Blood Test for Receptor Predicts Prostate Cancer Treatment Response

Prostate cancer patients whose tumors contain a shortened receptor called androgen-receptor splice variant 7 messenger ribonucleic acid (AR-V7) are less likely to respond to two widely used drugs for metastatic prostate cancer.

The detection of AR-V7 in circulating tumor cells may be associated with resistance to enzalutamide and abiraterone in patients with castration-resistant prostate cancer. AR-V7 is the only known androgen-receptor variant encoding a functional protein product that is detectable in clinical specimens.

Scientists at the Johns Hopkins’ Kimmel Cancer Center (Baltimore, MD, USA) evaluated two groups of 31 men with prostate cancer that had spread and whose blood levels of prostate-specific antigen (PSA) were still rising despite low testosterone levels. Investigators gave each man either enzalutamide or abiraterone and tracked whether their PSA levels continued to rise, an indication that the drugs were not working.

Circulating tumor cell (CTC) analyses were conducted using the commercially-available Alere CTC AdnaTest platform (AdnaGen; Langenhagen, Germany). A Prostate Cancer Detect kit was used to make complementary DNA (cDNA) for detection of prostate cancer-associated RNA transcripts using multiplexed polymerase chain reaction (PCR) and the signals were detected by the Agilent Bioanalyzer (Agilent Technologies; Palo Alto, CA, USA). RNA in situ hybridization (RISH) was performed to detect the androgen receptor (AR) and AR-V7 on formalin-fixed paraffin-embedded (FFPE) tissue or cell pellet blocks using the ACD RNAscope 2.0 Brown kit (Advanced Cell Diagnostics; Hayward, CA, USA).

In the enzalutamide group, none of 12 patients whose blood samples tested positive for AR-V7 responded to the drug, compared with 10 responders among 19 men who had no AR-V7 detected. In the abiraterone group, none of six AR-V7-positive patients responded, compared with 17 responders among 25 patients lacking AR-V7. Enzalutamide and abiraterone target proteins called androgen receptors and block the receptors’ ability to activate prostate cancer cells. AR-V7 is a shortened form of the androgen receptor that lacks a binding spot targeted by enzalutamide and abiraterone. AR-V7 is therefore free to manipulate prostate cancer cells’ genetic material, which makes the cancer cells grow and spread.

Emmanuel S. Antonarakis, MD, assistant professor of oncology and lead author of the study said, “Patients whose blood samples contained AR-V7 got no benefit from either enzalutamide or abiraterone. This test could be used before starting enzalutamide or abiraterone therapy, and if the test shows the presence of AR-V7, patients may opt for a different therapy. It could also be used to monitor patients receiving enzalutamide or abiraterone for AR-V7, providing an indication these drugs may not work for much longer.” The study was published on September 3, 2014, in the New England Journal of Medicine.

Related Links:
Johns Hopkins’ Kimmel Cancer Center
AdnaGen 
Advanced Cell Diagnostics