Development and Validation of the Predictive and Prognostic ChemoResist Signature in Resected Pancreatic Ductal Adenocarcinoma: Multicenter Study.

Abstract

To develop and validate a signature to precisely predict prognosis in pancreatic ductal adenocarcinoma (PDAC) undergoing resection and adjuvant chemotherapy. PDAC is largely heterogeneous, and responds discrepantly to treatment. 551 consecutive patients with PDAC from 3 tertiary centers were initially enrolled. Genetic events of the four most commonly mutated genes in PDAC and expressions of 12 PI3K/AKT/mTOR pathway markers were examined. A 9-feature signature for prediction of chemotherapy benefits was constructed in the training cohort using the LASSO Cox regression model, and validated in 2 independent cohorts. Utilizing the LASSO model, a predictive and prognostic signature, named ChemoResist, was established based on KRAS SNV, PTEN and mTOR expressions, and six clinicopathologic features. Significant differences in survival were observed between high- and low-ChemoResist patients receiving chemotherapy in both the training (median OS, 17 vs. 42 months, P<0.001; median DFS, 10 vs. 23 months, P<0.001) and validation cohorts (median OS, 18 vs. 35 months, P=0.034; median DFS, 11 vs. 20 months, P=0.028). The ChemoResist classifier also significantly differentiated patient survival in the whole patients regardless of chemotherapy. Multivariable-adjusted analysis substantiated the ChemoResist signature as an independent predictive and prognostic factor. For predicting 2-year OS, the ChemoResist classifier had significantly higher AUC than TNM stage (0.788 vs. 0.636, P<0.001), other clinicopathologic characteristics (0.505-0.668), and single molecular markers (0.507-0.591) in the training cohort. Furthermore, patients with low ChemoResist score exhibited a more favorable response to adjuvant chemotherapy compared to those with high ChemoResist score (HR for OS: training, 0.22 vs. 0.57; validation, 0.26 vs. 0.50; HR for DFS: training, 0.35 vs. 0.54; validation, 0.18 vs. 0.59). The ChemoResist signature was further validated in the total cohort undergoing R0 resection. The ChemoResist signature could precisely predict survival in PDAC undergoing resection and chemotherapy, and its predictive value surpassed TNM stage and other clinicopathologic factors. Moreover, the ChemoResist classifier could assist with identifying patients who would more likely benefit from adjuvant chemotherapy.