Clinical cancer research : an official journal of the American Association for Cancer Research
October 13, 2026 · via Europe PMC
Differential impact of tumor-derived ESR1 mutations on elacestrant benefit in metastatic breast cancer.
Sledge GW, Xiu J, Fuqua S, +5 more, Kaklamani V
AI summary — for doctors, generated from the abstract only
Not all ESR1 mutations respond equally to elacestrant: L536-mutated tumors and tumors with multiple ESR1 mutations had shorter time on treatment.
What was studied
Real-world analysis of ESR1-mutated breast tumors sequenced at Caris Life Sciences (n = 3,344; transcriptome in n = 1,663), using claims-based time-on-treatment (TOT) with elacestrant as a proxy for benefit.
Key findings
- ESR1 mutation frequency rose with longer prior endocrine therapy, particularly regimens including CDK4/6 inhibitors
- L536-mutated tumors had shorter TOT than Y537 and D538G tumors (HR = 2.089, p = 0.001) and lower GREB1 expression
- Multiple ESR1 mutations were linked to shorter TOT than single mutations (adjusted HR = 1.62, p = 0.038)
Clinical relevance
Suggests variant-specific stratification and ER-signaling biomarkers could refine selection for oral SERDs.
Who should care
Limitations
Retrospective, TOT is an indirect surrogate for benefit, no control arm, confounding by line of therapy possible.
ESR1 variants appear functionally non-equivalent, but this needs prospective confirmation.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
BACKGROUND
ESR1 mutations are a well-established mechanism of endocrine therapy resistance in estrogen receptor (ER)-positive metastatic breast cancer and are a biomarker for treatment benefit from oral selective estrogen receptor degraders (SERDs) such as elacestrant. However, variant-specific and context-dependent effects on therapy response remain poorly understood.
METHODS
Breast tumors carrying ESR1 mutations that underwent DNA sequencing at Caris Life Sciences were studied (n=3,344), with whole-transcriptome sequencing available for a subset (n=1,663). Time-on-treatment (TOT) was obtained from insurance claims and defined as the interval from initiation to discontinuation of elacestrant. Cox proportional hazards models were used to calculate hazard ratios (HRs), and log-rank tests assessed statistical significance.
RESULTS
ESR1 mutation frequency increased with longer duration of prior endocrine therapy including combined treatment regimens, particularly those including CDK4/6 inhibitors. Heterogeneity in treatment benefit was observed across ESR1 variants. Tumors harboring ESR1-L536 mutations demonstrated reduced elacestrant benefit, with significantly shorter TOT compared to more common mutations such as Y537 and D538G (HR=2.089, p=0.001). L536-mutated tumors had lower expression of GREB1, a key estrogen-responsive gene, and reduced enrichment of estrogen response pathways, suggesting reduced ER pathway activation compared to other variants. Additionally, patients with multiple ESR1 mutations had significantly shorter TOT compared to those with single mutations (adjusted HR=1.62, p=0.038).
CONCLUSIONS
ESR1 mutations are likely not functionally equivalent in their impact on elacestrant benefit. These findings highlight the importance of variant-specific stratification in optimizing endocrine therapy and suggest that biomarkers of ER signaling activity may further refine patient selection for SERD treatment.
DOI
10.1158/1078-0432.CCR-26-2215
PMID
42868272
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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