Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor-Positive...

Area of Science:

• Oncology
• Genomics
• Translational Research

Background:

• Lack of clinical biomarkers to predict response to CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET).
• Need for noninvasive methods to monitor treatment resistance in metastatic breast cancer (MBC).

Purpose of the Study:

• To identify genomic features in circulating tumor DNA (ctDNA) for predicting and monitoring resistance to ET + CDK4/6i.
• To evaluate the utility of blood tumor mutational burden (bTMB) and blood copy-number burden (bCNB) as predictive biomarkers.

Main Methods:

• Comprehensive ctDNA analysis using boosted whole-exome sequencing (WES) and low-pass whole-genome sequencing.
• Analysis of plasma samples from 51 patients with HR+/HER2- MBC on a phase II trial.
• Evaluation of genomic alterations, mutational signatures, bTMB, and bCNB at baseline and clinical progression.

Main Results:

• High bTMB and bCNB were associated with lack of clinical benefit and shorter progression-free survival (PFS).
• Dominant APOBEC signatures and ESR1 alterations were enriched in patients with high bTMB.
• Increased bCNB score preceded radiographic progression in 66.7% of patients during serial monitoring.

Conclusions:

• Noninvasive profiling of bTMB and bCNB predicts poor outcomes in patients treated with ET + CDK4/6i.
• Genomic complexity detected by ctDNA identifies early disease progression before imaging.
• Novel treatment strategies, including immunotherapy combinations, should be investigated for this patient population.