Yaomin Xu
Last active: 4/6/2017

Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.

Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, Ennis RC, Fabrizio D, Chalmers ZR, Greenbowe J, Ali SM, Balasubramanian S, Sun JX, He Y, Frederick DT, Puzanov I, Balko JM, Cates JM, Ross JS, Sanders C, Robins H, Shyr Y, Miller VA, Stephens PJ, Sullivan RJ, Sosman JA, Lovly CM
Cancer Immunol Res. 2016 4 (11): 959-967

PMID: 27671167 · PMCID: PMC5134329 · DOI:10.1158/2326-6066.CIR-16-0143

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol Res; 4(11); 959-67. ©2016 AACR.

©2016 American Association for Cancer Research.

MeSH Terms (21)

Adult Aged Aged, 80 and over Antineoplastic Agents, Immunological B7-H1 Antigen Biomarkers, Tumor DNA Mutational Analysis Female Gene Expression Profiling Gene Expression Regulation, Neoplastic High-Throughput Nucleotide Sequencing Humans Middle Aged Mutation Neoplasm Metastasis Neoplasms Neoplasm Staging Prognosis Programmed Cell Death 1 Receptor T-Lymphocytes Transcriptome

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