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Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer
Janice M. Mehnert, … , Jonathan Cheng, Shridar Ganesan
Janice M. Mehnert, … , Jonathan Cheng, Shridar Ganesan
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2334-2340. https://doi.org/10.1172/JCI84940.
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Brief Report Oncology

Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

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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.

Authors

Janice M. Mehnert, Anshuman Panda, Hua Zhong, Kim Hirshfield, Sherri Damare, Katherine Lane, Levi Sokol, Mark N. Stein, Lorna Rodriguez-Rodriquez, Howard L. Kaufman, Siraj Ali, Jeffrey S. Ross, Dean C. Pavlick, Gyan Bhanot, Eileen P. White, Robert S. DiPaola, Ann Lovell, Jonathan Cheng, Shridar Ganesan

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Figure 2

Comparison of immune markers in POLE, MSI, and MSS endometrial cancers in the TCGA data set.

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Comparison of immune markers in POLE, MSI, and MSS endometrial cancers i...
(A) The relative numbers of nonsynonymous mutations found in POLE-mutant, MSI, and MSS endometrial cancers. (B) Heat map showing relative expression of differentially expressed immune-related genes in POLE-mutant, MSI, and MSS endometrial cancers. Number of samples: 27 POLE, 64 MSI, 104 MSS. Box plots (shown in A) use the following default convention: the horizontal line represents the median value, the box covers the interquartile range (IQR), the whiskers cover values within 1.5 IQR beyond the box, and values beyond 1.5 IQR are represented as dots.
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