FOLFIRINOX is nowadays the standard combination chemotherapy for patients with advanced pancreatic ductal adenocarcinoma (PDAC). However, not all patients benefit from this intense therapy and biomarkers to monitor response are lacking. MicroRNAs (miRNAs) have been shown to regulate multiple genes involved in cancer and are able to serve as biomarker. Therefore, this study aimed to explore the role of circulating miRNAs as stratifying and monitoring biomarkers to predict response to FOLFIRINOX. Further, we investigated the effects of miR-181a-5p in vitro on cell proliferation, key targets, and drug sensitivity to 5-fluorouracil, oxaliplatin and irinotecan. In a discovery cohort of 11 patients grouped according to their long vs. short progression-free survival (PFS), the profiles of 179 miRNAs were analyzed with a specific microarray for plasma/serum miRNAs in matched plasma samples before and after FOLFIRINOX therapy. Using quantitative RT-PCR, nine selected miRNAs were validated in a second cohort (n=43). Circulating miR-181a-5p emerged as the most promising miRNA, with significant down-regulation in non-progressive compared to progressive patients after FOLFIRINOX (p=0.003; fold change = -1.70 versus 3.84, respectively). This down-regulation correlated with improved PFS and OS in uni- and multi-variate analyses, especially in combination with decrease of CA19.9 (log-rank p<0.001 and p=0.033, respectively). In situ hybridization in tissue-microarrays built with representative cores from 15 patients revealed that miR-181a was mostly expressed in tumor cells and not in stromal tissue. Remarkably, tissue expression displayed similar down-regulation of miR-181a after treatment. In vitro oligonucleotide transfection of miR-181a showed that enhanced expression of miR-181a increased proliferation of PDAC cells and decreased expression of ATM, a key target of miR-181a. Most strikingly, inhibition of miR-181a in combination with oxaliplatin treatment increased DNA damage and decreased cell viability. This study supports the use of miR-181a-5p as monitory biomarker to select patients most likely to respond to FOLFIRINOX and guide therapy. MiR-181a-5p inhibition could enhance response to oxaliplatin by amplifying DNA damage response and cell death. In conclusion, our clinical data, together with our in vitro findings, strongly suggest that miRNA profiling in plasma provides promising tools for prognostic, predictive, and therapeutic purposes in PDAC patients.
Citation Format: Laura L. Meijer, Ingrid Garajová, Chiara Caparello, Tessa Y.S. Le Large, Niccola Funel, Enrico Vasile, Geert Kazemier, Elisa Giovannetti. Circulating microRNA-181a monitors response to FOLFIRINOX chemotherapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3649.