Background: Transcriptomic FOLFIRINOX-component sensitivity signatures have been clinically evaluated in resected and advanced PDAC, but their relevance and longitudinal stability in the neoadjuvant BR/LA setting are unknown. Patients and methods: We retrospectively studied 77 patients with borderline resectable or locally advanced PDAC treated with neoadjuvant FOLFIRINOX followed by resection. Pretreatment sensitivity to 5-fluorouracil, oxaliplatin and irinotecan was determined using previously developed locked transcriptomic classifiers and integrated into a regimen-level FOLFIRINOX classification. The primary molecular cohort comprised 53 patients whose pretreatment biopsies had [≥]10% tumour cellularity. Cox models assessed associations with survival. Longitudinal changes were assessed in 35 paired tumours. Results: Thirty-one pretreatment tumours were classified as FOLFIRINOX-sensitive (FFX-Sens), and 22 were not classified as FOLFIRINOX-sensitive (FFX-Res). FFX-Sens status was associated with longer overall survival (OS; hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.25-0.93; p=0.029). In the complete-case model adjusted for baseline carbohydrate antigen 19-9 (CA19-9) and tumour size (n=50), the association with OS persisted (adjusted HR 0.47, 95% CI 0.23-0.96; p=0.037), whereas the adjusted association with disease-free survival was not statistically significant (adjusted HR 0.55, 95% CI 0.28-1.10; p=0.090). Among paired tumours, 15 changed from FFX-Sens to FFX-Res and four in the opposite direction (exact McNemar p=0.019). The OS association also persisted after adjustment for postoperative pathological factors (adjusted HR 0.40; p=0.015). Conclusions: Pretreatment FOLFIRINOX sensitivity was associated with OS under neoadjuvant FOLFIRINOX, while matched pretreatment and residual-tumour analyses revealed significant directional reclassification after treatment. These findings extend the clinical evaluation of validated drug-specific FOLFIRINOX sensitivity classifiers to the neoadjuvant setting and provide a longitudinal assessment of their stability during treatment. They support prospective evaluation of both pretreatment stratification and molecular reassessment of residual disease.
Gaucher, C., Kaya, M., Garnier, J., Barthelemy, A., Rochigneux, P., Poizat, F., Rubis, M., Moussard, P., Roques, J., Fraunhoffer, N., Dusetti, N. J., Chanez, B.
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