Abstract PD10-11: Differential Benefit to Elacestrant in A Large Cohort of ER+ HER2- Breast Cancer: Impact of ESR1 Mutants and Prior Therapy

Abstract Background: ESR1 activating mutations are predominantly located in the ligand-binding domain near helix 12. They drive ligand-independent activation of the estrogen receptor pathway and confer resistance to conventional endocrine therapies. However, tumors often retain sensitivity to selective estrogen receptor degraders (SERDs) like elacestrant. Here, we interrogate a large real-world cohort to explore how specific ESR1 variants and prior endocrine therapy influence elacestrant clinical benefit. Methods: A total of 3,340 breast tumors carrying ESR1 mutations that underwent tumor profiling at Caris Life Sciences (Phoenix, AZ)—including Whole Exome Sequencing and Whole Transcriptome Sequencing—were studied. Real-world clinical data were obtained from insurance claims. Time on treatment (TOT) was defined as the interval from the start to the end of treatment. Cox proportional hazards models were used to calculate hazard ratios (HRs), and log-rank tests were used to determine p-values. Results: In this large real-world database of breast cancer patients, 8.59% (N=3340) of tumors harbored an ESR1 mutation. Mutations most frequently occurred at D538 (G: 1,303; others: 10), Y537 (S: 839; N: 324; C: 192; others: 30), L536 (SNV: 233; others: 8), and E380 (Q/K: 411). While the vast majority of tumors carried a single ESR1 mutation (7.85%), a small fraction harbored more than one ESR1 mutation (0.75%; double mutants: 0.67%; more than double: 0.08%). Among elacestrant-treated patients with a single ESR1 mutation (N=382), the TOT was significantly shorter for patients with a L536 SNV (N = 20; 1.38 months; 95% CI: 0.43-2.17) compared to patients with other variants: D538G (N = 119; 2.76 months; 1.97-3.29), Y537 SNV (N = 116; 3.4 months; 2.73-4.11), and E380 variants (N = 20; 3.45 months; 0.2-5.46). When comparing L536 with all other variants combined, HR was 2.089 (95% CI: 1.312-3.325, p = 0.001). This coincides with significantly lower expression levels of the ER-responsive gene GREB1 in L536-mutant tumors (7.94 transcripts per million TPM) compared to D538 (20.75 TPM), Y537 (38.61 TPM), and E380 (13.65 TPM) tumors (p 0.001). When investigating tumors carrying double ESR1 mutations, elacestrant TOT was significantly shorter compared to single ESR1 variants (1.94 vs. 2.90 months; HR = 1.716 1.096-2.686, p = 0.016). While fulvestrant use prior to sequencing was more frequent in patients with multiple ESR1 mutations (29% for single mutants vs. 40% for multiple mutants, p 0.0001), prior fulvestrant exposure did not impact elacestrant TOT (HR = 1.181 0.885-1.58, p = 0.259). Conclusions: In a large cohort of patients with HR+HER2- ESR1 mutated breast cancer treated with elacestrant, a relatively common mutation of ESR1 L536 and/or multiple ESR1 mutations conferred significantly less benefit to elacestrant than other variants. Citation Format: G. Sledge, H. McArthur, J. Xiu, M. J. Oberley, M. Su, M. Radovich, D. Spetzler, V. Kaklamani. Differential Benefit to Elacestrant in A Large Cohort of ER+ HER2- Breast Cancer: Impact of ESR1 Mutants and Prior Therapy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD10-11.