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

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.

Liquid biopsies: Potential and challenges

“…ctDNA is also a valuable target for genomic aberrations of the AR gene including mutations and amplifications or splice variants that can convey resistance to ADT; investigation of these biomarkers could identify patients that might benefit more from other therapeutic approaches such as taxane chemotherapy, poly‐ADP‐ribose polymerase inhibition or bone tropic radioisotopes 71,79 . For example, the high number of AR amplifications (+8 copies) on ctDNA was associated with primary resistance to the ADT.…”

AR-V7 as a Biomarker for Resistance to Treatment with Abiraterone/Enzalutamide in Three Latin American Countries: A Hypothetical Cost-Saving Analysis

“…We performed an additional net saving estimation analysis in different scenarios for AR‐V7 positivity prevalence rates (5%, 15%, 30%), according to the percentage of prevalence recently reported in the literature [9, 10, 12, 13, 21, 26, 28, 29]. Overall, there is a direct relation between AR‐V7 positivity prevalence and net savings.…”

Circulating Tumor Cells Expressing the Prostate Specific Membrane Antigen (PSMA) Indicate Worse Outcome in Primary, Non-Metastatic Triple-Negative Breast Cancer

“…The multimarker RT-qPCR AdnaTest ProstateCancerPanel AR-V7 detecting CD45 (PTPRC), PSA (KLK3), PSMA (FOLH1), full-length AR (AR-FL), AR splice variant seven ( AR-V7) , and GAPDH (QIAGEN GmbH, Hilden, Germany) has been described in detail recently ( 71 – 73 ). The primer set to detect AR-FL does not detect the AR-V7 transcript.…”