ctDNA-Detected ESR1 Mutations Guide First-Line Switch to Camizestrant in Advanced Breast Cancer
The SERENA-6 phase 3 trial used serial ctDNA monitoring to detect emerging ESR1 resistance mutations in patients on first-line aromatase inhibitor plus CDK4/6 inhibitor therapy for ER-positive breast cancer. Switching to camizestrant upon ctDNA-detected ESR1 mutation nearly doubled progression-free survival (16.0 vs 9.2 months, HR 0.44), establishing a new paradigm for ctDNA-guided adaptive therapy in breast oncology.
The original study
First-Line Camizestrant for Emerging
- Authors
- Bidard FC, Mayer EL, Park YH, Janni W, Ma C, Cristofanilli M, et al.
- Journal
- The New England journal of medicine
- Type
- Journal Article, Randomized Controlled Trial, Multicenter Study, Clinical Trial, Phase III
- PMID
- 40454637
Original abstract
BACKGROUND: Mutations in ESR1 are the most common mechanism of acquired resistance to treatment with an aromatase inhibitor plus a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor for advanced breast cancer. Camizestrant, a next-generation selective estrogen-receptor (ER) degrader and complete ER antagonist, has shown antitumor activity in ER-positive advanced breast cancer. METHODS: We tested patients with advanced breast cancer with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative tumors for ESR1 mutations in circulating tumor DNA (ctDNA) once every 2 to 3 months. All the patients had received at least 6 months of first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Patients who were found to have an ESR1 mutation and did not have radiologic progression were assigned in a 1:1 ratio to switch to camizestrant (75 mg once daily) with a continued CDK4/6 inhibitor plus placebo in place of an aromatase inhibitor or to continue to receive an aromatase inhibitor plus a CDK4/6 inhibitor plus placebo in place of camizestrant. The primary outcome was investigator-assessed progression-free survival. RESULTS: A total of 3256 patients were tested for an ESR1 mutation. The 315 eligible patients were assigned to switch to camizestrant (157 patients) or to continue to receive an aromatase inhibitor (158 patients). At an interim analysis at a median follow-up of 12.6 months, the median progression-free survival was 16.0 months (95% confidence interval [CI], 12.7 to 18.2) in the camizestrant group and 9.2 months (95% CI, 7.2 to 9.5) in the aromatase-inhibitor group (hazard ratio for progression or death, 0.44; 95% CI, 0.31 to 0.60; P<0.0001). The median time until a deterioration in the patient-reported global health status and quality of life occurred was 21.0 months with camizestrant and 6.4 months with an aromatase inhibitor (hazard ratio, 0.54; 95% CI, 0.34 to 0.84). The frequency of discontinuation because of adverse events was 1.3% with camizestrant and 1.9% with an aromatase inhibitor. CONCLUSIONS: In patients with ER-positive, HER2-negative advanced breast cancer with an ESR1 mutation that emerged during treatment, those who were switched to camizestrant with continuation of a CDK4/6 inhibitor during first-line therapy had significantly longer progression-free survival than those who maintained the aromatase-inhibitor combination. (Funded by AstraZeneca; SERENA-6 ClinicalTrials.gov number, NCT04964934.).