Pancreatic Ductal Adenocarcinoma Subtyping using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by immunohistochemistry for KRT81 (QM/squamous/basal like) and HNF1A (non-QM, overlap with exocrine/ADEX subtype). Experimental Design: We validated the different outcome of the HNF1A / KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were either treated with FOLFIRINOX (64 patients) or Gemcitabine (61 patients). Results: In both cohorts with resected PDAC the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst and the double negative subtype an intermediate survival (p <0.013 and <0.009, respectively). In the chemotherapy cohort the survival difference between the double negative and the HNF1A-positive subtype was lost, while the dismal prognosis of KRT81-positive PDAC patients was retained (p <0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX-therapy, while those with HNF1A-positive tumors responded better compared to Gemcitabine-based treatment (p <0.038). Conclusions: Immunohistochemical stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly differing outcomes and responses to chemotherapy. These results may pave the way towards future pretherapeutic biomarker based stratification of PDAC patients.

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