Exosomal miRNA signatures as predictors of response to neoadjuvant FOLFIRINOX and GEM/nab-paclitaxel in resectable pancreatic cancer: The PRECEPT study.

Abstract

4223 Background: Neoadjuvant chemotherapy (NAC) with FOLFIRINOX or gemcitabine plus nab-paclitaxel (GEM/nab-PTX) is widely used for resectable and borderline-resectable pancreatic ductal adenocarcinoma (PDAC). However, 10–20% of patients experience disease progression or severe toxicity during NAC, leading to loss of opportunity for curative resection. Given substantial differences in treatment responsiveness between regimens, reliable regimen-specific predictive biomarkers are needed to improve preoperative risk stratification and treatment selection. The PRECEPT trial (NCT07226154) aims to develop circulating exosomal microRNA (exo-miRNA)–based predictors of NAC response. Methods: Pre-treatment plasma samples were collected from patients with resectable or borderline-resectable PDAC prior to NAC. Exo-miRNAs were profiled by small RNA sequencing in a discovery cohort of 49 patients (FOLFIRINOX, n = 31; GEM/nab-PTX, n = 18) to identify regimen-specific candidate exo-miRNAs, which were subsequently quantified by qRT-PCR in a validation cohort of 73 patients (FOLFIRINOX, n = 43; GEM/nab-PTX, n = 30). Regimen-specific miRNA panels were constructed using stepwise selection followed by Firth penalized logistic regression. To benchmark against conventional biomarkers, multivariable Firth logistic regression models including the panel score and baseline CA19-9 were performed to evaluate the incremental predictive value of the exo-miRNA panels. Predictive performance was assessed by receiver operating characteristic (ROC) analysis. Results: In the discovery cohort, exo-miRNA signatures achieved areas under the curve (AUC) of 0.953 for the FOLFIRINOX panel and 1.000 for the GEM/nab-PTX panel. In the qRT-PCR validation cohort, performance remained robust (AUC 0.835 and 0.882, respectively). Higher panel scores were significantly associated with non-response to NAC ( p < 0.01). In multivariable analyses, the exosome-derived miRNA panels provided predictive information beyond CA19-9 and remained independent predictors of treatment non-response in both therapeutic cohorts, demonstrating incremental value over conventional biomarkers. Both panels showed high sensitivity with low false-negative rates, supporting their clinical utility in identifying patients unlikely to benefit from neoadjuvant chemotherapy for each regimen. Conclusions: We developed two regimen-specific circulating exo-miRNA panels capable of predicting response to FOLFIRINOX and GEM/nab-PTX prior to treatment initiation. These panels provide predictive information beyond CA19-9 and may support individualized NAC selection, risk-adapted treatment planning, and improved preoperative decision-making in resectable PDAC. Clinical trial information: NCT07226154 .