Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide

Abstract

Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.

In Situ Detection and Quantification of AR-V7, AR-FL, PSA, and KRAS Point Mutations in Circulating Tumor Cells

“…In addition, heterogeneity among CTCs can be easily visualized. Although the AR-V7 mRNA expression is shown to correlate with worse clinical outcomes in recent literature, we cannot simply conclude that every mRNA transcript will be translated to protein (31 ). Indeed, Scher et al showed that resistance toward novel hormonal therapy (NHT) depends on the nuclear-specific location of AR-V7 protein rather than on cytoplasmic localization (32 ).…”

AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer

“…deny v tab. 4, všechny rozdíly byly statisticky signifikantní [11]. U pa cientů s CTC AR-V7+ bylo PFS zkráceno na dobu 4 vs. 10,1 měsíce ve skupine CTC AR-V7-.…”

“…Antonarakis et al [11] 202 149 (73,7 %) 36 (29,0 %) 113 (56 %) Výsledky potvrdili negativní prognostický dopad CTC+ AR-V7+ ve skupině s terapií ABI/ ENZA (zkrácení PFS u CTC AR-V7+). Poprvé byla zdokumentována taky skupina CTC-pacientů (53 a 26,2 %) podstupujících léčbu u mCRCP.…”

“…podle publikace Antonarakise et al pouze 4,8 % (1 pa cient z 21) [11]. Proto je možné doporučit testování AR-V7, pokud se u nemocného předléčeného jedním typem ARTA zvažuje léčba jiným lékem z této skupiny.…”

Why Targeting of PSMA Is a Valuable Addition to the Management of Castration-Resistant Prostate Cancer: The Urologist’s Point of View

“…In patients not willing to be treated with chemotherapy or not eligible for chemotherapy because of the respective toxicity profile, AA or enzalutamide is often used as the second-line therapy of choice. However, the second-line treatment success of AA or enzalutamide is often limited and short-lived because of cross resistance caused by, for example, alternative splicing of the androgen receptor (3,4). Novel targeted therapies with favorable toxicity profiles are therefore needed to broaden the therapeutic armamentarium.…”