Phase 2 study of circulating microRNA biomarkers in castration-resistant prostate cancer

Abstract

Background:Biomarkers of therapeutic response and prognosis are needed to assist in the sequencing of treatments for metastatic castration-resistant prostate cancer (CRPC). Previously in a Phase 1 discovery study, we identified 14 circulating microRNAs that were associated with response to docetaxel chemotherapy or overall survival. We performed a Phase 2 validation study to verify these findings.Methods:Using real-time PCR, the levels of the 14 microRNAs were measured in plasma collected before and after the first cycle of docetaxel from a Phase 2 cohort of 89 patients.Results:The microRNAs were not associated with docetaxel response in the Phase 2 cohort. Higher baseline levels of six microRNAs, predominantly of the miR-200 family, were confirmed to be associated with shorter overall survival. A microRNA signature comprising these six microRNAs predicted high-risk patients in the Phase 2 cohort with a hazard ratio of 4.12 (95% CI 2.20–7.70, P=0.000001). The signature was an independent predictor in multivariable analysis with clinicopathological factors.Conclusions:The association of circulating microRNAs with overall survival suggests their involvement in CRPC progression.

Circulating miR-141 and miR-375 are associated with treatment outcome in metastatic castration resistant prostate cancer

“…The decreased plasma level of most of the investigated miRs in this study after introduction of both docetaxel and abiraterone and the subsequent increase at radiological progression argue for an oncogenic role in PCa. These changes of circulating miRs as a treatment response has also been reported in previous studies [22][23][24] .…”

“…Lin et al 23 documented a significant association between changes in circulating levels of six miRs (three of them are members of miR-200 family, namely miR-200b, -200c, and miR-429) and PSA response in mCRPC patients receiving docetaxel. However these results couldn't be validated in a larger independent mCRPC cohort receiving docetaxel in a phase 2 study performed by the same group 24 . Dispite a small population size ( www.nature.com/scientificreports www.nature.com/scientificreports/ patients), a predictive value of high serum miR-21 (4/10) were proposed for those who were resistant to docetaxel treatment 22 .…”

“…This observation was validated in a follow-up cohort of another independent 100 mCRPC patients 34 . Futhermore, in a phase 2 study Lin et al has observed associations between baseline levels of circulating miR-375 and poor outcome 24 .…”

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

“…Teng and colleagues [13] demonstrated that miR-193a interacts with major vault protein to promote cancer progression by regulating cell cycle and proliferation. Lin et al [14] found that six circulating miRNAs are correlated with overall survival in castration-resistant prostate cancer. Other studies have reported the molecular function and potential clinical utility of miRNAs in PDAC [15,16].…”

Free Circulating miRNAs Measurement in Clinical Settings

“…In a randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer, baseline plasma hsa-miR-141, hsa-miR-200a, and hsa-miR-375 levels were associated with baseline circulating tumor cells count and baseline hsa-miR-375 was also associated with the trial endpoint of 28-week prostate-specific antigen (PSA) response [33]. Furthermore, Lin et al demonstrated, in a phase II study in castration-resistant prostate cancer patients, that higher baseline levels of miRNAs belonging to the hsa-miR-200 family were associated with a shorter overall survival [34]. In a study exploring miRNAs as predictive biomarkers of the efficacy of peptide vaccines alone (phase I) and in combination with chemotherapy (phase II) in colorectal cancer, hsa-miR-125b-1 and hsa-miR-378a have been negatively associated with overall survival [35].…”