Tyler M. Bauman
Detection of androgen receptor variant-7 (AR-V7) in circulating tumor cells has been associated with a lack of response to next-generation antiandrogen therapies, such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi) in patients with castration-resistant prostate cancer (CRPC). However, the slice variants role in carcinogenesis and early stage prostate cancer has not been well defined.
Findings presented at the 2015 American Urological Association (AUA) Annual Meeting hope to shed more light on the potential biomarker. At the meeting, Tyler M. Bauman, BS, presented data suggesting that AR-V7 signaling could be involved in the early stages of prostate cancer development.
“There is not a lot known about AR-V7, particularly in early stages of prostate cancer,” Bauman, from the Washington University in St. Louis, Missouri, said during his presentation. “It has been studied in castration-resistant disease, but its baseline expression in epithelial and stromal tissue remains unclear.”
Overall, the researchers found that AR-V7 was expressed in both the epithelia and stroma during early stages of prostate cancer development. Additionally, expression of AR-V7 was increased in those with high-grade intraepithelial neoplasia (HGPIN), even in the absence of androgen receptor (AR) expression.
Prostate development and cancer progression have been long known to be dependent upon androgens and AR signaling. AR signaling may play a role in regulating prostate cancer, but prostate tumors can rapidly evolve and develop mechanisms of resistance against targeted agents.
A central mechanism of resistance is persistent activation of the AR, usually achieved through mutations in the ligand-binding domain or in formation of splice variants. These variants occur in about one-third of patients with CRPC. AR-V7 encodes receptors lacking the C-terminal domain, which contains the ligand-binding portion. It has been posited that AR-V7 prostate cancer cell lines have been involved in ligand-independent AR signaling in CRPC.
In the study, researchers used antibodies to detect full length AR and AR-V7 on hormone-naïve tumor-adjacent normal prostate, HGPIN, primary prostate cancer samples, and metastases. Tissue-specific protein expression and co-localization of AR and AR-V7 were measured using multispectral imaging technology. Ratios of AR and AR-V7 were determined.
AR and AR-V7 were present in stromal and epithelial cells in the normal and pathologic specimens. In epithelial tissue, AR-V7 was significantly increased in HGPIN and metastases compared with normal tissue, but not in the prostate cancer tissue. Bauman said expression of AR was increased in prostate cancer tissue and metastases but not HGPIN.
Double-negative cells (AR-/AR-V7-) were lower in HGPIN, prostate cancer, and metastases compared with normal prostate in epithelial tissue. In addition, the proportion of AR-/AR-V7+ was higher in HGPIN and the number of AR+/AR-V7- cells was higher in prostate cancer. Double-positive (AR+/AR-V7+) cells were more abundant in metastases, according to the researchers.
In the stromal tissue specimens, investigators observed that AR-V7 was increased in HGPIN and metastases, but not prostate cancer. The presence of AR was similar in HGPIN and prostate cancer as compared with normal prostate tissue, but higher in metastases.
In stromal specimens, double-negative variants were lower in HGPIN and metastases. Researchers reported that AR-/AR-V7+ was increased in HGPIN and no changes were found in single positive (AR+/AR-V7-) cells.
The proportion of double-positive cells was higher in metastases than normal tissue. The epithelial ratio of AR-V7 to AR was significantly higher in prostate cancer than normal prostate tissue (P
= .0003) but not HGPIN (P
= .99) or metastases (P
= .57). In the stroma specimens, the ratio of AR-V7 to AR was higher in HGPIN (P
= .02) but not prostate cancer (P
> .99) or metastases (P
“Overall, our data suggest that AR-V7 has the potential to affect carcinogenesis and androgen independent growth in early stages of prostate cancer development,” said Bauman. “The next step will be creating a cell-line model to look more closely at this in culture, but there’s obviously a lot more to explore on this.”
According to results published in The New England Journal of Medicine
, men with CRPC treated with enzalutamide (n = 31) with AR-V7–positive disease (39%) experienced a lower PSA response (0% vs 53%; P
= .004), shorter clinical or radiographic progression-free survival (PFS; median 2.1 vs 6.1 months; P
<.001), and a shorter overall survival (median 5.5 vs not reached; P
= .002) compared with those with AR-V7-negative CRPC.