Prognostic and predictive values of transcriptomic signatures in metastatic pancreatic cancer: A biomarker analysis of three French multicenter prospective randomized controlled phase 2 trials (Prodige35, Prodige37 and AFUGEM)

To evaluate the clinical applicability of previously established transcriptomic signatures (molecular subtypes, components and GemPred status) in metastatic pancreatic cancer, we conducted a retrospective pooled analysis of 178 patients from three phase 2 trials (PRODIGE35/37, AFUGEM; 2013-2016) testing first-line regimens (FOLFIRINOX, GemNab, FuNab, FOLFIRI3). RNA sequencing was performed on primary/metastatic tumors across French centers, with blinded assessment of subtypes (immune classical, pure basal-like, stroma-activated), quantitative components, and GemPred status. Primary endpoint: progression-free survival (PFS). Immune classical subtype showed superior median PFS (9.03 months) and OS (11.27 months) versus basal-like and stroma-activated subtypes (PFS: p = 0.015; OS: p = 0.010). Higher classical component correlated with improved OS (HR = 0.737, p = 0.005) but not PFS (HR = 0.90, p = 0.339). Inactive stroma predicted better PFS (HR = 0.66, p = 0.003) and OS (HR = 0.697, p = 0.013). GemPred-negative patients treated with FOLFIRINOX versus GemNab had higher ORR (46.9% vs. 19.1%, p = 0.046), longer PFS (8.2 vs. 2.3 months; HR = 2.28, p = 0.008), and OS (11.6 vs. 5.0 months; HR = 2.04, p = 0.021). No differences occurred in GemPred-positive patients. In a formal treatment-by-GemPred interaction analysis (FOLFIRINOX vs. GemNab), the interaction was significant for OS (adjusted p-interaction = 0.050) but not for PFS (adjusted p-interaction = 0.51). Transcriptomic signatures retain prognostic and predictive utility in metastatic pancreatic cancer, with GemPred representing a hypothesis-generating predictive signal for OS (e.g., a FOLFIRINOX OS benefit in GemPred-negative). Prospective validation is warranted for clinical implementation.