Abstract PR05: Exceptional Response to PD-1 antibody treatment in a POLE-mutant endometrial cancer

Abstract

Abstract Genomic assessment of exceptional responders is a promising approach to identify predictors of response to antibody therapy directed against the immune checkpoint programmed death 1 (PD-1) receptor, which has been shown to yield prolonged and deep responses in multiple types of human cancer. We identified a patient with endometrial cancer who experienced an exceptional response to pembrolizumab, an antibody to programmed death 1 (PD-1) receptor. The primary endometrial cancer specimen and the biopsy from the recurrent supraclavicular lymph node (LN) metastasis obtained prior to treatment were analyzed by hybrid-capture based genomic profiling at a commercial CLIA-certified laboratory, Foundation Medicine, targeting all exons of 315 cancer-related genes. In the patient's pre-treatment endometrial cancer specimens we identified a mutation in DNA polymerase epsilon gene (POLE), which is associated with disruption of the exonuclease activity required for proofreading function and results in a high mutation burden or “ultramutator” phenotype. This tumor did harbor a large number of mutations: 32 likely pathogenic sequence variants and 116 variants of unknown significance (VUS). We next reviewed genomic alterations in 252 deidentified endometrioid endometrial cancers that underwent genomic profiling with the FoundationOne assay and determined that 23 (9.1%) had sequence variants in POLE. The cancers with POLE sequence variants had a mean of 21.2 +/-4.1 mutations identified as likely pathogenic and 82.2 +/-25 variants identified as VUS, compared with a mean of 7.5+/-0.5 likely pathogenic variants and 12.8 +/- 2.6 VUS in POLE wt cases (mean +/- S.E.; p<0.005 and P = 0.015, respectively). This is consistent with TCGA data showing that POLE mutant cancers typically harbor an extremely high mutational burden. To determine if POLE mutant cancers were associated with an immune signature, analysis of RNA sequencing data from endometrioid endometrial cancers in TCGA was performed. POLE mutant cancers have higher expression of several genes encoding for immune checkpoint-related proteins, including PD-L1 and PD-L2, than either MSI or MSS endometrioid cancers. POLE mutant cancers also showed higher expression of T-cell markers such as CD8A, CD3G, PD-1 and CTLA-4, suggesting the presence of a pre-existing T-cell infiltrate. Analysis of histologic image data from TCGA confirmed that POLE mutant cancers had presence of a robust lymphocytic infiltrate. These data suggest that endometrial cancers harboring POLE mutations are associated with expression of immune checkpoint genes and evidence of lymphocytic infiltration. Thus, these tumors may be exceptionally vulnerable to treatment with immune checkpoint inhibitor therapy. We propose further clinical investigation with immunotherapy in endometrial and other cancers with POLE mutations. Citation Format: Janice M. Mehnert, Anshuman Panda, Hua Zhong, Kim M. Hirshfield, Sherri Damare, Katherine Stiles, Levi Sokol, Mark N. Stein, Lorna Rodriguez-Rodriguez, Howard L. Kaufman, Siraj Ali, Jeffery Ross, Dean C. Pavlick, Gyan Bhanot, Eileen P. White, Robert S. DiPaola, Ann Lovell, Jonathan Cheng, Shridar Ganesan. Exceptional Response to PD-1 antibody treatment in a POLE-mutant endometrial cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR05.