Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study
| Autor: | Colin Rothwell, Russell Z. Szmulewitz, Giuseppe Galletti, Blair Thornburg, Yan Chen, David M. Nanus, Daniel J. George, Gabor Kemeny, Julia Rasmussen, Santosh Gupta, Emmanuel S. Antonarakis, Ryan Dittamore, William R. Berry, Paraskevi Giannakakou, Jason A. Somarelli, Jun Luo, Rhonda Wilder, Scott T. Tagawa, Susan Halabi, Changxue Lu, Andrew J. Armstrong, Monika Anand, Howard I. Scher, Daniel C. Danila, Patrick Healy, Simon G. Gregory, John L. Silberstein |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research business.industry medicine.medical_treatment Alternative splicing ORIGINAL REPORTS Androgen Receptor Splice Variant 7 medicine.disease Genitourinary Cancer Clinical trial 03 medical and health sciences Prostate cancer 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis medicine Cancer research Hormone therapy Progression-free survival Receptor business Prospective cohort study |
| Zdroj: | Journal of Clinical Oncology |
| ISSN: | 1527-7755 0732-183X |
| Popis: | PURPOSE Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies, including abiraterone or enzalutamide. Given that previous reports suggested that circulating tumor cell (CTC) AR-V7 detection is a poor prognostic indicator for the clinical efficacy of secondary hormone therapies, we conducted a prospective multicenter validation study. PATIENTS AND METHODS PROPHECY ( ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospective-blinded study of men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment. The primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS) by using the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay. Overall survival (OS) and prostate-specific antigen responses were secondary end points. RESULTS We enrolled 118 men with mCRPC who were starting abiraterone or enzalutamide treatment. AR-V7 detection by both the Johns Hopkins and Epic AR-V7 assays was independently associated with shorter PFS (hazard ratio, 1.9 [95% CI, 1.1 to 3.3; P = .032] and 2.4 [95% CI, 1.1 to 5.1; P = .020], respectively) and OS (hazard ratio, 4.2 [95% CI, 2.1 to 8.5] and 3.5 [95% CI, 1.6 to 8.1], respectively) after adjusting for CTC number and clinical prognostic factors. Men with AR-V7–positive mCRPC had fewer confirmed prostate-specific antigen responses (0% to 11%) or soft tissue responses (0% to 6%). The observed percentage agreement between the two AR-V7 assays was 82%. CONCLUSION Detection of AR-V7 in CTCs by two blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, and such men with mCRPC should be offered alternative treatments. |
| Databáze: | OpenAIRE |
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