TMPRSS2-ERG Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated With Abiraterone Acetate

Abstract

Background Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors. Objective To study the role of transmembrane protease, serine 2 (TMPRSS2)–v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA. Design, setting, and participants The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials. Intervention Patients received AA 1000 mg daily and continuously. Measurements TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria. Results and limitations Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7–103 cells per 7.5 ml). A PSA decline ≥50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes. Conclusions Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer–specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.

Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer

“…In our present study, a time of 16 months to mCRPC significantly predicted a 50% PSA response. Other factors, including the Gleason score and the TMPRSS2-ERG translocation, did not appear to estimate the response to abiraterone acetate (21,22). The baseline testosterone level was reported to be significantly prognostic of OS, but did not predict the response to treatment (23).…”

Clinical Implications of Current Developments in Genitourinary Pathology

“…Studies by Attard et al 21,22 found that a significantly higher percentage of patients with ETS fusion-positive adenocarcinoma of the prostate had more than a 90% decline in their PSA levels on abiraterone therapy. However, a more-recent study by Danila et al 23 does not show any correlation. In the future, ETS fusions may be useful not only for the detection and prognostics of prostate cancer but also for therapies based on RNA interference that acts on downstream target genes.…”

Prognostic and Predictive Biomarkers for Castration Resistant Prostate Cancer

“…The feasibility of CTCs as an easily obtained tissue for molecular analysis by techniques such as FISH and RT-PCR has been explored to investigate the ERG, AR, and PTEN expression in CTCs from men with CRPC. Danila et al reported that the frequency of detection of the TMPRSS2-ERG fusion in CTCs by RT-PCR from patients with metastatic CRPC was 37 % and the androgen-driven TMPRSS2-ERG fusion in CTCs is a potential predictive biomarker of sensitivity to abiraterone (Danila et al 2011). AR amplification is infrequent in primary and/or diagnostic tumor specimens in prostate cancer, but is detected in up to 50 % of castration-resistant lesions (Holzbeierlein et al 2004).…”