DOI: 10.1200/jco-25-02508 ISSN: 0732-183X

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

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