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Cancer Immunol Res. 2016 Nov;4(11):959-967. Epub 2016 Sep 26.

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

Author information

1
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee. Douglas.b.johnson@vanderbilt.edu.
2
Foundation Medicine Inc., Cambridge, Massachusetts.
3
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
4
Department of Bioinformatics, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
5
Adaptive Biotechnologies, Seattle, Washington.
6
Department of Biostatistics, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
7
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
8
Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
9
Department of Pathology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.

Abstract

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.

PMID:
27671167
PMCID:
PMC5134329
DOI:
10.1158/2326-6066.CIR-16-0143
[Indexed for MEDLINE]
Free PMC Article

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