Abstract and Introduction
Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P=0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is warranted.
Pancreatic ductal adenocarcinoma is among the deadliest solid cancers, with little improvement in overall survival achieved in the past few decades.[1–3] Lack of effective screening modalities and late presentation with advanced stage disease result in fewer than 20% of patients being eligible for surgical resection. Even in surgically-treated patients, the 5-year survival rate is lower than 20%, highlighting the need for more effective and personalized systemic therapeutic approaches. Adjuvant chemotherapy is considered the standard of care for patients with resectable pancreatic ductal adenocarcinoma.[6,7] Pyrimidine analogs (gemcitabine or 5-fluorouracil (5-FU)) are the most commonly used agents, with gemcitabine demonstrating an improved survival compared with no treatment in CONKO-001, and an improved toxicity profile compared with 5-FU in ESPAC-3.
Molecular studies have shown that pancreatic ductal adenocarcinomas contain a high number of gene deletions, mutations, amplifications and rearrangements,[9,10] yet the contribution of these genetic abnormalities to tumor behavior and response to systemic therapy is not well understood. The DNA mismatch repair system is integral to maintaining genomic stability, and mismatch repair deficiency is observed in many malignancies. Mismatch repair deficiency often has hereditary implications, but these tumors also have a genetic hypermutation signature,[12,13] and have been shown to follow a different natural history than their mismatch repair-proficient counterparts.[14,15] The mismatch repair-deficient phenotype may affect the natural history of malignancies through immunologic mechanisms, but this phenotype has also been associated with drug resistance. In vitro studies have shown that mismatch repair-deficient cells are resistant to certain alkylating, methylating and platinum-containing agents as well as select antimetabolites. The mechanisms of drug resistance in mismatch repair-deficient malignancies include increased tolerance to DNA damage, which allows for accumulation of (and selection for) critical mutations, inability to induce cell-cycle arrest, and/or defective apoptotic signaling.[11,17] In fact, the clinical utility of mismatch repair status as a predictor of response to chemotherapy with 5-FU has already been shown in colorectal cancer (reviewed in Sinicrope and Sargeant).
Pancreatic ductal adenocarcinomas are among the cancers that harbor mismatch repair-deficient phenotypes, with an estimated prevalence of 13–17% of tumors in some studies.[18–20] There is conflicting evidence regarding the prognostic value of mismatch repair status in pancreatic ductal adenocarcinoma.[18–22] One study, analyzing pancreatic ductal adenocarcinomas from 78 patients, found no prognostic significance associated with mismatch repair status. In contrast, Dong et al have shown that somatic variants in mismatch repair genes are positively correlated with increased overall survival, supporting earlier studies that suggested microsatellite instability (a surrogate marker of mismatch repair status) is prognostically important in pancreatic ductal adenocarcinoma.[18,20] Moreover, in contrast with colorectal cancer, the predictive value of mismatch repair status for treatment with pyrimidine analogs has not yet been studied in pancreatic ductal adenocarcinoma. We therefore tested the hypotheses that mismatch repair status influences the natural course of pancreatic ductal adenocarcinoma as well as its response to pyrimidine-based chemotherapy.
Mod Pathol. 2015;28(10):1383-1389. © 2015 Nature Publishing Group