# Characterization of ESR1 alterations in patients with breast and gynecologic cancers

## TL;DR

This study characterizes ESR1 gene changes in breast and gynecologic cancers, showing they are more common in metastatic tumors and may help guide treatment decisions.

## Contribution

The study provides new insights into the frequency and clinical relevance of ESR1 alterations in metastatic breast cancer and gynecologic cancers.

## Key findings

- ESR1 alterations were more frequent in metastatic compared to local breast cancer samples.
- CCDC170 was the most common fusion partner in ESR1 fusion genes across both cancer types.
- Therapeutically actionable co-alterations were identified in ESR1-altered HR+/HER2- breast cancer samples.

## Abstract

ESR1 alterations present a common mechanism of resistance to endocrine therapy (ET) in hormonally driven tumors. The clinical significance of these alterations continues to evolve with newly approved targeted therapies and a range of ongoing investigational trials.

A retrospective study of 2574 breast cancer (BC) and 1110 gynecologic cancer samples that underwent whole exome and whole transcriptome profiling was conducted to assess the distribution of ESR1 and associated co-alterations in local (primary breast or regional lymph node) versus metastatic BC samples and in the major BC subtypes. Prior treatment history was unknown.

ESR1 alterations were present in 6.2% (n = 159/2574) of BC samples and 3.4% (n = 38/1110) of gynecologic cancer samples. In HR + /HER2- BC, ESR1 alterations overall and ESR1 missense mutations were more frequent in samples from metastatic compared to local/regional sites (overall: n = 86/321 (26.8%) and n = 53/1427 (3.7%), respectively (P < 0.001); missense: n = 72/321 (22.4%) and n = 20/1427 (1.4%), respectively (P < 0.001)). Whole transcriptome sequencing detected ESR1 fusion genes in 2.1% (n = 55/2574) of BC samples and in 1.9% (n = 21/1110) of gynecologic cancer samples, and CCDC170 was the most common fusion partner in both cancer types. In HR + /HER2- BC, ESR1 fusions were more common in metastatic samples compared to local/regional (n = 17/321 (5.3%) and n = 29/1427 (2.0%), respectively; P < 0.001). Evaluation of 21 therapeutically actionable biomarkers identified co-alterations enriched in ESR1-altered HR + /HER2- BC, including FGF3/4/19 and CCND1 amplifications. No significant co-alterations were found in gynecologic cancer samples.

ESR1 alterations were most frequent in HR + /HER2- BC samples and missense mutations were more frequent in metastatic samples, consistent with their role in ET resistance and disease progression. ESR1 alterations co-occurred with therapeutically relevant alterations in other genes that may help inform clinical decision-making. Gynecologic tumors harbored ESR1 alterations that have prognostic and potentially therapeutic relevance.

The online version contains supplementary material available at 10.1186/s13058-025-02217-0.