Biomarker Revealed Helps Guide Cancer Treatment Decisions

In two back-to-back studies, researchers demonstrate how a testosterone-related genetic abnormality can help monitor and predict individual patient responses to specific prostate cancer (PC) therapies.

The studies, both from Cleveland Clinic (Cleveland, OH, USA), suggest that men who inherit this variant would benefit from a personalized treatment plan that targets specific hormonal pathways. The research teams, led by Nima Sharifi, MD, of the Cleveland Clinic Lerner Research Institute, studied the role of the HSD3B1(1245C) genetic variant in 2 different PC patient populations, following androgen deprivation therapy (ADT). ADT works by blocking PC’s supply of male hormones in the testes. It is a cornerstone treatment for recurrent PC, but it often stops working, allowing cancer to progress and spread. Previously, Dr. Sharifi & group discovered that PC cells with the genetic abnormality survive ADT by producing their own androgens.

In the first new study, Dr. Sharifi and colleagues from Memorial Sloan Kettering Cancer Center, Harvard/Dana-Farber Cancer Institute, and University of Michigan Comprehensive Cancer Center analyzed 213 men who’s PC recurred after radiation therapy and underwent ADT. They found for the first time that following radiation and ADT, PC was much more likely to spread—and spread rapidly—in men who had the HSD3B1(1245C) variant.

The second study, performed in collaboration with researchers at University of California San Francisco, examined a group of 90 men with metastatic PC that had become resistant to ADT. These patients were subsequently treated with the drug ketoconazole, which blocks the production of androgens outside of the testes (e.g. by PC cells that are evading ADT treatment). Surprisingly, men with the genetic anomaly fared better on ketoconazole than men without the variant. This finding raises the possibility that targeting variant tumors’ backup androgen supply (outside of the testes) could be a successful strategy when ADT fails.

“We hypothesized that HSD3B1(1245C) variant tumors become resistant to ADT because they have a backup supply of androgens,” said Dr. Sharifi. “However, relying on these extra-gonadal androgens makes them more sensitive to ketoconazole.”

These discoveries complement earlier studies and support the use of HSD3B1(1245C) as a predictive biomarker to help guide critical treatment decisions. While the outlook of patients with this gene variant is still poor, these studies offer new hope. “We are hopeful that these findings will lead to more personalized and effective treatments for prostate cancer,” Dr. Sharifi said. More studies are needed using next-generation androgen inhibitors, such as abiraterone and enzalutamide.

The two studies were published together in the October 12, 2017, issue of the journal JAMA Oncology.

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