Clinical outcome for gastrointestinal cancers with polymerase epsilon mutations treated with immunotherapy.

Abstract

828 Background: Predictive factors for immunotherapy benefit across gastrointestinal (GI) cancers are limited to those with deficient mismatch repair (dMMR). Mutations in DNA polymerase E (POLE) can cause a hypermutated phenotype irrespective of MMR status and may serve as a predictor factor for immunotherapy. Methods: All POLE-mutant GI cancers with tumor mutation burden (TMB) measured at MD Anderson Cancer Center were identified (N = 58) from 2014 to 2019 and those that had received immunotherapy (N = 18) were studied. TMB was measured by genomic profiling assays FoundationOne or STGA 2018. Samples were analyzed using Kaplan-Meier method and compared using log rank test, with a predefined high TMB threshold of 20 muts/mb. Results: Of the 58 POLE-mutant GI tumors a high TMB was present in 50% of the cases. 18 patients (median age 64, female gender 16.7%, median prior lines of therapy 2) with locally advanced (N = 4) or metastatic (N = 14) POLE-mutant GI cancers (13 colorectal, 1 small intestine, 1 esophageal, 1 pancreatic, and 2 gallbladder) were identified. Immunotherapy agents were PD-1/PD-L1 based in 17 and CTLA-4 based in 1. High TMB was present in 11 patients. dMMR was present in 7 patients, all with high TMB. Treatment response was seen in 3 patients (2 CR and 1 PR), all TMB high and dMMR. Progression-free survival (PFS) was significantly longer in those with high TMB (median: 10.1 months vs. 3 months, p = 0.048). Of the 11 pMMR patients median PFS was 9.3 months in high TMB and 3 months in low TMB (p = 0.246). Conclusions: POLE mutations in GI cancers were associated with a high TMB ( > 20muts/mb) in 50% of patients. Within POLE mutant GI cancers a high TMB may identify patients who benefit from immunotherapy irrespective of mismatch repair status.