KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer

Background: First-line chemotherapy (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin [FOLFIRINOX]) benefits few patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Prognostic markers for treatment-related survival are needed. This study validated the added benefit of whole-genome sequencing (WGS) to transcriptome-based classification in modeling FOLFIRINOX-related survival. Methods: Patients with mPDAC planning to start FOLFIRINOX were included in a prospective nationwide cohort. Pretreatment biopsies were submitted to WGS and RNA sequencing. Samples of non-FOLFIRINOX-treated patients were included for exploratory analyses. Findings: WGS was performed in biopsies from 108 FOLFIRINOX-treated patients and 51 non-FOLFIRINOX-treated patients. 12% of the tumors were KRAS wild type. These tumors had more targetable alterations (42% vs. 17%) and were associated with a longer median overall survival (mOS) than KRAS mutant tumors (7.8 months in KRAS mutant vs. 17.7 months in wild-type tumors, p = 0.0024). Transcriptome-based clustering revealed a tumor subgroup showing low classical and basal-like gene expression, enriched for KRAS wild-type status (p < 0.0001), a so-called “classifier-negative” subtype. The gene expression of these classifier-negative tumors correlated with neural-like signatures. For patients with a homologous recombination-deficient (HRD) tumor, mOS was not increased (8.0 months in homologous recombination-proficient [HRP] vs. 13.3 months in HRD tumors, p = 0.21). Conclusions: KRAS wild-type tumors are a distinct PDAC subgroup with a better prognosis. Consequently, KRAS status assessment before transcriptome-based subtyping can stratify patients into three prognostic molecular subgroups (KRAS wild type, KRAS mutant classical, and KRAS mutant basal like). This integrative way of classification should be validated prior to incorporation in diagnostic practice. Funding: ZonMw “Good Use of Medicine” program (848101012).