Caris Reveals ESR1 Mutation Insights in Breast Cancer

Irving, Texas, United States, November 9, 2026

Comprehensive Profiling Identifies Differences in ESR1 Mutations

ESR1 is the gene responsible for producing the estrogen receptor alpha protein, which plays an important role in the growth and development of hormone receptor-positive breast cancer. Mutations in ESR1 can alter estrogen receptor activity and contribute to resistance to endocrine therapies, particularly in patients with advanced or metastatic disease. Although ESR1 mutation testing is already an important biomarker for selecting certain treatments, different mutations may have distinct biological characteristics and therapeutic implications. In the Caris study, researchers examined molecular profiling information from 3,344 ESR1-mutated breast tumors and evaluated the relationship between individual mutation types and treatment outcomes. Whole-transcriptome sequencing was also available for a subset of 1,663 tumors, allowing investigators to examine gene expression patterns and estrogen receptor signaling activity. The analysis identified differences among common ESR1 variants, including L536, E380Q/K, Y537 and D538G. Researchers found that tumors carrying the L536 mutation were associated with shorter treatment duration with elacestrant compared with tumors containing other commonly observed ESR1 variants. These findings indicate that ESR1 mutations should not necessarily be considered biologically equivalent, highlighting the potential value of more detailed molecular characterization in metastatic breast cancer research.

ESR1 L536 Mutations Associated With Shorter Treatment Duration

One of the important findings involved patients receiving elacestrant, an oral selective estrogen receptor degrader (SERD) approved for certain patients with ER-positive, HER2-negative advanced or metastatic breast cancer carrying ESR1 mutations. Researchers linked molecular profiling results with real-world insurance claims data to evaluate time on treatment, defined as the period between treatment initiation and discontinuation. Patients whose tumors carried ESR1 L536 mutations had a median treatment duration of 1.38 months, compared with 2.99 months among patients with other common ESR1 variants. This association remained statistically significant after adjustment for prior treatment history and specimen collection site. The study also identified differences based on the number of ESR1 mutations present in individual tumors. Patients with two ESR1 mutations had a median time on elacestrant of 2.04 months, compared with 3.16 months among those with a single ESR1 mutation. These findings suggest that both mutation type and mutation burden may influence treatment outcomes. However, time on treatment is a real-world measure and does not independently establish the biological cause of treatment discontinuation or prove differences in drug efficacy. The results provide important insights into potential molecular factors associated with variable treatment outcomes and support further investigation into more refined biomarker strategies.

RNA Profiling Provides Additional Insights Into Tumor Biology

The research also examined estrogen receptor pathway activity using RNA sequencing to understand how gene expression differences may contribute to treatment outcomes. Investigators found that tumors carrying the ESR1 L536 mutation demonstrated lower expression of GREB1 (Growth Regulation by Estrogen in Breast Cancer 1), an important downstream marker of estrogen receptor signaling. These tumors also showed reduced enrichment of estrogen-response pathways compared with tumors carrying other common ESR1 mutations. Furthermore, patients whose tumors demonstrated lower GREB1 expression experienced shorter treatment duration with elacestrant than those with higher expression. These observations suggest that RNA-based molecular measurements may provide additional biological context beyond conventional DNA mutation testing. By combining whole-exome or targeted genomic information with whole-transcriptome sequencing and real-world clinical outcomes, researchers can investigate tumor characteristics that may otherwise remain unidentified through standard biomarker classification. Caris Life Sciences uses comprehensive molecular profiling, artificial intelligence and advanced computational technologies to study cancer biology and support precision medicine research. The company believes that integrating genomic and transcriptomic information with clinical outcomes could contribute to the development of more detailed molecular classifications and future treatment-selection strategies. The publication represents an important contribution to precision oncology research, particularly in understanding endocrine therapy resistance in metastatic breast cancer. Caris Life Sciences’ findings demonstrate the potential value of identifying specific ESR1 variants and evaluating estrogen receptor pathway activity when studying treatment outcomes. However, the researchers emphasized that these findings require prospective validation and are not yet ready to guide clinical decision-making. Further research will be necessary to determine how these molecular differences can be translated into improved patient stratification and personalized cancer treatment strategies.

Source: Caris Life Sciences press release