Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study

PURPOSE Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)–associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio [sHR], 0.48 [95% CI, 0.31 to 0.77]). Among KRAS- mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 [95% CI, 0.45 to 0.79]; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, P int. = 0.010). HRR and BRCA status were not predictive ( P int. = .568 and P int. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.

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Journal
Journal of Clinical Oncology
Published
2026-08-03
DOI
https://doi.org/10.1200/jco-25-02508
Primary Topic
Pancreatic and Hepatic Oncology Research
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article
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article

Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study

Nelson Dusetti, Marjorie Mauduit, Alexandre Harlé, James Biagi et al.
Journal of Clinical Oncology
Pancreatic and Hepatic Oncology Research
article

Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study

Nelson Dusetti, Marjorie Mauduit, Alexandre Harlé, James Biagi, Corentin Richard, Thierry Conroy, Andréa Witz, Rémy Nicolle, Anthony Turpin, Jérôme Cros, Jean‐Baptiste Bachet, Juan Iovanna, Julia Salleron, Aurélien Lambert, Laure Monard, Pascal Hammel, Marie Husson, Aboubacar Diallo, Daniel J. Renouf
article en

Abstract

PURPOSE Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)–associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio [sHR], 0.48 [95% CI, 0.31 to 0.77]). Among KRAS- mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 [95% CI, 0.45 to 0.79]; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, P int. = 0.010). HRR and BRCA status were not predictive ( P int. = .568 and P int. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.

Journal of Clinical Oncology
Centre National de la Recherche Scientifique (FR), University of British Columbia (CA), Inserm (FR), Université de Bourgogne (FR), Queen's University (CA), Université Paris Cité (FR), Université de Lille (FR), Université Paris-Saclay (FR), Hôpital Beaujon (FR), Institut Pasteur de Lille (FR), Sorbonne Université (FR), Lille’s Cardiology Hospital (FR), Universidad Nacional Arturo Jauretche (AR), Centre Georges François Leclerc (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut de Cancérologie de Lorraine (FR), Centre de Recherche en Automatique de Nancy (FR), Pitié-Salpêtrière Hospital (FR), Centre de Recherche sur l'Inflammation (FR), UniCancer Group (FR), Centre de Recherche en Cancérologie de Marseille (FR), Hospital El Cruce (AR), Hôpital Paul-Brousse (FR), Interdisciplinarité en Santé Publique Interventions et Instruments de mesure complexes – Région Est (FR), Université de Lorraine (FR)
Good health and well-being
Openalex Percentile: Top 12%
Pancreatic and Hepatic Oncology Research
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