Analysis of AR/ARV7 Expression in Isolated Circulating Tumor Cells of Patients with Metastatic Castration-Resistant Prostate Cancer (SAKK 08/14 IMPROVE Trial).

Hench Hench,Ruiz Ruiz,Hermanns Hermanns,Fischer Fischer,Vlajnic Vlajnic,Mingrone Mingrone,Mestre Mestre,Tolnay Tolnay,Püschel Püschel,Bubendorf Bubendorf,Burg Burg,(Sakk) (Sakk),Costa Costa,Rothermundt Rothermundt,Kremer Kremer,Cathomas Cathomas,Gillessen Gillessen

doi:10.3390/cancers11081099

Abstract

Despite several treatment options and an initial high response rate to androgen deprivation therapy, the majority of prostate cancers will eventually become castration-resistant in the metastatic stage (mCRPC). Androgen receptor splice variant 7 (ARV7) is one of the best-characterized androgen receptor (AR) variants whose expression in circulating tumor cells (CTCs) has been associated with enzalutamide resistance. ARV7 expression analysis before and during enzalutamide treatment could identify patients requiring alternative systemic therapies. However, a robust test for the assessment of the ARV7 status in patient samples is still missing. Here, we implemented an RT-qPCR-based assay for detection of AR full length (ARFL)/ARV7 expression in CTCs for clinical use. Additionally, as a proof-of-principle, we validated a cohort of 95 mCRPC patients initiating first line treatment with enzalutamide or enzalutamide/metformin within a clinical trial. A total of 95 mCRPC patients were analyzed at baseline of whom 27.3% (26/95) had ARFL+ARV7+, 23.1% (22/95) had ARFL+ARV7−, 23.1% (22/95) had ARFL−ARV7−, and 1.1% (1/95) had ARFL−ARV7+ CTCs. In 11.6% (11/95), no CTCs could be isolated. A total of 25/95 patients had another CTC analysis at progressive disease, of whom 48% (12/25) were ARV7+. Of those, 50% (6/12) were ARV7− and 50% (6/12) were ARV7+ at baseline. Our results show that mRNA analysis of isolated CTCs in mCRPC is feasible and allows for longitudinal endocrine agent response monitoring and hence could contribute to treatment optimization in mCRPC.

Highlights

While most newly diagnosed prostate cancer (PC) patients have potentially curable localized disease, still a significant proportion of patients progress or present initially with locally advanced or the metastatic stage [1]
Gene expression of PSA, PSMA, AR full length (ARFL), and Androgen receptor splice variant 7 (ARV7) before spiking the cultured cells was individually tested on all cell lines by qRT-PCR (Figure S1)
While VCAP and LNCAP featured a high expression of PSA, PSMA, ARFL, and ARV7, DU145 and PC3 were negative for PSA, ARFL, and ARV7 mRNA

Summary

Introduction

While most newly diagnosed prostate cancer (PC) patients have potentially curable localized disease, still a significant proportion of patients progress or present initially with locally advanced or the metastatic stage [1]. The backbone treatment of metastatic PC (mPC) is androgen deprivation therapy (ADT). Therapeutic options for metastatic castration-resistant prostate cancer (mCRPC) include novel androgen receptor (AR). Targeting drugs (abiraterone, enzalutamide), taxane chemotherapy, immunotherapy (sipuleucel-T), and bone tropic radioisotopes (radium-223). Current recommendations for treatment strategies mainly depend on patient characteristics, extent of metastatic disease, prior treatments, and symptoms, but there is no randomized data for the optimal therapy sequence [5]. There is a consensus that novel AR targeting drugs should be used in treatment for asymptomatic men with mCRPC progressing on or after docetaxel (without prior abiraterone or enzalutamide) [6]

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