The value of GATA6 immunohistochemistry and computer-assisted diagnosis to predict clinical outcome in advanced pancreatic cancer

Abstract

Combination chemotherapy, either modified FOLFIRINOX (mFFX) or gemcitabine–nabpaclitaxel, are used in the treatment of most patients with advanced pancreatic ductal adenocarcinoma (PDAC), yet robust biomarkers of outcome are currently lacking to guide regimen selection. Here, we tested GATA6 immunohistochemistry (IHC) as a putative biomarker in advanced PDAC. GATA6 is a transcription factor in normal pancreas development. Two pathologists, blinded to clinical and molecular data, independently assessed GATA6 IHC in biopsy specimens of 130 patients with advanced PDAC, in 2 distinct phases (without and with computer assistance using the open source software QuPath). Low GATA6 IHC expression was associated with shorter overall survival [median OS 6.2 months for patients with GATA6 low tumors vs. 11.5 months for patients with GATA6 high tumors, HR 1.66 (95% CI 1.15–2.40), P = 0.007]. Progression appears to be higher in GATA6-low tumors compared to GATA6-high tumors in patients treated with mFFX (P = 0.024) but not in patients treated with gemcitabine regimens. GATA6 IHC expression was significantly associated with molecular subtypes (P = 0.0003). Digital assistance markedly improved interrater concordance (Cohen’s kappa scores of 0.32 vs. 0.95). Our results provide strong evidence that GATA6 IHC can be used as a single biomarker in the clinic to predict clinical outcome in advanced PDAC, warranting further investigation in prospective clinical trials. These results provide the basis for an improved classification of PDAC and future biomarker design using digital pathology workflow.

Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis

“…Another way to select patients that most benefit for neoadjuvant chemotherapy would be incorporating biomarkers selection, one example is the evaluation of GATA6 expression 8 , 17 . Tumors that express GATA6 , either detected by RNA sequencing or immunohistochemistry, are defined as classical subtype, and tend to have higher responses to FOLFIRINOX, in opposite of the basal-like subtype, which have low expression or do not express GATA6 , and have worse outcomes 8 , 17 , 18 . Finally, circulating cell-free tumor DNA could be a factor to stratify patients with better outcomes in future prospective trials, and possibly select patients that have benefit to neoadjuvant approaches 19 – 22 .…”

Molecular Landscape and Prognostic Biomarker Analysis of Advanced Pancreatic Cancer and Predictors of Treatment Efficacy of AG Chemotherapy

“…Classical PDAC showed that higher GATA6 mRNA expression is associated with a better prognosis ( 35 , 36 ). Additionally, low GATA6 expression is associated with shorter OS ( 37 ). Our data showed that GATA6 mutations were associated with a shorter PFS.…”

Prognostic value and computer image analysis of p53 in mantle cell lymphoma

“…The limitation of computer image analysis is the inability to distinguish between different cell types such as normal cells and tumor cells 17 . Consequently, representative regions of lymphoma must be chosen carefully by pathologists.…”