Nuclear Circulating Tumor Cell Androgen Receptor Variant 7 in Castration-Resistant Prostate Cancer

Abstract

Biomarker studies of circulating tumor cells (CTCs) have clinical utility in castration-resistant prostate cancer (CRPC) and constitutively active androgen receptor (AR) splice variants, especially the most common AR variant 7 (AR-V7), are undoubtedly associated with decreased sensitivity to endocrine therapy. In this issue of JAMA Oncology, Scher et al 1 present a correlative study of CTC nuclear AR-V7 protein expression as a biomarker for treatment selection in CRPC. They claim that assay positivity supports choosing taxane chemotherapy rather than administering abiraterone after enzalutamide, or enzalutamide after abiraterone, in keeping with previous reports. 2 Multiple studies have described AR-V7 messenger RNA (mRNA) positivity by binary assays, in CTCs or whole blood, associating AR-V7 positivity with decreased response rates to endocrine therapy and sensitivity to taxanes. 3 Scher et al 1 describe CTC nuclear AR-V7 protein, correctly pointing out the advantages of protein measurements, although CTC mRNA can be collected by methods providing years of stability. Overall, if confirmed by prospective randomized studies generating level 1 evidence, data on AR-V7 could affect survival and quality of life and substantially decrease the high costs of therapy. A test that truly demonstrates futility of a specific treatment could be important, since treatment efficacy currently requires following prostatespecific antigen response for at least 4 weeks of abiraterone after enzalutamide, or enzalutamide after abiraterone. 4 Neither of these treatment switches have, however, been proven to impart survival benefit with modest antitumor activity, and are not widely reimbursed. Nonetheless, such validation of predictive biomarkers and clinical qualification would have major implications, especially in earlier treatment settings, although many challenges need to be met.First, intrapatient heterogeneity with contemporaneous AR-V7-positive and ARV7-negative CTCs is an issue; follow up tissue studies need to explore intermetastatic and intrameta-

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

“…Recently, Scher and colleagues demonstrated increased survival for AR-V7-positive patients receiving taxanes in a blinded retrospective multicenter study [ 26 ]. However, AR-V7 assay positivity and taxane therapy were both correlated to tumor burden, obscuring interpretation and further highlighting the need for a prospective randomized clinical trial to determine if AR-V7 can be applied as a predictive biomarker [ 27 ].…”

The Clinicopathological Characteristics of Androgen Receptor Splicing Variant 7 (AR-V7) Expression in Patients with Castration Resistance Prostate Cancer: A Systematic Review and Meta‐Analysis

“…AR-V7 positive has been associated with unfavorable baseline characteristics; therefore, it may re ect a larger neoplasm burden [20,30,31]. We compared the association between Gleason score and different AR-V7 status.…”

The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer

“…In men treated with enzalutamide or abiraterone, the AR-V7 splice variant (up to 60% prevalence) has been suggested as a negative response marker [31,32]. However, the combination of TP53 inactivation (occurring in 25-40% of mCRPC patients) and multiple AR alterations has demonstrated more promising results [33][34][35]. Metastatic prostate cancer with DNA repair deficiency (DRD), occurring in about 20% of mCRPC cases, has been suggested to have a higher sensitivity to PARP inhibition [36] and platinum-based chemotherapy [37,38].…”