Tumor genomic alterations and transcriptomic subtypes may provide prognostic information in patients with resected pancreatic ductal adenocarcinoma (PDAC), but most did not predict differential benefit from adjuvant modified FOLFIRINOX (mFOLFIRINOX) vs gemcitabine, according to an analysis of the PRODIGE-24/CCTG PA6 trial. The findings, reported by Witz et al in the Journal of Clinical Oncology, support mFOLFIRINOX as the standard adjuvant regimen for PDAC.
Study Details
The investigators characterized tumors from patients enrolled in the multicenter, open-label phase III PRODIGE-24/CCTG PA6 trial. Of 493 patients enrolled in the original study, 350 had available surgical tumor specimens, and tumor DNA sequencing was successfully performed in 317 patients who received adjuvant treatment: 168 received mFOLFIRINOX and 149 received gemcitabine. Tumors underwent targeted sequencing with a 524-gene panel, and transcriptomic subtyping was performed using the Purity Independent Subtyping of Tumors (PurIST) classifier.
The researchers examined four key PDAC driver genes and 24 genes associated with homologous recombination repair, as well as single-base substitution mutational signatures. The primary and secondary endpoints were disease-free survival and cancer-specific survival, respectively.
Key Results
Classical tumors accounted for 79.8% of tumors classified by PurIST. Among patients with classical tumors, mFOLFIRINOX was associated with longer disease-free survival than gemcitabine (stratified hazard ratio [sHR] = 0.62, 95% confidence interval [CI] = 0.46–0.84) and improved cancer-specific survival (sHR = 0.65, 95% CI = 0.46–0.91). Within the mFOLFIRINOX group, classical tumors also had significantly better disease-free survival than basal-like tumors (sHR = 0.48, 95% CI = 0.31–0.77). However, the interaction between adjuvant treatment and PurIST subtype was not significant for disease-free survival (P for interaction = .298) or cancer-specific survival (P for interaction = .262).
Oncogenic KRAS mutations were detected in 87.4% of tumors. Among patients with KRAS-mutated tumors, mFOLFIRINOX significantly improved disease-free survival vs gemcitabine (sHR = 0.60, 95% CI = 0.45–0.79), whereas no benefit was observed in the KRAS wild-type subgroup (sHR = 1.73, 95% CI = 0.76–3.95; P for interaction = .010). Within the mFOLFIRINOX group, disease-free survival was significantly longer for patients with KRAS-mutated vs wild-type tumors (sHR = 0.44, 95% CI = 0.25–0.78; P = .005).
Homologous recombination repair–associated alterations occurred in 29.7% of patients, and pathogenic or likely pathogenic BRCA mutations were identified in 11.6%. Neither homologous recombination repair status nor BRCA status predicted differential benefit from mFOLFIRINOX vs gemcitabine. Similarly, the benefit of mFOLFIRINOX was consistent regardless of single-base substitution status.
The investigators concluded: “Overall, these results do not support a change in current adjuvant treatment strategies. [mFOLFIRINOX] 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.”
Andrea Witz, PharmD, of Service de Médecine de Précision et Recherche Translationnelle, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France, and Université de Lorraine, CNRS UMR 7039 CRAN, Vandœuvre-lès-Nancy, France, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Institut National du Cancer and by the French National League against Cancer. For full disclosures of the study authors, visit ascopubs.org.
