Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations

Abstract

Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC. Archival and prospectively acquired samples and matched normal DNA from = 833 PDAC cases were analyzed using a hybridization capture-based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status. MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease). An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients. .

Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes

“…Identifying these patients is of increasing relevance and importance because of the potential benefit from immunotherapy approaches such as PD-L1 inhibition. 8,9,12,[14][15][16] In our cohort, 2 patients were found to have a high TMB with an associated high MSIsensor score indicating a mismatch repair deficiency. Both patients were without recurrent disease after resection at the data cutoff time; however, should they have recurrent disease, they would be strong candidates for PD-L1-directed immunotherapy approaches.…”

“…13 Moreover, in pancreatic and colorectal cancer, deficiencies in mismatch repair, either sporadic or due to Lynch syndrome, that lead to hypermutated tumors and microsatellite instability benefit from programmed death-ligand 1 (PD-L1) inhibition. 8,9,12,[14][15][16] Cancer May 1, 2019 Notably, in AC, Pinto et al 17 19 also identified a patient with known Lynch syndrome and a mismatch repair deficiency as harboring AC. These findings indicate that there are patients with AC with therapeutically actionable PGAs and associated clinical implications that have thus far not been fully elucidated and optimally therapeutically exploited in AC.…”

EUS fine-needle pancreatic core biopsy can determine eligibility for tumor-agnostic immunotherapy

“…Among the 39 patients, 36 had specimen blocks available for retrieval from the tissue archive and 35 (97.2 %) patients (FNB passes 2 3 4 5 ) had histologic specimen adequacy to assess dMMR by IHC. One patient (2.9 %) displayed loss of MLH1-PMS2 ( Fig.…”

“…The fact that dMMR is rarely present among PDAC patients was further demonstrated in a study of 833 surgically resected PDAC tumors revealing a frequency of 0.8 %, all of whom were patients found to have Lynch syndrome 3 . …”

Publish or Perish v2

“…Where are the results with immune-oncologic agents for pancreatic cancer? Very hard to find beyond the responses observed in patients with tumors bearing mismatch repair deficiency, a subset of tumors for which a histology-agnostic FDA approval exists [15][16][17][18].As a solution for the failure to publish, enter Clinical Trial…”