Longitudinal on-treatment plasma microRNA profiling for identification of biomarker signatures associated with gemcitabine/nab-paclitaxel therapy in pancreatic ductal adenocarcinoma.

e16387 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcomes and limited benefit from systemic therapy. Non-invasive biomarkers capable of dynamically capturing treatment response are needed to improve therapeutic monitoring. Circulating plasma microRNAs (miRNAs) represent a promising class of longitudinal biomarkers. We evaluated on-treatment changes in plasma miRNA profiles in PDAC patients receiving gemcitabine plus nab-paclitaxel (GnP). Methods: Patients with histologically confirmed PDAC were enrolled in a prospective clinical study of GnP. Plasma samples were collected longitudinally at baseline and during treatment. Total RNA was isolated from plasma and subjected to miRNA sequencing, with differential expression analysis performed between pre- and on-treatment samples. Selected miRNAs were validated by RT-qPCR. Exploratory functional studies were conducted in PDAC cell lines. Results: Twenty-eight patients were enrolled, 13 of them had a paired microRNA blood samples (before and on treatment) to be evaluable for longitudinal biomarker analyses. Longitudinal plasma miRNA profiling revealed reproducible on-treatment modulation of circulating miRNAs, including upregulation of miR-296-3p, miR-127-3p, miR-766-5p, miR-202-3p, miR-449c-5p, miR-993, and miR-625-3p, and downregulation of miR-15b-5p, miR-3150a, miR-3158-3p, and miR-4669, which were confirmed by RT-qPCR. The forced expression of miR-3158-3p inhibited cell growth and increased the drug sensitivity to GnP in MiaPaCa2 cells. Correlation of selected miRNAs with therapeutic response and resistance is ongoing using gain- and loss-of-function approaches with miRNA mimics and inhibitors in PDAC models. The correlation of clinical outcomes with the microRNA panel changes is ongoing. Conclusions: Longitudinal on-treatment plasma miRNA profiling identifies dynamic biomarker signatures associated with GnP therapy in PDAC. These circulating miRNAs may serve as minimally invasive biomarkers for treatment monitoring and provide biologic insight into therapy-associated tumor responses. Continued enrollment and longitudinal follow-up are ongoing to further assess clinical relevance.