PO-472 MicroRNA as biomarkers of resistance to regorafenib in metastatic colorectal cancer patient

Abstract

IntroductionRegorafenib demonstrated efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. Limited clinical benefit in unselected patient populations highlights the unmet need for better patient selection and identification of mechanisms of action. MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis, carcinogenesis and control multiple oncogenic pathways. Numerous miRs deregulation in mCRC are associated with clinical outcome and cancer progression.Material and methodsWe ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients with biopsiable metastases. Tissue biopsies were obtained at baseline (BL), after 2 months of treatment, and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed in BL serum of all patients by NanoString nCounter platform and validated with digital droplet (dd)PCR in serum, plasma and exosomes and by In Situ Hybridization (ISH) in matching tissue biopsies. Fisher’s exact test investigated potential associations between patient groups and categorical variables whilst t-test or non-parametric equivalent tests were used for continuous variables. Progression Free Survival (PFS) was measured from date of registration to date of first progression/relapse or death from cancer progression. Overall Survival (OS) was measured from date of randomisation to death from cancer. The Kaplan-Meier method summarised the survival estimates while the Cox proportional hazards model used to compare the survival rates between patient groups with and without adjustment for the effect of covariates.Results and discussionsMiR expression was tested in 43 BL sera. Dysregulation in 28 miRs was associated with PFS and/or OS. Among these miRs, up-regulation of miR-652–3 p and down-regulation of miR-3614–3 p was associated with worse PFS and OS. Results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed dysregulation of two miRs in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance. Validation in an independent patient’s cohort (n=70) is ongoing. Functional experiments to define miR-mediated resistance are ongoing.ConclusionCirculating miR-652–3 p and miR-3614–3 p might be exploited as biomarkers for the upfront selection of patients’ candidate to regorafenib treatment and might be used to track and forecast acquired resistance to treatment.