Findings suggest ESR1 variant type, number of mutations and estrogen receptor (ER) pathway activity may provide information beyond ESR1 mutation status alone

IRVING, Texas, Nov. 9, 2026 /PRNewswire/ — Caris Life Sciences ® (Caris), a leading TechBio company, today announced the publication of a study in Clinical Cancer Research that used comprehensive molecular profiling to identify important biological differences among ESR1 -mutated breast tumors and examine their association with time on treatment among patients receiving elacestrant.

The study, “Differential impact of tumor-derived ESR1 mutations on elacestrant benefit in metastatic breast cancer,” analyzed molecular profiling data from 38,865 breast tumors, including 3,344 harboring pathogenic or likely pathogenic ESR1 mutations. For patients treated with elacestrant, researchers linked comprehensive molecular profiling results with real-world insurance claims data to assess time on treatment. Elacestrant is an oral selective estrogen receptor degrader approved for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1 -mutated advanced or metastatic breast cancer whose disease has progressed following endocrine therapy. The study identified molecular features associated with shorter time on elacestrant.

ESR1 mutations are a well-recognized mechanism of acquired resistance to endocrine therapy and have become an important biomarker for treatment selection in metastatic breast cancer. However, ESR1 mutation status is commonly treated as a binary biomarker despite laboratory evidence suggesting individual ESR1 variants may differ in their biology and therapeutic sensitivity.

“This study highlights the complexity that exists within biomarkers that are often considered binary,” said Caris Chief Medical Officer George W. Sledge, Jr., MD, lead author of the study. “Our findings suggest that not all ESR1 mutations behave the same way. By combining comprehensive molecular profiling with real-world clinical outcomes, we can begin to identify biologically meaningful differences that may contribute to a more refined understanding of treatment benefit in metastatic breast cancer. Importantly, these findings require prospective validation and are not yet ready to guide clinical decision-making.”

Among patients treated with elacestrant, tumors harboring ESR1 L536 mutations were associated with shorter median time on treatment compared with tumors carrying other common ESR1 variants, including E380Q/K, Y537 and D538G. Patients with L536-mutant tumors remained on therapy for a median of 1.38 months versus 2.99 months for patients with other common ESR1 variants. This association remained significant after adjustment for prior therapy and specimen site.

The study also found that patients whose tumors contained two ESR1 mutations had a median time on elacestrant of 2.04 months compared with 3.16 months among patients with a single ESR1 mutation, further supporting the finding that comprehensive molecular profiling may provide additional information beyond a binary ESR1 mutation result.

In the subset of tumors with RNA sequencing data, L536-mutant tumors had lower expression of GREB1, a downstream marker of ER signaling, as well as reduced enrichment of estrogen-response pathways. Patients with lower GREB1 expression also experienced shorter time on elacestrant treatment than those with higher expression. Together, the findings suggest that variant-level ESR1 characterization and RNA-based measures of ER pathway activity may provide biological context beyond a simple positive-or-negative ESR1 result.

The study further highlights the value of linking comprehensive molecular profiling with large-scale real-world outcomes data to uncover additional insights within established biomarkers. By integrating molecular profiling with longitudinal outcomes information, researchers can better characterize tumor biology and identify opportunities for future biomarker development.

The publication is available through the Caris website .

About Caris Life Sciences
Caris Life Sciences® (Caris) is a leading TechBio company actively developing and commercializing innovative solutions to transform healthcare. Through comprehensive molecular profiling (Whole Genome, Whole Exome and Whole Transcriptome Sequencing), advanced AI and machine learning, Caris has created the large-scale, multimodal clinico-genomic database and computing capability needed to analyze and further unravel the molecular complexity of disease. This convergence of next-generation sequencing, AI and machine learning technologies and high-performance computing provides a differentiated platform for developing the latest generation of advanced precision medicine diagnostic solutions for early detection, diagnosis, monitoring, therapy selection and drug development.

Caris was founded with a vision to realize the potential of precision medicine to improve the human condition. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Cambridge (MA), Tokyo, Japan and Basel, Switzerland. Caris or its distributor partners provide services in the U.S. and other international markets.

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