Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

Area of Science:

• Oncology
• Genomics
• Translational Research

Background:

• Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are a standard treatment for hormone receptor-positive metastatic breast cancer (HR+ MBC).
• Predicting resistance to CDK4/6i therapy is crucial for optimizing patient outcomes.
• Genomic alterations can influence response and resistance to targeted therapies.

Purpose of the Study:

• To identify genomic biomarkers associated with resistance to CDK4/6 inhibitors in HR+ MBC patients.
• To analyze the relationship between specific gene mutations, amplifications, or losses and progression-free survival (PFS).
• To leverage real-world clinical data for biomarker discovery.

Main Methods:

• Retrospective analysis of genomic and RNA sequencing data from 795 HR+ MBC patients treated with CDK4/6 inhibitors and antiestrogen therapy.
• Patients were categorized based on time to progression (early, intermediate, late).
• Association analysis between genomic alterations (including gene mutations, amplifications, and losses) and PFS, with survival analysis stratified by prior chemotherapy lines.

Main Results:

• Genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations were significantly associated with shorter PFS.
• Seventeen genes showed associations with PFS in patients receiving CDK4/6i as first- or second-line therapy.
• Whole transcriptome RNA sequencing identified 56 genes associated with PFS in patients with limited prior therapy.

Conclusions:

• FGFR1 amplification, PTEN loss, and DNA repair gene mutations are potential genomic biomarkers predicting shorter PFS in HR+ MBC patients treated with CDK4/6 inhibitors.
• These findings highlight the role of specific genomic alterations in mediating resistance to CDK4/6i therapy.
• Real-world genomic data can identify biomarkers to guide treatment decisions for HR+ MBC.