Abstract 1413: Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study
Authors: Boerrigter Emmy , Benoist Guillemette E. , van Oort Inge M. , Verhaegh Gerald W. , van Hooij Onno , Groen Levi , Smit Frank , Oving Irma M. , de Mol Pieter , Smilde Tineke J. , Somford Diederik M. , Mehra Niven , Schalken Jack A. , van Erp Nielka P. 
Published: September 2020

Abstract
Background Abiraterone acetate is registered for treatment of metastatic prostate cancer, including those with castration-resistant disease (mCRPC). Although it improves overall survival and progression free survival (PFS), treatment response differs between patients. Biomarkers to predict treatment response are lacking. Liquid biopsies containing microRNAs (miRNAs) are a promising source of prognostic biomarkers in mCRPC patients. Furthermore, the exposure to abiraterone in plasma is highly variable and subtherapeutic exposure might contribute to the variability in response to therapy. We explored the prognostic value of microRNAs and drug exposure in mCRPC patients treated with abiraterone.
Methods In a prospective multi-center observational study, 53 patients with mCRPC were included who started pre-chemotherapy abiraterone treatment. Blood was drawn at baseline, 1, 3 and 6 months after start of treatment. The following predefined miRNAs were selected; miR-21, miR-141, miR-200a, miR-200c, miR-375, miR-3687 and abiraterone concentrations were measured. MiRNA-levels in 30 healthy individuals served as controls. Relative miRNA-levels were calculated by the ΔΔCt method. If the geometric mean of a miRNA was more than 2-fold higher in patients versus healthy controls, they were included for survival analysis. Ctrough levels after 1, 3 and 6 months of therapy were measured. The average Ctrough level per patient was used for further analysis. The prognostic value of miRNAs and drug exposure for PFS (radiographic, biochemical or clinical progression) was analyzed with Kaplan-Meier (KM) analysis and tested with a log-rank test. Cut-off values for miRNAs in KM analysis were calculated using maximally selected rank statistics and for the relation with abiraterone Ctrough the earlier defined threshold of 8.4ng/ml was used.
Results Of the miRNAs analyzed, miR-375 was more than 2-fold higher in mCRPC patients versus healthy controls. Patients with more than 2.16 fold higher miR-375 compared to healthy controls showed a trend towards shorter PFS, median 352 vs. 456 days (p=0.076). No PFS benefit was shown for patients with a mean abiraterone Ctrough concentration ≥8.4ng/ml compared to patients below this threshold, median 411 vs. 409 days (p=0.81).
Conclusion High levels of miR-375 might be a prognostic biomarker for PFS in patients with mCRPC treated with abiraterone. The prognostic value of this miRNA should be further explored in a larger cohort of patients. Additionally, the functionality of miR-375 should be further elucidated. The beneficial effect of higher abiraterone exposure levels could not be confirmed in this study for this patient population.
Citation Format: Emmy Boerrigter, Guillemette E. Benoist, Inge M. van Oort, Gerald W. Verhaegh, Onno van Hooij, Levi Groen, Frank Smit, Irma M. Oving, Pieter de Mol, Tineke J. Smilde, Diederik M. Somford, Niven Mehra, Jack A. Schalken, Nielka P. van Erp. Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1413.