Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer

Abstract

Background Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSis) abiraterone acetate, enzalutamide, and apalutamide. Objective To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization (“nuclear-agnostic”) identifies more patients who would benefit from a taxane over an ARSi. Design, setting, and participants The study used a coss-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy because of disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs. Outcome measurements and statistical analyses Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. Results and limitations A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 wk. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078–0.79; p = 0.019). This interaction was not significant when nuclear-agnostic criteria were used. Conclusions To reliably inform treatment selection using an AR-V7 protein biomarker in CTCs, nuclear-specific localization is required. Patient summary We analyzed outcomes for patients with metastatic castration-resistant prostate cancer on androgen receptor signaling inhibitors and standard chemotherapy. Patients with circulating tumor cells that had AR-V7 protein in the cellular nuclei were very likely to survive longer on chemotherapy, and tests unable to distinguish where the protein is located in the cell are not as predictive of benefit.

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…In contrast, enzalutamide did not reduce PDX-O growth, consistent with its parental biopsy being from a CRPC patient who had developed resistance to enzalutamide (Figure 6B and C). AR-V7 expression increases as PC patients progress to CRPC and develop treatment resistance (14,15,(22)(23)(24)(25)(26). Consistent with this, castration of CP50 PDX for 14 days significantly increased AR-V7 expression, with a less pronounced impact on AR-FL, C-MYC expression and AR signaling (Figure 6D Figure S13A and B).…”

“…However, primary and secondary resistance to both therapies is common and may, in part, be due to the expression of constitutively active AR splice variants of which AR variant 7 (AR-V7) is considered the most significant and best studied (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Consistent with this, recent studies have demonstrated that AR-V7 expression increases as patients progress to CRPC, and associates with resistance to current AR directed therapies (14,15,(22)(23)(24)(25)(26). AR-V7 lacks the AR ligand binding domain (LBD), but contains a cryptic exon 3 (derived from an intron) after AR exon 3 (27).…”

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

“…Scher HI et al [13] 193 vzorků (161 pacientů) ARTA -androgen-receptor targeting agents, CTC -cirkulující nádorové buňky, AR-V7 -varianta androgen receptoru , PSA -prostata-specifický antigen, PFS -přežívání bez progrese tenciální úspory nákladů při provádění testů AR-V7 u pa cientů s mCRPC před zahájením léčby abirateronem nebo enzalutamidem s vyloučením těchto léků u pa cientů s AR-V7+ CTC. Pro srovnání bylo použito současné situace, kdy jsou abirateronem nebo enzalutamidem empiricky léčení všichni pa cienti s mCRPC.…”

“…Všichni pa cienti s detekovanými AR-V7+ CTC byli rezistentní na léčbu ARTA. AR-V7+ pa cienti dosahovali na léčbě taxany výrazně lepších výsledků než na ARTA (HR OS 0,24; 95% CI 0,10-0,57; p = 0,035) [12,13].…”

“…Celkově 12 % vzorků vykazovalo pozitivitu AR-V7 jen v cytoplazmě. Pro cytoplazmatickou pozitivitu AR-V7 korelace s přežitím nebyla prokázána [13]. Toto tvrzení je možné diskutovat na více úrovních.…”