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August 8, 2026Clinical and Experimental Medicine0 citationsOpen Access

Clinical insights into the genomic landscape of ESR1-mutated breast cancer and implications for treatment decision-making: a large-scale analysis of 6,162 patients

LXLinhao Xie MWMengxiao Wang MGMinghui Ge

Key Points

This research aims to elucidate the distribution and clinical implications of ESR1 mutations in breast cancer patients.
Analyzed genomic data from 6,162 breast cancer patients in the Simceredx Cohort and the MSK 2024 Cohort.
Evaluated ESR1 mutation frequency, co-mutation pathways, and survival prognosis, with a focus on tumor mutation burden (TMB).
Provided actionable drug targets based on OncoKB annotations.
ESR1 mutation rates were 5.7% and 6.3% in the respective cohorts, with a high concentration in the ligand-binding domain.
Associated with significantly elevated overall TMB (P ≤ 0.003) and worse overall survival (HR = 2.29).
Drug evidence supports selective estrogen receptor degraders (SERDs) for most ESR1 mutations.

Abstract

Estrogen receptor 1 (ESR1) mutations are key drivers of endocrine resistance in hormone receptor–positive breast cancer. However, their genomic spectrum, co-mutation landscape, and prognostic relevance in real-world populations remain insufficiently characterized. This study aimed to define the distribution and clinical implications of ESR1 mutations by integrating commercial genomic testing data with the MSK public cohort. Collect genomic data from breast cancer patients in the Simceredx Cohort and the MSK 2024 Cohort to evaluate ESR1 mutation frequency, domain distribution, pathogenicity classification, co-mutation pathways, and mutation feature tags. Compare Tumor Mutation Burden (TMB) differences between ESR1-mutant and wild-type tumors, and evaluate survival prognosis in the MSK cohort. Summarize potential actionable targets and drug evidence levels based on OncoKB annotations. The ESR1 mutation rates in the two cohorts were 5.7% and 6.3%, with mutations highly enriched in the ligand-binding domain. The majority of variants were classified as likely pathogenic (LP)/ pathogenic (P) (> 98%) and predominantly represented gain-of-function missense mutations. ESR1-mutant tumors exhibited a co-mutation axis centered on TP53, PIK3CA, and GATA3, accompanied by differential enrichment in MAPK, PI3K, and DDR pathways. ESR1 mutant tumors with significantly elevated overall TMB ( P ≤ 0.003). In the MSK cohort, ESR1 mutation was associated with markedly worse overall survival (HR = 2.29). Drug evidence indicates that selective estrogen receptor degraders (SERDs) provide Level 1 evidence-based support for most mutations. This study reveals the domain specificity and co-mutation background of ESR1 mutations in breast cancer, supporting its potential role in endocrine resistance stratification and providing genomic evidence relevant to SERD-directed therapeutic development.

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