Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by Next Generation Sequencing (NGS) from plasma/serum derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers. Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers, were prospectively collected and analyzed in a single-blinded study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 non-cancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed. Results: Elevated CNI-scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25 of 30) and a positive predictive value of CNI-score for progression of 92% (11 of 12). The combination of CNI-score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI-score also correctly identified cases of pseudo-tumor progression from hyper-progression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs. Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation.
- Received January 25, 2017.
- Revision received March 16, 2017.
- Accepted March 16, 2017.
- Copyright ©2017, American Association for Cancer Research.