Mutant KRAS and GATA6 Stratify Survival in Patients Treated with Chemotherapy for Pancreatic Adenocarcinoma: A Prospective Cohort Study

TL;DR

This study finds that mutant KRAS and GATA6 RNA levels in pancreatic cancer patients can predict survival and treatment outcomes when receiving chemotherapy.

Contribution

The study prospectively validates mutant KRAS ctDNA and GATA6 RNA as prognostic biomarkers in pancreatic adenocarcinoma.

Findings

High mutant KRAS ctDNA concentration correlates with poor progression-free and overall survival.

Elevated GATA6 RNA expression is associated with longer progression-free and overall survival.

Combining these biomarkers with CA19-9 can guide therapeutic decisions in pancreatic cancer.

Abstract

Comprehensive studies on biomarkers in pancreatic adenocarcinoma (PA) remain scarce. The aim of our prospective cohort study was to assess the potential prognostic value of several biomarkers in real-world practice. Among several blood- and tissue-driven biomarkers, mutant KRAS and GATA6 RNA expression are significant prognostic biomarkers in PA. High mutant KRAS ctDNA concentration correlates with poor survival. Elevated GATA6 RNA expression is associated with longer survival outcomes. These biomarkers, along with CA19-9, can guide therapeutic decisions in PA.

Background: Several pancreatic adenocarcinoma (PA) biomarkers beyond the traditional carbohydrate antigen (CA)19-9 have been identified but are lacking large-scale prospective validation. This prospective cohort study evaluated the prognostic impact of potential PA biomarkers. Methods: We enrolled 238 of 288 patients with histologically proven PA. We assessed candidate biomarkers, including CA19-9, germline BRCA1/2, and ATM mutations, as well as mutant KRAS circulating tumor DNA (ctDNA) in blood samples. Additionally, we evaluated the expression of SLC29A1 (hENT1), DCK, CES2, and GATA6. We examined the association of candidate biomarkers with progression-free survival (PFS) and overall survival (OS). Results: We analyzed biomarker efficacy in 200 (median age 65 years; 55% male) of the enrolled patients who received chemotherapy. A high mutant KRAS ctDNA concentration (hazard ratio [HR]: 1.508 and 95% confidence interval [CI]: 1.052–2.161 for PFS; HR: 1.796 and 95% CI: 1.203–2.681 for OS) and high CA19-9 level (HR: 1.647 and 95% CI: 1.177–2.306 for PFS; HR: 1.803 and 95% CI: 1.248–2.605 for OS) were associated with poor prognosis. High GATA6 RNA expression was linked to longer PFS (HR: 0.336 and 95% CI: 0.195–0.582) and OS (HR: 0.304 and 95% CI: 0.165–0.560). Conclusions: Plasma mutant KRAS ctDNA concentrations and GATA6 expression could serve as significant prognostic biomarkers in patients with PA, potentially guiding therapeutic decisions and prognostication.

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