Review maps ctDNA-guided ESR1 treatment sequencing in advanced breast cancer

A review of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer concludes that circulating tumor DNA testing can reveal emerging ESR1-mutant clones before radiographic progression, while evidence from clinical trials supports switching endocrine therapy at this molecular stage. The analysis, published in the Journal of Translational Medicine, examines how these mutations develop under treatment pressure and evaluates a framework for selecting among estrogen receptor-targeted medicines, pathway-directed combinations and antibody-drug conjugates after progression on a cyclin-dependent kinase 4/6 inhibitor.

The review identifies ESR1 mutations as among the most clinically relevant markers of acquired endocrine resistance. They emerge under selection pressure from aromatase inhibitors and stabilize estrogen receptor signaling in a ligand-independent manner, directly compromising estrogen-deprivation treatment while preserving the receptor as a therapeutic vulnerability. This resistance is not limited to isolated failure of CDK4/6 inhibitors. Instead, progression represents a heterogeneous resistance state within a tumor population, making the timing and interpretation of treatment changes central to the proposed sequencing strategy.

The authors describe ESR1 mutations as dynamic markers of clonal evolution rather than fixed features of a tumor. Analysis of circulating tumor DNA can detect emerging mutant clones before changes become visible on imaging, defining an interval that the review calls “molecular progression.” The PADA-1 trial established proof of concept for changing endocrine therapy at molecular progression, and the confirmatory phase III SERENA-6 trial subsequently led to regulatory approval of camizestrant, an oral selective estrogen receptor degrader, for ESR1-mutated advanced breast cancer. Vepdegestrant, described as the first proteolysis-targeting chimera estrogen receptor degrader, has also been approved in the ESR1-mutant setting. Together, these results support the feasibility of linking blood-based mutation detection with a treatment capable of targeting the altered receptor.

Beyond the pairing of a biomarker with a single drug, the review develops an ESR1-based framework for treatment sequencing after CDK4/6 inhibitor progression. It integrates emerging estrogen receptor-targeted agents, pathway-directed combinations and antibody-drug conjugates into that framework. The authors also critically appraise the available evidence for endocrine switching at molecular progression and acknowledge that important limitations remain, including the need to interpret circulating tumor DNA findings appropriately in clinical practice. The review therefore presents ctDNA-guided detection and sequencing as a developing approach for addressing heterogeneous endocrine resistance, rather than as a universal strategy for making treatment decisions before imaging-confirmed progression.

Subject of Research: ctDNA-guided ESR1 detection and treatment sequencing in advanced breast cancer

Article Title: ESR1 mutations in HR+/HER2− advanced breast cancer: ctDNA-guided detection and treatment sequencing

Article References: Zha, Y., Fan, P., Chai, Y., Liu, X., & Zhu, Y. (2026). ESR1 mutations in HR+/HER2− advanced breast cancer: ctDNA-guided detection and treatment sequencing. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09090-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09090-1

Keywords: ESR1 mutations, advanced breast cancer, circulating tumor DNA, endocrine resistance, molecular progression, estrogen receptor, camizestrant, vepdegestrant, CDK4/6 inhibitors, treatment sequencing, ESR1, mutations