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.

Trial registration: ClinicalTrials.gov: NCT00474383 (COU-AA-003), NCT00485303 (COU-AA-004).

Fig. 1

TMPRSS2-ERG fusion reverse transcription polymerase chain reaction (RT-PCR) assay: (a) schematic of TMPRSS2-ERG fusion and design of TaqMan probes for the RT-PCR assay; (b) dynamic range of the assay was determined for TMPRSS2-ERG, glyceraldehyde-3-phosphate dehydrogenase, androgen receptor (AR), and prostate-specific antigen (PSA) genes.

Fig. 2

(a) Patients with circulating tumor cell (CTC) counts of five or more at 4 wk after therapy showed significantly shorter overall survival compared with patients with CTC counts of less than five (p < 0.001 by log-rank test); (b) waterfall plots showing prostate-specific antigen (PSA) decline from baseline at 12 wk and TMPRSS2-ERG fusion measured by reverse transcription polymerase chain reaction in CTCs from patients with castration-resistant prostate cancer treated with abiraterone acetate (41 of 48 patients); (c) overall survival by TMPRSS2-ERG fusion status in CTCs (p = 0.782 by log-rank test).