Abstract

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-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer 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% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). 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 hyperprogression. 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. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR.

Highlights

  • The assessment of efficacy of systemic antitumor therapy is essential for the optimal management of cancer patients

  • Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cell-free DNA (cfDNA), or surrogate T regulatory cells (Tregs)

  • Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy

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Summary

Introduction

The assessment of efficacy of systemic antitumor therapy is essential for the optimal management of cancer patients. Current assessments are accomplished with imaging procedures at defined intervals evaluated using standard (RECIST 1.1) criteria [1] with or without frequent measurement of protein humoral tumor markers. Depending on the localization of the tumor, other procedures, such as ultrasound, can be useful. Tumor markers may be absent or variably expressed. Imaging may be influenced by nontumor burden factors such as inflammatory responses in the microenvironment of the neoplasm. Assessment of response to immunotherapy remains an unmet need to discern response/ pseudo-tumor progression [2, 3] from progression/hyperprogression [4]

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