Virginia Kaklamani

Purpose: 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 (SERD) such as elacestrant. However, variant-specific and context-dependent effects on therapy response remain poorly understood. Experimental Design: 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 (HR), and log-rank tests were used to assess statistical significance. Results: ESR1 mutation frequency increased with longer duration of prior endocrine therapy, including combined treatment regimens, particularly those including cyclin-dependent kinase 4/6 inhibitors. Heterogeneity in treatment benefit was observed across ESR1 variants. Tumors harboring ESR1-L536 mutations demonstrated reduced elacestrant benefit, with significantly shorter TOT compared with more common mutations such as Y537 and D538G (HR, 2.089; P = 0.001). L536-mutated tumors had lower expression of growth regulation by estrogen in breast cancer 1, a key estrogen-responsive gene, and reduced enrichment of estrogen response pathways, suggesting reduced ER pathway activation compared with other variants. Additionally, patients with multiple ESR1 mutations had significantly shorter TOT compared with those with one ESR1 mutation (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.

Purpose: Treatment options for progression on first-line endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for estrogen receptor–positive/human epidermal growth factor receptor 2–negative (ER+/HER2−) advanced breast cancer (ABC) include ET plus targeted agents [CDK4/6i or phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (PAM) pathway inhibitors]. Elacestrant is the first single-agent oral selective ER degrader that significantly improved progression-free survival (PFS) versus standard-of-care (SOC) ET in ESR1-mutated and overall ER+/HER2− ABC populations. Patients and Methods: This phase Ib/II umbrella trial enrolled patients with ER+/HER2− ABC who received 1 to 2 lines of ET + CDK4/6i (including prior fulvestrant and primary endocrine resistance) and no prior chemotherapy for ABC. Patients received elacestrant with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib, or palbociclib. We evaluated PFS of elacestrant plus everolimus. Results: In phase Ib (N = 23), the optimal recommended phase II dose was determined as elacestrant 345 mg plus everolimus 7.5 mg. The phase II patient population (N = 50) included 100% prior CDK4/6i, 50% prior fulvestrant, 72% visceral metastasis, 20% primary endocrine resistance, 42% ESR1-mutated, and 50% PIK3CA-mutated. Median PFS was 8.3 months [95% confidence interval (CI), 4–10.2] in all patients; 8.3 months (95% CI, 3.5–12.9) in ESR1-mutated, 9 months (95% CI, 4.2–12.7) in ESR1 wild-type, 8.3 months (95% CI, 3.6–10.2) in PIK3CA-mutated, and 9.4 months (95% CI, 4–not reached) in PIK3CA wild-type. Adverse events (AEs) were consistent with the known safety of everolimus plus SOC ET. The most common AEs were grades 1 to 2. Any AE leading to drug withdrawal or dose reduction was 6% and 2%, respectively. Conclusions: Elacestrant plus everolimus showed a clinically meaningful PFS benefit across clinical/genomic subgroups, irrespective of ESR1 or PIK3CA mutation status. Elacestrant has the potential to become an ET backbone for combinations to inhibit the PAM pathway with everolimus as a promising all-oral treatment.

