Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Area of Science:

• Oncology
• Genomics
• Cancer Research

Background:

• Chromosomal instability (CI) is a hallmark of cancer.
• Next-generation sequencing (NGS) of cell-free DNA (cfDNA) allows quantification of CI.
• CI may serve as a real-time indicator of cancer progression and treatment response.

Purpose of the Study:

• To evaluate if cfDNA-derived chromosomal number instability (CNI) scores can predict immunotherapy response in advanced cancers.
• To compare the efficacy of CNI scores against traditional tumor biomarkers and T regulatory cell surrogates.
• To determine if CNI scores can serve as a real-time surrogate for imaging in assessing disease status.

Main Methods:

• Prospective collection of plasma cfDNA from 56 advanced cancer patients and 126 controls.
• Analysis of cfDNA for copy number variations to calculate a quantitative CNI score.
• Single-blind study design with training and blinded validation cohorts, comparing CNI with tumor biomarkers and Tregs.

Main Results:

• Elevated CNI scores were detected in 51 of 56 patients before therapy.
• The CNI score achieved 83% overall prediction accuracy and 92% positive predictive value for progression in the validation cohort.
• CNI scores accurately predicted progression, distinguished pseudo-progression from hyperprogression, and showed no correlation with tumor markers or Tregs early in treatment.

Conclusions:

• Quantification of chromosomal instability in plasma cfDNA is a promising early indicator of immunotherapy response.
• This cfDNA-based method has the potential to improve cancer patient management and reduce healthcare costs.
• Further validation is needed to fully establish cfDNA CNI as a clinical tool for monitoring cancer patients.