surgery of University of Naples Federico II and formerly Adjunct Professor at the Lester and Sue Smith Breast Center of Baylor College of Medicine. Professor Giuliano has experience on phase II and III clinical trials and basic/translational research projects in breast cancer and rare tumors.

© 2022 The Authors. Published by Elsevier B.V.