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

Marjolein F Lansbergen; Mark P G Dings; Jan Koster; Mariette Labots; Emile D Kerver; Anouk Jochems; Marjolein Y V Homs; Judith de Vos-Geelen; Mathijs P Hendriks; Michael W T Tanck; Johanna W Wilmink; Hanneke W M van Laarhoven; Maarten F Bijlsma

doi:10.1016/j.medj.2025.100601

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

Marjolein F Lansbergen, Mark P G Dings, Jan Koster, Mariette Labots, Emile D Kerver, Anouk Jochems, Marjolein Y V Homs, Judith de Vos-Geelen, Mathijs P Hendriks, Michael W T Tanck, Johanna W Wilmink, Hanneke W M van Laarhoven, Maarten F Bijlsma^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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).

Original language	English
Article number	100601
Number of pages	17
Journal	Med
Volume	6
Issue number	6
DOIs	https://doi.org/10.1016/j.medj.2025.100601
Publication status	Published - 13 Jun 2025

Keywords

DNA mutation
FOLFIRINOX
KRAS gene
RNA sequencing
Translation to patients
chemotherapy
pancreatic cancer
pancreatic ductal adenocarcinoma
prognostic biomarkers
subtype
whole-genome sequencing

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Lansbergen, M. F., Dings, M. P. G., Koster, J., Labots, M., Kerver, E. D., Jochems, A., Homs, M. Y. V., de Vos-Geelen, J., Hendriks, M. P., Tanck, M. W. T., Wilmink, J. W., van Laarhoven, H. W. M., & Bijlsma, M. F. (2025). KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer. Med, 6(6), Article 100601. https://doi.org/10.1016/j.medj.2025.100601

@article{b9490dcae7ca4fb3b88c38a655f4db21,

title = "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",

author = "Lansbergen, \{Marjolein F\} and Dings, \{Mark P G\} and Jan Koster and Mariette Labots and Kerver, \{Emile D\} and Anouk Jochems and Homs, \{Marjolein Y V\} and \{de Vos-Geelen\}, Judith and Hendriks, \{Mathijs P\} and Tanck, \{Michael W T\} and Wilmink, \{Johanna W\} and \{van Laarhoven\}, \{Hanneke W M\} and Bijlsma, \{Maarten F\}",

year = "2025",

month = jun,

day = "13",

doi = "10.1016/j.medj.2025.100601",

language = "English",

volume = "6",

journal = "Med",

issn = "2666-6340",

publisher = "Cell Press",

number = "6",

}

Lansbergen, MF, Dings, MPG, Koster, J, Labots, M, Kerver, ED, Jochems, A, Homs, MYV, de Vos-Geelen, J, Hendriks, MP, Tanck, MWT, Wilmink, JW, van Laarhoven, HWM & Bijlsma, MF 2025, 'KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer', Med, vol. 6, no. 6, 100601. https://doi.org/10.1016/j.medj.2025.100601

TY - JOUR

T1 - KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer

AU - Lansbergen, Marjolein F

AU - Dings, Mark P G

AU - Koster, Jan

AU - Labots, Mariette

AU - Kerver, Emile D

AU - Jochems, Anouk

AU - Homs, Marjolein Y V

AU - de Vos-Geelen, Judith

AU - Hendriks, Mathijs P

AU - Tanck, Michael W T

AU - Wilmink, Johanna W

AU - van Laarhoven, Hanneke W M

AU - Bijlsma, Maarten F

PY - 2025/6/13

Y1 - 2025/6/13

N2 - 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).

AB - 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).

KW - DNA mutation

KW - FOLFIRINOX

KW - KRAS gene

KW - RNA sequencing

KW - Translation to patients

KW - chemotherapy

KW - pancreatic cancer

KW - pancreatic ductal adenocarcinoma

KW - prognostic biomarkers

KW - subtype

KW - whole-genome sequencing

U2 - 10.1016/j.medj.2025.100601

DO - 10.1016/j.medj.2025.100601

M3 - Article

SN - 2666-6340

VL - 6

JO - Med

JF - Med

IS - 6

M1 - 100601

ER -

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

Abstract

Keywords

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