Limitations of GATA6 and CK5 as surrogate markers for molecular subtyping in pancreatic cancer.

BACKGROUND: Molecular subtyping of pancreatic ductal adenocarcinoma (PDAC) may inform prognosis and treatment selection, and its clinical application remains under investigation. Although PurIST is a validated transcriptomic classifier, immunohistochemical (IHC) markers such as GATA6 and CK5 have been proposed as practical surrogates. We evaluated whether GATA6 and CK5 IHC could substitute for transcriptomic PDAC subtyping. METHODS: RNA-seq and GATA6/CK5 IHC were performed on 130 matched tumor samples. Most patients received neoadjuvant therapy. PurIST subtype assignment served as the reference. Concordance was assessed using Cohen's kappa and overall survival using log-rank tests. RESULTS: PurIST classified 8 tumors (6%) as basal-like. GATA6 alone showed poor concordance with PurIST (kappa=0.18, 95% CI -0.06 to 0.42) and was not prognostic of survival (P=0.98). CK5 showed better concordance (kappa=0.39, 95% CI 0.07 to 0.70) but was not significantly prognostic (P=0.084). Combined GATA6/CK5 improved concordance modestly (kappa=0.54, 95% CI 0.18 to 0.90) and stratified OS in the survival cohort (P=0.041), but generated categories that did not align cleanly with established subtypes. GATA6 IHC correlated weakly with RNA-seq expression (rho=0.178, P=0.0429). DISCUSSION: In predominantly post-neoadjuvant PDAC specimens, GATA6 and CK5 capture aspects of subtype biology but are not reliable substitutes for transcriptomic classification.