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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 1

Histologic, radiologic, and genomic characteristics of a patient with POLE-mutant endometrial cancer responding to pembrolizumab.

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Histologic, radiologic, and genomic characteristics of a patient with PO...
(A) Histology from surgical resection of primary endometrial cancer. Top inset shows region of peritumoral lymphocytic infiltration; bottom inset shows separate region with peritumoral lymphocytic micronodules. Original magnification, ×10 (left); ×20 (right). T, tumor; L, lymphocytic infiltrate. (B) Histology from supraclavicular LN biopsy taken 4 years after original diagnosis. Original magnification, ×20. (C) Sections of LN metastasis: hematoxylin counterstain (negative control; top image); IHC staining with anti–PD-L1 antibody clone 22C3 (Merck) (bottom image). Original magnification, ×20. (D) Representative abdominal (top) and thoracic (bottom) CT images taken prior to pembrolizumab treatment and 8 weeks after initiation of therapy. Arrows highlight paraaortic and supraclavicular tumor masses, which substantially decreased. (E) Number of nonsynonymous somatic variants, including somatic variants of unknown significance, found in 315 cancer-related genes shown for primary and recurrent tumor samples.
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