GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer.

Abstract

To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker. Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of <i>GATA6</i> with the subtypes using gene expression profiling, <i>in situ</i> hybridization (ISH) was explored. Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (<i>P</i> = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (<i>n</i> = 22), the progression rate was 60% compared with 15% in classical PDAC (<i>P</i> = 0.0002). Median OS in the intention-to-treat population (<i>n</i> = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32-0.69; <i>P</i> = 0.0001). <i>GATA6</i> expression by RNA-seq highly correlated with the classifier (<i>P</i> < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (<i>P</i> = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell-inflamed gene expression signature. The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.<i>See related commentary by Collisson, p. 4715</i>.