Genetic mutations are a major driver for the development and progression of metastatic castrate-resistant prostate cancer (mCRPC) and were the topic of discussion at the “Metastatic Prostate Cancer Precision Medicine: Challenges and Solutions” session at the 2014 American Association for Cancer Research (AACR) Annual Meeting.
High Frequency of Mutations in mCRPC
Over 90% of sequenced specimens in a multicenter cohort of men with mCRPC had clinically actionable genetic mutations, according to Arul M. Chinnaiyan, MD, PhD, of the University of Michigan in Ann Arbor, MI.1
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As expected, 60% were located within the androgen receptor (AR); however, mutations were also detected in PI3 kinase, DNA repair modulators such as BCRA1 and BRCA2 (>20%), BRAF, the cell cycle pathway (20%), Wnt pathway members (18%), and those of the germline (8% to 10%).
“Germline mutations suggested that these patients could benefit from genetic counseling,” said Dr. Chinnaiyan and mutations in Wnt pathway members were particularly intriguing because “this is suggestive that these patients may actually be susceptible to porcupine or hedgehog inhibitors.”
“Probably the most compelling and clinically actionable findings from this initial cohort were actually in the DNA repair pathway,” highlighted Dr. Chinnaiyan. Both somatic and germline mutations in the DNA repair pathway were identified, and the highest rate of mutations was located in the BRCA2 gene, with mutations also identified in BRCA1 and ATM, as well as in other genes.
“This was quite intriguing because this suggests that these patients may be potentially susceptible to PARP inhibitors, especially with the high frequency of BRCA and ATM inactivation.”
AR Variants as a Clinical Target
Genetic mutations in the AR occur frequently and tend to be specific to mCRPC. In addition, there are multiple splice variants of AR. “The good news is, all you only need to focus on, in my opinion, is AR-V7,” said Jun Luo, PhD, of Johns Hopkins Medical Institutions in Baltimore, MD.2
Developed by Luo’s group, a simple, rapid blood test combined with reverse transcriptase polymerase chain reaction (RT-PCR) can identify AR-V7 in a variety of different settings, such as in patients receiving different types of therapy.
According to Dr. Luo, AR-V7 expression levels can be similar to that of the full-length transcript of the AR (AR-FL), and in vitro data from the VCaP and LNCaP95 cell lines suggest that AR-V7 does not form heterodimers with AR-FL.
The importance of AR-V7 detection has recently been demonstrated in a study published last year in the New England Journal of Medicine,3 in which poorer prostate-specific antigen (PSA) response and progression-free survival were associated with AR-V7 positivity in patients with mCRPC. In addition, patients who were initially AR-V7-negative and became positive for AR-V7 demonstrated outcomes between those of patients who were positive or negative for the variant transcript.
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“If you detect AR-V7 before therapy, you can actually predict that patient’s response to abiraterone and enzalutamide,” Dr. Luo said. There was a 68% PSA response rate in patients who were AR-V7-positive compared with 0% in patients who were AR-V7-negative.3
“It is certainly good that we have multiple therapies, all of which have therapeutic benefit, but on the other hand, we have a problem here because you don’t know which one to choose, how to sequence, when to start, when to stop. All of these decisions are difficult for clinicians,” stated Dr. Luo.
Therefore, a predictive marker would be clinically valuable. AR-V7 may have predictive value for response to abiraterone and enzalutamide.
“I do think it’s possible that there are additional variants out there and we could modify the test to detect them,” stated Dr. Luo.
