Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Area of Science:

• Oncology
• Pharmacology

Background:

• Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are standard therapy for hormone-positive metastatic breast cancer (mBC).
• These inhibitors, combined with endocrine therapy, offer significant progression-free survival benefits in first- and second-line settings.
• Despite clinical advantages, CDK4/6 inhibitors present challenges related to cost and potential toxicities.

Purpose of the Study:

• To systematically review molecular markers that predict response to CDK4/6 inhibitors in mBC.
• To identify biomarkers associated with both intrinsic and acquired resistance to CDK4/6 inhibition.
• To capture the evolving molecular landscape influencing treatment efficacy.

Main Methods:

• Systematic review of published literature on CDK4/6 inhibitors in mBC.
• Analysis of molecular data from next-generation sequencing (DNA/RNA), liquid biopsies (ctDNA), and protein analyses.
• In-depth discussion of individual molecular candidates with strong predictive evidence.

Main Results:

• CDK4/6 inhibitors demonstrate median progression-free survival exceeding 2 years when combined with aromatase inhibitors in the first-line metastatic setting.
• Various molecular markers are emerging as predictive of response and resistance.
• Next-generation sequencing and liquid biopsies are key technologies for profiling the molecular landscape.

Conclusions:

• Understanding predictive molecular markers is crucial for optimizing CDK4/6 inhibitor therapy in mBC.
• Identifying resistance mechanisms can guide future treatment strategies and drug development.
• Personalized treatment approaches based on molecular profiling hold promise for improving outcomes in mBC.