Liquid biopsy reveals KLK3 mRNA as a prognostic marker for progression free survival in patients with metastatic castration‐resistant prostate cancer undergoing first‐line abiraterone acetate and prednisone treatment

Abstract

Circulating RNAs extracted from liquid biopsies represent a promising source of cancer and therapy-related biomarkers. We screened whole blood from patients with metastatic castration-resistant prostate cancer (mCRPC) following their first-line treatment with abiraterone acetate and prednisone (AA-P) to identify circulating RNAs that may correlate with progression free survival (PFS).In a prospective multi-center observational study, 53 patients with mCRPC were included after they started first-line AA-P treatment. Blood was drawn at baseline, one, three and six months after treatment initiation.The levels of pre-defined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g. microRNAs, long non-coding RNAs and messenger RNAs), were analyzed. Uni-and multi-variable Cox regression and Kaplan-Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment.Detectable levels of KLK3 mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P=0.00054). Three months after AA-P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression.Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA-P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA-P treatment might reflect treatment response or early signs of progression.

A Personalized Genomics Approach of the Prostate Cancer

“…In this gene selection, kallikrein-related peptidase 3 ( KLK3 ) had by far the largest average expression level (measured in median gene average expression level units) in all regions (364 in “N”, 139 in “A”, 82 in “B” and 164 in “C”). KLK3 is a prognostic marker for progression-free survival in patients with metastatic prostate cancer [ 58 ]. However, KLK3 has not the largest REVs, nor the highest correlation coefficients with TP53 in any of the regions, verifying the independence of the three characteristics.…”

RNA Biomarkers as a Response Measure for Survival in Patients with Metastatic Castration-Resistant Prostate Cancer

“…Two prospective, observational, multicenter studies were conducted in several hospitals in the Netherlands (ClinicalTrials.gov: NCT02426333 and ILUMINATE: NCT02471469) [ 22 , 23 ]. Eligible patients were patients with mCRPC starting first-line enzalutamide or abiraterone acetate treatment in the ILUMINATE or OPTIMUM study respectively, according to the drug label.…”

“…Thirty healthy individuals (10 men <35 year, 10 men between 55–70 year, and 10 women (no age restriction)), donated an aliquot of their blood, after written informed consent was given. Their blood was used as control, to correct for background levels of the RNAs [ 22 , 23 ].…”

“…Biomarker analysis in whole blood RNA (PAXGENE tubes) for the ILUMINATE and OPTIMUM study, are described in detail by Benoist et al and Boerrigter et al respectively [ 22 , 23 ]. Based on the previous analysis of the biomarkers in the ILUMINATE and OPTIMUM study, only the biomarkers that were upregulated compared to healthy controls were selected for further analysis.…”

“…In our two multi-center prospective clinical trials (ClinicalTrials.gov Identifier: NCT02426333 and ClinicalTrials.gov Identifier: NCT02471469) in which patients with mCRPC started first-line treatment with enzalutamide and abiraterone acetate respectively, several liquid biomarkers were measured longitudinally [ 22 , 23 ]. Four biomarkers were identified that were upregulated in mCRPC patients compared to healthy controls, the prostate-specific kallikrein-related peptidase 3 ( KLK3 ) mRNA, which codes for prostate-specific antigen (PSA), the microRNAs (miR) miR-375 and miR-3687, and the long non-coding RNA (lncRNA) N-acetylated alpha-linked acidic dipeptidase like 2 antisense RNA 2 ( NAALADL2-AS2) [ 22 , 23 ]. These biomarkers are relatively easy and inexpensive to quantify in blood.…”