Plasma miR-181a-5p down-regulation predicts response and improved survival after FOLFIRINOX in pancreatic ductal adenocarcinoma

Purpose: FOLFIRINOX has become standard therapy for patients with advanced stages pancreatic ductal adenocarcinoma (PDAC). However, only a subset of patients benefits from this therapy and biomarkers to guide clinical decisions are lacking. This study aimed to discover circulating microRNAs (miRNAs) as potential stratifying and monitoring biomarkers in patients with PDAC treated with FOLFIRINOX and to investigate their functional roles. Methods: A microarray was used in plasma samples from a first cohort of 11 patients selected based on their long versus short progression-free survival (PFS) after FOLFIRINOX. Nine miRNAs were validated using RT-qPCR in an independent cohort (n=43). The best discriminative miRNA was evaluated in tumor tissue samples and associated with clinicopathological features by Cox regression analyses. In vitro studies explored its role on cell proliferation, key downstream targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin. Results: MiR-181a-5p was validated as significantly down-regulated in non-progressive compared to progressive patients after FOLFIRINOX. In multivariate analysis, this down-regulation correlated with improved PFS and overall survival, especially combined with CA19.9 decline (log-rank p<0.001, HR=0.153, 95% C.I. 0.067–0.347 and log-rank p=0.033, HR=0.201, 95% C.I. 0.070–0.576, respectively). Overexpression of miR-181a-5p increased proliferation of PDAC cells and inversely correlated with expression of ATM. Furthermore, inhibition of miR-181a-5p coupled with oxaliplatin exposure increased DNA damage and decreased cell viability. Conclusion: Our findings endorse miR-181a-5p as a biomarker for monitoring response to FOLFIRINOX and prognostication. MiR-181a-5p inhibition can potentially enhance sensitivity to oxaliplatin by amplifying the DNA damage response and cell death. For the first discover cohort of this study, a microarray was performed on plasma samples of 11 patients. These samples included five patients with early disease progression and six patients with no progression during FOLFIRINOX chemotherapy. Of these patients, blood samples were collected both before FOLFIRINOX therapy and after 5-6 cycles of FOLFIRINOX. Of each sample, RNA was isolated with the Small RNA isolation kit (Exiqon). Technical duplicates were included in the subsequent analysis. The plasma microRNA expression before FOLFIRINOX therapy of progressive patients was compared to the microRNA expression of non-progressive patients. In addition, the miRNA expression after FOLFIRINOX was compared to miRNA expression before therapy to determine the change in miRNA expression during therapy.