Abstract
Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti-PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 2334-2340 |
| Number of pages | 7 |
| Journal | Journal of Clinical Investigation |
| Volume | 126 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2016 |
Bibliographical note
Funding Information:J.M. Mehnert is the principal investigator for clinical trial MK-3475-028/KEYNOTE-28, funded by Merck and Co. (ClinicalTrials.gov NCT02054806). H.L. Kaufman serves on a scientific advisory board and a speaker's bureau for Merck and Co. (funds returned to Rutgers University); serves on scientific advisory boards for Alkermes, Amgen, Bristol-Myers Squibb, EMD Serono Inc., and Prometheus Laboratories Inc.; provides consulting services for Sanofi; and receives clinical trial funding from Amgen, EMD Serono Inc., Prometheus Laboratories Inc., and Viralytics. S. Ali, J.S. Ross, and D.C. Pavlik are employees of Foundation Medicine. A. Lovell and J. Cheng are employees of Merck and Co. S. Ganesan serves on a scientific advisory board and as a consultant to Inspirata and has equity in Inspirata; serves on an advisory board for Novartis Pharmaceuticals Corp.; and has a patent (PCT/US2010/022891) on digital imaging technology licensed to Inspirata. This research was supported by the Functional Genomics and Biospecimen Repository Shared Resource(s) of the Rutgers CINJ (P30CA072720) and a generous gift to the Genetics Diagnostics to Cancer Treatment Research Initiative of the Rutgers CINJ and RUCDR Infinite Biologics. Funding for this research was also provided by Merck and Co.
Publisher Copyright:
© 2016, American Society for Clinical Investigation. All rights reserved.
ASJC Scopus subject areas
- Medicine (all)
