KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer
- PMID: 39938521
- DOI: 10.1016/j.medj.2025.100601
KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer
Abstract
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).
Keywords: DNA mutation; FOLFIRINOX; KRAS gene; RNA sequencing; Translation to patients; chemotherapy; pancreatic cancer; pancreatic ductal adenocarcinoma; prognostic biomarkers; subtype; whole-genome sequencing.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests J.d.V.-G. has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier and has received institutional research funding from Servier. J.W.W. had an advisory function for MSD, Astra Zeneca, and Servier and has received research grants from MSD, Nordic, and Servier. M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma and has served as a consultant to Servier, Olympus, and Wholomics. H.W.M.v.L. has served as a consultant or advisor for Amphera, Anocca, Astellas, AstraZeneca, Beigene, Boehringer, Daiichy-Sankyo, Dragonfly, MSD, Myeloid, and Servier; has received research funding, medication supply, and/or other research support from Auristone, Incyte, Merck, ORCA, and Servier; and had a speaker role for Astellas, Beigene, Benecke, BMS, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Springer, and Travel Congress Management B.V. None of these parties were involved in the design or execution of the study.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous
