Faculty Collaboration Database

Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor-Based Immunotherapy. Clin Cancer Res 2017 Oct 01;23(19):5729-5736

Date

10/04/2017

Pubmed ID

28972084

Pubmed Central ID

PMC5678984

DOI

10.1158/1078-0432.CCR-17-1439

Scopus ID

2-s2.0-85032026566 (requires institutional sign-in at Scopus site)   169 Citations

Abstract

Purpose: Tumor mutational burden detected by tissue next-generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response.Experimental Design: We assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived ctDNA NGS testing (54-70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), progression-free survival (PFS), and overall survival (OS) were assessed based on total and VUS alterations.Results: Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD ≥6 months/PR/CR 45% versus 15%, respectively; P = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 vs. <6). Statistically significant OS improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders versus nonresponders with VUS >3 had a median PFS of 23 versus 2.3 months (P = 0.0004).Conclusions: Given the association of alteration number on liquid biopsy and checkpoint inhibitor-based immunotherapy outcomes, further investigation of hypermutated ctDNA as a predictive biomarker is warranted. Clin Cancer Res; 23(19); 5729-36. ©2017 AACR.

Author List

Khagi Y, Goodman AM, Daniels GA, Patel SP, Sacco AG, Randall JM, Bazhenova LA, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
Circulating Tumor DNA
DNA, Neoplasm
Disease-Free Survival
Female
Gene Expression Regulation, Neoplastic
Genes, cdc
High-Throughput Nucleotide Sequencing
Humans
Immunotherapy
Male
Middle Aged
Mutation
Neoplasm Proteins
Neoplasms