Journal Article

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma

Fischer, Sandra, Berry, Scott, Prince, Rebecca, Notta, Faiyaz, Schaeffer, David F, Knox, Jennifer, Holter, Spring, Zogopoulos, George, Grant, Robert C, Zhang, Amy, Wilson, Julie, Simeone, Diane, Nowak, Klaudia M, Jang, Gun Ho, Jang, Raymond, Dodd, Anna, Gallinger, Steven, Denroche, Robert, Topham, James T, Karasinska, Joanna M, O'Kane, Grainne, Borgida, Ayelet, Wang, Yifan, Renouf, Daniel J

2021

Overview

ObjectiveTo describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).DesignWe identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).Results12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.ConclusionsMMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - pathology / cancer genetics / cancer immunobiology / cancer syndromes / Cancer therapies / Clinical trials / Colorectal cancer / Colorectal Neoplasms, Hereditary Nonpolyposis - genetics / Colorectal Neoplasms, Hereditary Nonpolyposis - pathology / CTLA-4 protein / DNA methylation / DNA repair / DNA Repair-Deficiency Disorders - genetics / DNA Repair-Deficiency Disorders - pathology / Female / Gene expression / Genetic disorders / Genetic screening / Genetic Testing / Genomes / Genomics / Humans / Immunogenicity / Immunohistochemistry / Immunotherapy / Janus kinase / Lymphocytes / Male / Medical research / Microsatellite Instability / Mismatch repair / molecular genetics / Mutation / Neoantigens / Ontario / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - pathology / Pathology / Patients / PD-L1 protein / Proteins / Retrospective Studies / Smad4 protein / Statistical analysis / Surgery / Transcription / Tumors / Whole Genome Sequencing