Integrated driver gene-based survival prediction in resected pancreatic cancer.

Abstract

Background: The aim of this study was to develop an overall survival (OS) prediction model integrating key somatic driver gene mutations in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative-intent pancreatectomy.

Methods: Patients with resected PDAC from a prospectively maintained pancreatectomy database from 2018 to 2023 were identified. Somatic mutations in KRAS, TP53, SMAD4, and CDKN2A were assessed using in-house or commercial sequencing panels. Restricted cubic spline analyses were used to assess non-linear effects. An integrated Cox proportional hazards model incorporating genomic and clinicopathological variables was developed to predict OS and validated using 1000 bootstrap resamples.

Results: In total, 885 patients were identified, of whom 663 met the inclusion criteria. After a median follow-up of 40.8 months, 387 deaths occurred (median OS of 28.4 months). The 1-, 2-, and 3-year OS rates were 80.0%, 56.2%, and 41.5% respectively. In univariable analysis, mutations in KRAS, TP53, SMAD4, and CDKN2A were each associated with inferior OS. Mortality risk increased with the cumulative number of mutated driver genes and remained independently significant in multivariable analysis (0-4; HR per mutation 1.27; P < 0.001). Other independent OS predictors included advanced age, resectability status, elevated pretreatment carbohydrate antigen 19-9 (CA19-9), larger tumour size, positive nodal stage, lymphovascular invasion, poor differentiation, neoadjuvant response classification, and receipt of adjuvant chemotherapy. The integrated model showed moderate discrimination (C-index 0.690 (95% c.i. 0.669 to 0.723); optimism-corrected C-index 0.676), which was significantly higher than AJCC eighth edition pathological staging alone (C-index 0.568 (95% c.i. 0.545 to 0.599); ΔC = 0.122; P < 0.001), with reasonable calibration.

Conclusion: The cumulative burden of driver gene mutations provided independent and incremental prognostic information after PDAC resection. External validation is required before clinical application.