Dr Gatti on the Prognostic Impact of ESR1 Mutations and Co-Alterations in Breast Cancer

“Endocrine resistance, when it’s composed [of] many different mutations, could represent and select a worse-prognosis group, and we should focus on this group to build strategies, [plan treatment] sequencing, and better the life quality for these patients.”

Federica Gatti, MD, of the Department of Oncology at Sapienza at the Università di Roma, discussed findings from a retrospective, real-world analysis that evaluated the prognostic impact of circulating tumor DNA (ctDNA)–detected ESR1 alterations and genomic co-alterations in patients with hormone receptor (HR)–positive/HER2-negative metastatic breast cancer.

The single-center study included 72 patients who underwent ctDNA analysis at radiologic progression between January 2024 and March 2026 at the IRCCS Regina Elena National Cancer Institute in Rome; sequencing was performed with the Oncomine Precision Assay. Nearly all patients (96%) had prior exposure to a CDK4/6 inhibitor. The primary end point was progression-free survival (PFS) with the treatment administered after ctDNA testing, which most commonly was chemotherapy (36.1%) or elacestrant (Orserdu; 19.4%).

Gatti and colleagues pondered whether an ESR1 mutation was associated with prognosis and whether the presence of an additional mutation alongside ESR1 had any further association with clinical outcomes, she explained. The results indicated that it did, Gatti said. Patients with ESR1-mutated disease had a median PFS of 6.1 months vs 11.0 months for those with ESR1 wild-type disease (log-rank P = .049). Among patients with ESR1 mutations plus additional alterations (n = 13), the median PFS was 7.0 months vs 16.0 months for all other patients (P = .042).

The investigators examined the co-occurrence of ESR1 mutations with all other possible mutations, according to Gatti. No single combination identified a worse-prognosis group, but ESR1 mutations appeared to be the principal contributor to the poorer outcomes, she noted.

Gatti emphasized that these results are hypothesis generating, as the analysis was retrospective and the sample size was small, so more patients are needed, and treatment strategy cannot be based on these data. Endocrine resistance driven by multiple mutations may select a subgroup with worse prognosis, she said. Gatti concluded that this group should be the focus of efforts to build better treatment strategies and sequencing and to improve quality of life for these patients.

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