REVIEW article
Front. Oncol.
Sec. Breast Cancer
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1596634
Pharmacologic Management of HR+/HER2-mBC: A Clinically Oriented Review
Provisionally accepted
- 1Cantonal Hospital Baselland (KSBL), Liestal, Switzerland
- 2Institute of Oncology Ljubljana, Ljubljana, Slovenia
- 3University of Ljubljana, Ljubljana, Slovenia
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Breast cancer (BC) remains the most prevalent cancer among women worldwide, with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) subtypes representing approximately 75% of cases. Endocrine therapy (ET) has been foundational in HR+ BC treatment, significantly reducing recurrence and mortality rates, yet resistance to ET remains a critical challenge, particularly in the metastatic setting. Recent treatment advancements-especially CDK4/6 inhibitors (CDK4/6i) in first-line therapy, have reshaped management of HR+ HER2-mBC. Additionally, novel agents like selective estrogen receptor degraders (SERDs) and proteolysistargeting chimeras (PROTACs), have proven to be effective against ER-resistance inducing mutations, such as ESR1, while poly ADP-ribose polymerase inhibitors (PARPi) showed targeted benefit in BRCA-mutated tumors. In breast cancer expressing AKT/PIK3CA pathway alterations, drugs like alpelisib, capivasertib, and inavolisib have recently been approved, demonstrating improved PFS in this specific patient population. Recent developments of antibody-drug conjugates (ADCs) have also extended therapeutic options to previously labeled HER2-negative tumors, with drugs like trastuzumab deruxtecan (T-DXd) demonstrating efficacy in newly emerged HER2-low and HER2-ultralow pathologic subgroups, extending median overall survival to almost 2 years. Most of these drugs have paved the way for personalized medicine and opened questions around optimal sequencing of ET and application of combination therapies, which continue to be investigated through clinical trials. This review seeks to highlight current and emerging treatment strategies addressing ET resistance to improve survival outcomes for HR+ mBC patients, emphasizing the need for personalized approaches.
Keywords: Hormone receptor positive breast cancer, Endocrine resistance, metastatic breast cancer, CDK4/6 inhibitors, Aromatase Inhibitors
Received: 19 Mar 2025; Accepted: 08 Aug 2025.
Copyright: © 2025 Chiru, Sojak, Landin, Vetter and Grašič Kuhar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Elena Diana Chiru, Cantonal Hospital Baselland (KSBL), Liestal, 4410, Switzerland
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