TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate.

Journal article

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).

Authors: Danila, D; Anand, A; Sung, C; Heller, G; Leversha, M

• Journal: European urology
• Volume: 60
• Issue: 5
• Pages: 897-904
• Publication date: 2011-11-01
• DOI: 10.1016/j.eururo.2011.07.011
• EISSN: 1873-7560
• ISSN: 0302-2838
• Language: English
• Keywords: In Situ Hybridization, Fluorescence; Reproducibility of Results; Kaplan-Meier Estimate; Humans; Patient Selection; Steroid 17-alpha-Hydroxylase; Chemotherapy, Adjuvant; Antineoplastic Agents, Hormonal; Neoplastic Cells, Circulating; Time Factors; Treatment Outcome; Prostatic Neoplasms; Androstadienes; Orchiectomy; Tumor Markers, Biological; Predictive Value of Tests; Prostatectomy; Enzyme Inhibitors; New York City; Male; Reverse Transcriptase Polymerase Chain Reaction; Genetic Markers; Survival Rate; Radiotherapy, Adjuvant; Oncogene Proteins, Fusion