title: Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer.
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.forename: Janice M
authors.initials: JM
authors.lastname: Mehnert
authors.forename: Anshuman
authors.initials: A
authors.lastname: Panda
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Kim
authors.initials: K
authors.lastname: Hirshfield
authors.forename: Sherri
authors.initials: S
authors.lastname: Damare
authors.forename: Katherine
authors.initials: K
authors.lastname: Lane
authors.forename: Levi
authors.initials: L
authors.lastname: Sokol
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.forename: Lorna
authors.initials: L
authors.lastname: Rodriguez-Rodriquez
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Dean C
authors.initials: DC
authors.lastname: Pavlick
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
authors.forename: Eileen P
authors.initials: EP
authors.lastname: White
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: Ann
authors.initials: A
authors.lastname: Lovell
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheng
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000276:immunology / Q000628:therapy; D004257:DNA Polymerase II / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C105992:PDCD1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; D004257:DNA Polymerase II; C119525:POLE protein, human