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Prostate Cancer Genetic Biomarker May Predict Response to Additional Treatments

NEW YORK (GenomeWeb) – Researchers at the Cleveland Clinic and colleagues have found that a testosterone-associated genetic variant can serve as a biomarker to help predict a patient's response to certain prostate cancer treatments.

Published today in two separate studies in JAMA Oncology, the researchers examined the role of the HSD3B1 (1245C) genetic variant in two prostate cancer patient populations who had received androgen deprivation therapy (ADT).

HSD3B1 encodes an enzyme that is involved in dihydrotestosterone synthesis from precursors outside the testes. The 1245A>C variant renders the enzyme more stable, and previous studies have shown that patients carrying the (1245C) allele are more likely to become resistant to ADT.  

Androgen deprivation — which can be achieved through drugs or castration surgery — blocks a prostate cancer's supply of male hormones in the testes. The treatment frequently stops working after a while, however, allowing the cancer cells to grow and metastasize.

"We hypothesized that HSD3B1 variant tumors become resistant to ADT because they have a backup supply of androgens," lead author Nima Sharifi of the Cleveland Clinic Lerner Research Institute said in a statement. "However, relying on these extra-gonadal androgens makes them sensitive to ketoconazole," a drug that blocks the production of androgens outside the testes.

In the first study, Sharifi's team, in collaboration with researchers from the University California, San Francisco, examined a group of 90 patients with metastatic castration-resistant prostate cancer. They were treated with the nonsteroidal CYP17A1 inhibitor ketoconazole, which blocks the production of androgens outside the testes. Patients with the HSD3B1 variant lasted longer on ketoconazole therapy than patients who lacked the variant, and the duration of therapy increased with the number of variant alleles present. The findings suggest that HSD3B1(1245C) can be used as a predictive biomarker of sensitivity to extragonadal androgen ablation by nonsteroidal CYP17A1 inhibitors.

In the second study, Sharifi and his team, in collaboration with researchers at Memorial Sloan Kettering Cancer Center, the Dana-Farber Cancer Institute, Harvard Medical School, and the University of Michigan Comprehensive Cancer Center, looked at 213 patients whose prostate cancer reappeared after radiation therapy and who were subsequently treated with ADT. They found that patients with the HSD3B1 (1245C) allele developed metastases more rapidly than those without, but the variant was not associated with shorter time to progression or overall survival.

The findings of the first study indicate that targeting the tumors' backup androgen supply could possibly be a successful plan for clinicians when cancer cells become resistant to ADT, and that men who inherit the HSD3B1(1245C) variant would potentially benefit from a personalized treatment plan that aims at these specific hormonal pathways.

However, more studies are required to find out whether the variant also predicts response to next-generation androgen inhibitors, such as abiraterone and enzalutamide.

"If that is indeed true, the inherited HSD3B1 variant allele would have the potential to become the first biomarker to aid in clinical decision making in men with [hormone-sensitive prostate cancer] choosing between abiraterone and docetaxel" — treatments that have shown benefit when added to ADT," wrote Neeraj Agarwal, of the Huntsman Cancer Institute at the University of Utah, and colleagues in a commentary accompanying the two studies.