Targeted Therapies in HR+/HER2– Breast Cancer

A better understanding of endocrine therapy (ET) resistance mechanisms has guided the development of targeted combination therapies for HR-positive/HER2-negative (HR+/HER2–) breast cancer, but resistance evolution complicates long-term disease management.

The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have
become foundational in the first-line treatment of HR+/HER2– breast
cancer, significantly improving survival outcomes.

Emerging next-generation targeted therapies, such as capivasertib
and elacestrant, target resistance mechanisms like ESR1 mutations
and alterations in the PI3K/AKT/mTOR pathway. These biomarker driven
approaches are critical but require testing standardization
across institutions.

Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan, represent a paradigm shift in treating ET-refractory metastatic breast cancer, showing efficacy even in heavily pretreated populations.

Despite improved outcomes with targeted therapies and their combinations, challenges remain regarding their optimal sequencing and rechallenge strategies post progression in the HR+/HER2– breast cancer treatment algorithm.