ESR1 Mutations Steer the Oral SERD Story in Breast Cancer: With Sara Nunnery, MD, MSCI; and MinhTri Nguyen, MD

Breast Cancer Briefing, hosted by Sara Nunnery, MD, MSCI, a breast medical oncologist and the director of Breast Cancer Research at Tennessee Oncology in Nashville, is a podcast series that breaks down the latest news in breast cancer research, one conversation at a time.

In this episode, Dr Nunnery sat down with MinhTri Nguyen, MD, a breast medical oncologist, assistant professor, and lead faculty for Health Equity at Rush MD Anderson Cancer Center in Chicago, Illinois.

They discussed the emergence of giredestrant, an investigational oral selective estrogen receptor degrader (SERD), across the hormone receptor–positive, HER2-negative breast cancer treatment paradigm. Unlike aromatase inhibitors, which lower estrogen levels, or tamoxifen, which blocks the estrogen receptor (ER), SERDs degrade the receptor entirely, Dr Nguyen explained. He noted that ESR1 mutations, an acquired resistance mechanism that renders the ER constitutively active, confer worse prognosis and appear to be where oral SERDs derive their strongest signal.

The conversation first addressed the phase 3 evERA Breast Cancer trial (NCT05306340), which randomly assigned patients with previously treated advanced disease to receive giredestrant plus everolimus (Afinitor) or standard-of-care endocrine therapy plus everolimus. Dr Nguyen emphasized the elegance of targeting 2 resistance pathways simultaneously: the endocrine pathway and the parallel mTOR/PI3K/AKT axis. The combination significantly improved median progression-free survival in both the population with ESR1-mutated disease and the intention-to-treat population, though the experts cautioned that the patients with ESR1-mutated disease likely drove the overall benefit, as wild-type outcomes mirrored those in the control arm. The experts characterized giredestrant-associated adverse effects as largely everolimus-driven, most notably stomatitis, and highlighted class-associated bradycardia. They also noted that no photopsia was reported.

They then turned to the phase 3 lidERA Breast Cancer trial (NCT04961996), in which patients with predominantly high-risk, early-stage disease received giredestrant or standard endocrine therapy. Giredestrant produced a reduction in the risk of invasive disease recurrence or death, with markedly lower discontinuation rates and consistent benefit across premenopausal and postmenopausal subgroups.

Finally, the experts contextualized findings from the negative first-line persevERA Breast Cancer trial (NCT04546009), concluding that a single negative readout does not close the oral SERD story, and that thoughtful patient selection will define giredestrant’s future role in the breast cancer treatment armamentarium.