Personalizing therapies over the course of hormone receptor-positive/HER2-negative metastatic breast cancer

Sep 23, 2026

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The hormone receptor (HR)-positive/HER2-negative breast cancer subtype represents most early and metastatic breast cancer cases, with a prolonged but variable clinical course. HR-positive/HER2-negative metastatic breast cancer shows marked intertumoral and intratumoral heterogeneity and, despite endocrine therapies being central, most patients eventually develop resistance. This review integrates current knowledge of intrinsic and acquired resistance mechanisms, including driver genomic alterations, and explains how genomic and transcriptomic profiling guides therapy selection and sequencing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages28

Reading Time1 h 11 min

AccessFree to download

Abstract

Introduction

Metastatic breast cancer burden and prognosis

Biomarker-based classification of HR-positive/HER2-negative disease

Treatment targets and therapeutic advances

DOI: 10. 3322/caac.70055 REVIEW ARTICLE Personalizing therapies over the course of hormone receptor-positive/HER2-negative metastatic breast cancer Akshara Singareeka Raghavendra MD, MS1 | Senthil Damodaran MD, PhD 1 | Carlos H. Barcenas MD, MSc1 | Suzanne A. Fuqua PhD2 | Rachel M. Layman MD 1 1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2Department of Medicine, Baylor College of Medicine, Houston, Texas, USA Correspondence Debu Tripathy, Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Email: [debu.tripathy@sbcglobal.net](debu.tripathy@sbcglobal.net) Debu Tripathy MD1 ABSTRACT The hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtype accounts for most early and metastatic breast cancer (MBC) cases. HR-positive/HER2-negative MBC is characterized by a relatively prolonged, although variable, disease course and substantial intertumoraland intratumoral heterogeneity. Although endocrine-based therapies remain the cornerstone of treatment, nearly all patients eventually develop resistance, which is increasingly addressed with biologically targeted agents and newer-generation cytotoxic drugs. This review summarizes the current understanding of HR-positive/HER2-negative MBC biology, highlighting mechanisms of intrinsic and acquired resistance, including driver genomic alterations that, along with clinical factors, help guide therapeutic choices and sequencing. The authors specify and discuss how genomic and transcriptomic profiling inform treatment selection and how side effects and overall patient experience are considered in decision making. Advancesin targeted therapies, such as CDK4/6 (cyclin-dependent kinase 4/6), PI3K (phosphatidylinositol 3-kinase), and AKT (protein kinase B) inhibitors, and nextgeneration estrogen receptor degraders are reviewed along with the expanding role of antibody–drug conjugates and biomarker-guided tumor-agnostic biologic therapies. The authors also explore evolving biologic concepts, including the impact of the tumor microenvironment on resistance and disease progression, and consider the distinct clinical behavior of invasive lobular carcinoma and current approaches. Emerging data from contemporary clinical trials promise to refine clinical and biomarker-driven algorithms and improve outcomes for patients with HR-positive/ HER2-negative MBC. Ongoing multi-omic research and adaptive clinical strategies will be essential to further the application of precision oncology in this most common subtype of MBC. Importantly, patient-reported outcomes, shared decision making, and real-world evidence are increasingly useful in formulating comprehensive care plans, guidelines, and policy. The modern treatment landscape features This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s). CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society. a personalized approach that integrates clinical features, biomarkers, and patient preferences across the disease continuum. KEYWORDS antibody–drug conjugates (ADCs), cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), endocrine resistance, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, patient-related outcomes (PROs), selective estrogen receptor degraders (SERDs), signal transduction phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) inhibitors INTRODUCTION Metastatic breast cancer (MBC) is one of the leading ca

FAQs

What characterizes HR-positive/HER2-negative metastatic breast cancer clinically and biologically?

It has a relatively prolonged but variable disease course and substantial intertumoral and intratumoral heterogeneity. Endocrine-based therapies are central, yet resistance eventually develops in nearly all patients.

How does the review describe resistance and its role in guiding treatment choices?

It summarizes mechanisms of intrinsic and acquired resistance, including driver genomic alterations. It also explains how these factors, along with clinical variables, support therapeutic decision-making and sequencing.

Which therapeutic approaches are highlighted for this subtype?

The review covers targeted agents such as CDK4/6, PI3K, and AKT inhibitors, newer-generation estrogen receptor degraders, and the growing role of antibody-drug conjugates. It also discusses biomarker-guided tumor-agnostic biologic therapies.

Sep 23, 2026

Upload by Himbo