Anna Katharina Seitz1, Silvia Thoene2, Andreas Bietenbeck3, Roman Nawroth1, Robert Tauber1, Mark Thalgott1, Sebastian Schmid1, Ramona Secci2, Margitta Retz1, Jürgen E Gschwend1, Jürgen Ruland2, Christof Winter4, Matthias M Heck5. 1. Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Germany. 2. Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium, partner site Munich, Germany; German Cancer Research Center, Heidelberg, Germany. 3. Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 4. Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium, partner site Munich, Germany; German Cancer Research Center, Heidelberg, Germany. Electronic address: christof.winter@tum.de. 5. Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Germany. Electronic address: matthias.heck@tum.de.
Abstract
BACKGROUND: It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. OBJECTIVE: To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. RESULTS AND LIMITATIONS: High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005). CONCLUSIONS: Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. PATIENT SUMMARY: We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice.
BACKGROUND: It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. OBJECTIVE: To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. RESULTS AND LIMITATIONS: High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005). CONCLUSIONS: Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. PATIENT SUMMARY: We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice.
Authors: Kristina Stuopelyte; Rasa Sabaliauskaite; Arnas Bakavicius; Benedikta S Haflidadóttir; Tapio Visakorpi; Riina-Minna Väänänen; Chintan Patel; Daniel C Danila; Hans Lilja; Juozas R Lazutka; Albertas Ulys; Feliksas Jankevicius; Sonata Jarmalaite Journal: J Urol Date: 2020-02-18 Impact factor: 7.450
Authors: Emmanuelle Hodara; Gareth Morrison; Alexander Cunha; Daniel Zainfeld; Tong Xu; Yucheng Xu; Paul W Dempsey; Paul C Pagano; Farideh Bischoff; Aditi Khurana; Samuel Koo; Marc Ting; Philip D Cotter; Mathew W Moore; Shelly Gunn; Joshua Usher; Shahrooz Rabizadeh; Peter Danenberg; Kathleen Danenberg; John Carpten; Tanya Dorff; David Quinn; Amir Goldkorn Journal: JCI Insight Date: 2019-03-07
Authors: Scott T Tagawa; Emmanuel S Antonarakis; Ada Gjyrezi; Giuseppe Galletti; Seaho Kim; Daniel Worroll; John Stewart; Atef Zaher; Ted P Szatrowski; Karla V Ballman; Katsuhiro Kita; Shinsuke Tasaki; Yang Bai; Luigi Portella; Brian J Kirby; Fred Saad; Mario A Eisenberger; David M Nanus; Paraskevi Giannakakou Journal: Clin Cancer Res Date: 2018-10-09 Impact factor: 12.531
Authors: Jun Luo; Gerhardt Attard; Steven P Balk; Charlotte Bevan; Kerry Burnstein; Laura Cato; Artem Cherkasov; Johann S De Bono; Yan Dong; Allen C Gao; Martin Gleave; Hannelore Heemers; Mayuko Kanayama; Ralf Kittler; Joshua M Lang; Richard J Lee; Christopher J Logothetis; Robert Matusik; Stephen Plymate; Charles L Sawyers; Luke A Selth; Howard Soule; Wayne Tilley; Nancy L Weigel; Amina Zoubeidi; Scott M Dehm; Ganesh V Raj Journal: Eur Urol Date: 2017-12-16 Impact factor: 20.096
Authors: Marc Carceles-Cordon; W Kevin Kelly; Leonard Gomella; Karen E Knudsen; Veronica Rodriguez-Bravo; Josep Domingo-Domenech Journal: Nat Rev Urol Date: 2020-03-16 Impact factor: 14.432