PURPOSE: Goserelin is a gonadotropin-releasing hormone agonist for ovarian function suppression in the treatment of pre- and perimenopausal patients with breast cancer and for the preservation of ovarian function during chemotherapy. Goserelin is available in doses of 3.6 mg once every 4 weeks or 10.8 mg once every 12 weeks. This study used US real-world evidence to characterize goserelin treatment patterns. METHODS: Electronic health record data of adults with a history of breast cancer and ≥2 goserelin prescriptions between January 1, 2017, and December 31, 2022, were identified through TriNetX. Patient demographics and treatment patterns were examined. RESULTS: Overall, 3,620 US patients were identified: 2,870 treated with goserelin 3.6 mg once every 4 weeks, 410 treated with 10.8 mg once every 12 weeks, and 340 switched from 3.6 mg once every 4 weeks to 10.8 mg once every 12 weeks. Peak utilization of 10.8 mg once every 12 weeks (36.6%) and dose switching to 10.8 mg once every 12 weeks (26.5%) occurred in 2020. Patients who switched to 10.8 mg once every 12 weeks had the longest median treatment duration (776 days), compared with the 3.6 mg once every 4 weeks and 10.8 mg once every 12 weeks cohorts (264 and 429 days, respectively). Of patients who switched, 65% were still being treated after 2 years, compared with 30% and 40% treated with 3.6 mg once every 4 weeks only or 10.8 mg once every 12 weeks only, respectively. Patients initially treated with or who switched to 10.8 mg once every 12 weeks were more adherent (64.4%-75.0%), compared with patients treated with 3.6 mg once every 4 weeks (45.4%). CONCLUSION: Treatment with goserelin 10.8 mg once every 12 weeks is associated with greater adherence and longer treatment duration, compared with 3.6 mg once every 4 weeks in patients with breast cancer in the United States.

Overall demographics and clinical characteristics.

Populations in three analyses.

MTTNT benefit in clinical subgroups: (A) 1–2 prior lines of ET ± CDK4/6i, (B) 1–2 prior lines of ET ± CDK4/6i ≥ 12 months, (C) 1 prior line of ET ± CDK4/6i, (D) 2 prior lines of ET ± CDK4/6i, (E) ≥3 prior lines of ET ± CDK4/6i, (F) visceral metastasis, (G) coexisting ESR1 and PI3K pathway mutations, (H) no prior fulvestrant, and (I) no prior chemotherapy.

Purpose:The EMERALD trial led to the approval of elacestrant for estrogen receptor (ER)–positive, HER2-negative, estrogen receptor 1 (ESR1)–mutated advanced or metastatic breast cancer (mBC) with disease progression following at least one line of endocrine therapy (ET). Subgroup analyses provided evidence suggesting that elacestrant enables ET sequencing in the second line before other targeted combinations, which could delay chemotherapy-based regimens.Experimental Design:This study used claims data from the Komodo Research Dataset linked with Foundation Medicine Inc. clinical genomic data from patients with estrogen receptor+/HER2− mBC harboring an ESR1 mutation treated with elacestrant. The primary outcome measure was time to next treatment (TTNT).Results:Among 306 patients, 93.8% had prior ET ± cyclin-dependent kinase 4/6 inhibitor for ≥12 months, 50.0% had prior chemotherapy, and 72.2% had prior fulvestrant. Median TTNT (mTTNT) was 8.2 months [95% confidence interval (CI), 6.3–13.0] in patients with 1 to 2 prior lines and 7.5 months (95% CI, 7.1–9.9) in those with ≥3 prior lines of ET. In patients with coexisting ESR1- and PI3K-pathway–mutated tumors, mTTNT was 6.3 months (95% CI, 4.8–7.9). mTTNT was 7.9 months (95% CI, 7.1–9.8) in all patients and was also sustained in patients with no prior fulvestrant [12.9 months (95% CI, 7.2–not reached)], no prior chemotherapy [8.4 months (95% CI, 7.1–13.3)], visceral metastasis [7.9 months (95% CI, 7.0–9.9)], and liver metastases [7.2 months (95% CI, 6.3–9.0)].Conclusions:Elacestrant demonstrated a durable benefit in real-world clinical practice, particularly in earlier lines and in patients with prolonged prior ET exposure. Despite coexisting ESR1 and PI3K pathway mutations, TTNT remained clinically meaningful, reinforcing the role of elacestrant in personalized ET sequencing strategies prior to chemotherapy, antibody–drug conjugates, or targeted combinations.See related article by Lloyd et al., p. 169

Median efficacy outcomes of elacestrant in three analyses.

Supplemental Figures and Tables

MTTNT benefit in relevant subgroups.