# Therapeutic advances in HR+/HER2- advanced breast cancer after failure of CDK4/6 inhibitor therapy

## TL;DR

This paper reviews treatment options for HR+/HER2- breast cancer after CDK4/6 inhibitors fail, focusing on new therapies and future directions.

## Contribution

The paper systematically reviews post-CDK4/6i therapeutic strategies and suggests potential future directions.

## Key findings

- CDK4/6 inhibitors combined with endocrine therapy are first-line for HR+/HER2- breast cancer.
- Resistance to CDK4/6 inhibitors is common and involves multiple mechanisms.
- Next-generation therapies like oral SERDs and ADCs are being explored post-CDK4/6i failure.

## Abstract

Breast cancer represents the most frequently diagnosed malignancy in women, with the hormone receptor-positive/HER2-negative (HR+/HER2-) subtype being the most prevalent. For advanced HR+/HER2- breast cancer, the combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy has become the established first-line standard, significantly prolonging both median progression-free survival (mPFS) and overall survival (OS). Nevertheless, the majority of patients eventually develop resistance, leading to disease progression. The underlying mechanisms of resistance are multifactorial, involving dysregulated cell cycle control, reprogramming of signaling pathways, and remodeling of the tumor microenvironment (TME). At present, there is no standardized treatment strategy for overcoming CDK4/6i resistance. This article systematically reviews current post-CDK4/6i therapeutic strategies, including next-generation endocrine therapies (e.g., oral SERDs), targeted agents directed at the PI3K/AKT/mTOR axis, AKT inhibitors, and antibody–drug conjugates (ADCs), and discusses potential future therapeutic directions.