1. Immune and Circulating Tumor DNA Profiling After Radiation Treatment for Oligometastatic Non-Small Cell Lung Cancer: Translational Correlatives from a Mature Randomized Phase II Trial.
- Author
-
Tang C, Lee WC, Reuben A, Chang L, Tran H, Little L, Gumbs C, Wargo J, Futreal A, Liao Z, Xia X, Yi X, Swisher SG, Heymach JV, Gomez D, and Zhang J
- Subjects
- Alleles, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Circulating Tumor DNA genetics, DNA Fingerprinting, Enzyme-Linked Immunosorbent Assay, Follow-Up Studies, Gene Expression Profiling methods, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor genetics, High-Throughput Nucleotide Sequencing methods, Humans, Lung Neoplasms blood, Lung Neoplasms genetics, Lung Neoplasms immunology, Mutation, Progression-Free Survival, Prospective Studies, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes radiation effects, Time Factors, Translational Research, Biomedical, Watchful Waiting, Biomarkers, Tumor blood, Carcinoma, Non-Small-Cell Lung radiotherapy, Circulating Tumor DNA blood, Cytokines blood, Lung Neoplasms radiotherapy
- Abstract
Purpose: NCT01725165 was a phase II prospective trial in which patients with non-small cell lung cancer were randomized to local consolidative therapy (LCT) versus maintenance therapy or observation (MT/O)., Methods and Materials: Peripheral blood from patients enrolled on NCT01725165 were labeled as (1) baseline, (2) early follow-up (FU) if obtained in the first or second FU evaluation (6-18 weeks), and (3) late FU if obtained in the third to sixth FU evaluations (22-50 weeks). All patients who underwent LCT and were included in this analysis received radiation. Among 49 randomized patients, 21 patients underwent T cell CDR3 variable region sequencing using immunoSEQ, 31 patients underwent circulating tumor DNA (ctDNA) analysis using next-generation sequencing with a 1021 cancer gene panel, and cytokine concentration was assayed in 19 patients using enzyme-linked immunosorbent assay. All analyses were exploratory and not corrected for multiple testing., Results: No associations were identified between baseline T cell repertoire and ctDNA metrics with patient outcomes. Among baseline cytokines, interleukin 1α was the only cytokine associated with both overall survival (hazard ratio, 0.02; 95% confidence interval, 0.1-0.5; P = .0006) and progression-free survival (hazard ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .03). At early FU, LCT was associated with decreased ctDNA burden, including lower number of detected mutations (median, 2 [interquartile range {IQR}, 1-6] vs 6 [IQR, 4-18]) and decreased average variable allele frequency (VAF; median, 0.006 [IQR, 0.003-0.010] vs 0.011 [IQR, 0.007-0.014]) compared with MT/O. Among 6 patients with serial ctDNA analysis, a rise in ctDNA detected mutation burden preceded clinical progression by 6.7 months. At early FU, LCT was associated with changes in T cell clonality that suggested oligoclonal expansion specifically increased T cell clonality (median, 0.15 [IQR, 0.12-0.24] vs 0.10 [IQR, 0.05-0.13]) and frequency of top 10 clones (median, 0.14 [IQR, 0.06-0.18] vs 0.21[IQR, 0.19-0.28])., Conclusion: LCT was associated with decreased ctDNA burden and oligoclonal expansion at early FU timepoints. Baseline interleukin 1α was associated with improved patient outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF