title: Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma.
abstract: 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.
authors.affiliation: Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Maziar
authors.initials: M
authors.lastname: Riazy
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Pancreas Centre BC, Vancouver, British Columbia, Canada.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.affiliation: Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Sheffield
authors.affiliation: Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Renata D
authors.initials: RD
authors.lastname: Peixoto
authors.affiliation: Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Hector H
authors.initials: HH
authors.lastname: Li-Chang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Pancreas Centre BC, Vancouver, British Columbia, Canada.|Division of General Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Scudamore
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Pancreas Centre BC, Vancouver, British Columbia, Canada.|Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Renouf
authors.affiliation: Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Pancreas Centre BC, Vancouver, British Columbia, Canada.
authors.forename: David F
authors.initials: DF
authors.lastname: Schaeffer
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D053843:DNA Mismatch Repair / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016016:Proportional Hazards Models; D046888:Tissue Array Analysis
chemical_list: D000970:Antineoplastic Agents