CDK4/6 Inhibitor Efficacy in ESR1-Mutant Metastatic Breast Cancer

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Estrogen receptor 1 (ESR1) mutations are a key mechanism of resistance to aromatase inhibitors in estrogen receptor-positive metastatic breast cancer.
• The impact of ESR1 alterations on the efficacy of CDK4/6 inhibitors (CDK4/6i) remains largely unestablished.
• Pre-clinical analyses suggest that ESR1 mutations and endocrine therapy partners may influence CDK4/6i sensitivity.

Purpose of the Study:

• To investigate the efficacy of CDK4/6 inhibitors in patients with ESR1-mutated (ESR1m) metastatic breast cancer using real-world data.
• To analyze the association between ESR1 mutations and clinical factors influencing CDK4/6i treatment outcomes.
• To evaluate the impact of ESR1 status on time-to-next-treatment in metastatic breast cancer patients receiving CDK4/6 inhibitors.

Main Methods:

• Utilized the GuardantINFORM database, linking genomic data from circulating-tumor DNA with claims data.
• Identified ESR1 mutations (ESR1m) and categorized patients as ESR1m or non-ESR1m.
• Analyzed real-world time-to-next-treatment (TTNT) for patients initiating CDK4/6 inhibitors within 30 days of sequencing.

Main Results:

• Analyzed 145 patients with ESR1m and 612 with non-ESR1m metastatic breast cancer.
• Found similar real-world time-to-next-treatment for ESR1m and non-ESR1m tumors on CDK4/6i regimens (HR, 1.02; 95% CI, 0.82-1.23).
• Observed comparable treatment durations regardless of ESR1 status, but worse outcomes with aromatase inhibitors and comparable outcomes with fulvestrant in ESR1m patients.

Conclusions:

• ESR1 variants are not associated with resistance to CDK4/6 inhibitors.
• CDK4/6 blockade combined with fulvestrant (a selective estrogen receptor degrader) is a potentially effective therapeutic strategy for ESR1m metastatic breast cancer.
• These findings support further investigation into combination therapies for ESR1-mutated breast cancer.