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Link Between Genetic Variant and Poor Outcomes in Men with Advanced Prostate Cancer Validated

Bringing a long-running research project to the patient bedside, Dr. Sharifi validated that men with the HSD3B1(1245C) variant more quickly develop treatment-resistant cancer and have shorter survival, suggesting genetic testing may be helpful in personalized treatment planning.


In a new clinical study published in JAMA Oncology, Nima Sharifi, MD, Department of Cancer Biology, and colleagues show that in men with low-volume metastatic prostate cancer, the genetic variant HSD3B1(1245C) is associated with faster progression to treatment resistance and shorter overall survival. This study—the first clinical trial validation of the relationship between HSD3B1 status and clinical outcomes—suggests that genetic testing for the presence of HSD3B1(1245C) may help physicians identify those patients most likely to benefit from additional and more aggressive treatment.

Dr. Sharifi and his collaborators retrospectively analyzed data from a large, multicenter clinical trial testing the efficacy of androgen deprivation therapy (ADT) alone or in combination with the drug docetaxel in prostate cancer. They compared clinical outcomes—including measures of castration resistance and overall survival—between men who carried the variant versus those who did not.

The researchers found that regardless of the use of docetaxel, HSD3B1(1245C) inheritance is associated with earlier development of castration resistant prostate cancer and shorter survival in men with low-volume metastatic prostate cancer. Interestingly, HSD3B1(1245C) exerted the same negative effect on survival despite the administration of any other therapies following the development castration resistance.

Dr. Sharifi notes that it is not necessarily surprising that HSD3B1(1245C) was not found to influence clinical outcomes in men with high-volume prostate cancer, as previous research has shown that disease progression and burden is vastly different between high- and low-volume prostate cancer.

Taken together, these findings suggest that the presence or absence of HSD3B1(1245C) can be used to help identify men with low-volume metastatic prostate cancer most at risk for quick progression to castration resistance and earlier death—a discovery with significant implications for clinical care and genetic counseling.

It is important to note that due to the patient population enrolled in the original clinical trial and genetic variant frequencies, only Caucasian men were included in this analysis. Validating this association with a more diverse population will be a central next line of investigation.

In 2013, Dr. Sharifi made the paradigm-shifting discovery that the HSD3B1(1245C) variant helps prostate cancer cells evade ADT, the first line defense against prostate cancer. ADT works by cutting off cells’ supply of testicular androgens, hormones that fuel cancer cells to grow and spread. He showed that in men with the genetic change, cancer cells adapt to produce their own androgens, which leads to progression to castration resistant prostate cancer. In 2017, he received the national Top Ten Clinical Achievement Award from the Clinical Research Forum for his discoveries linking HSD3B1(1245C) with poor prostate cancer outcomes.

“These findings represent a 7-year research story that started at the lab bench finally reaching the patient bedside,” said Dr. Sharifi. “As the team has shown here, incorporating clinical genotyping in prostate cancer as part of routine care has significant potential to improve treatment success and quality and length of life for men living with prostate cancer who carry the HSD3B1(1245C) variant. This work is another step in that direction.”

Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and directs the Cleveland Clinic Genitourinary Malignancies Research Center. He has joint appointments in the Glickman Urological & Kidney Institute and Taussig Cancer Institute.

Jason Hearn, MD, Department of Radiation Oncology, University of Michigan, is first author on the study, which was supported in part by the National Cancer Institute, part of the National Institutes of Health, the U.S. Department of Defense and the Prostate Cancer Foundation.

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