Prostate Cancer: Genetic Biomarker Predicts Response To Androgen Deprivation Therapy Interview with:

Neeraj Agarwal, MD Associate Professor, Division of Oncology, Department of Medicine University of Utah School of Medicine

Dr. Neeraj Agarwal

Neeraj Agarwal, MD
Associate Professor, Division of Oncology, Department of Medicine
University of Utah School of Medicine What is the background for this study?

Response: Biomarkers predicting response to cancer therapy help guide physicians personalize medicine. Significant advances have been made in the development of therapeutic biomarkers in various malignancies, but not in prostate cancer. Dr. Nima Sharifi’s group at the Cleveland Clinic recently discovered that a germline inherited polymorphic variant (1245A→C) in the HSD3B1 gene correlates with shorter duration of response to androgen deprivation therapy (ADT) in hormone sensitive prostate cancer (HSPC). HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen.

The authors found that the variant allele of HSD3B1 led to decreased progression-free survival in a dose-dependent manner in post-prostatectomy biochemical recurrence and metastatic HSPC (mHSPC). These results needed external validation before application in the clinic. In our study, we sought to provide the first independent validation of these results in patients with mHSPC. What are the main findings?

Response: Men diagnosed with new onset metastatic prostate cancer and treated at the University of Utah Huntsman Cancer Institute (Salt Lake City, UT) were eligible to be included in this study. The allelic frequency of the HSD3B1 (1245C) variant in our cohort was 31%, which is similar to that reported by Hearn et al (26% to 36% in their three cohorts). In multivariate analysis controlling for Gleason score and baseline log PSA, those men in the homozygous variant group had significantly shorter median PFS in comparison to those in the homozygous wild type group (11 months vs. 21 months, HR 2.16, 95% CI 1.01-4.58, p=0.046). No significant difference in median PFS was observed in those men in the heterozygous group compared to those in the homozygous wild type group (19 months vs. 21 months, HR 1.04, 95% CI 0.64-1.07, p=0.86) (Table). What should readers take away from your report?

Response: The main take away from our study is that a germ line variant HSD3B1 is a predictive biomarker for response to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic prostate cancer. . Patients with homozygous variant alleles for HSD3B1 have significantly shorter responses to first-line ADT and should be considered for more aggressive up-front therapy. What recommendations do you have for future research as a result of this study?

Response: Validation of the first predictive genetic biomarker for response to ADT in newly diagnosed metastatic prostate cancer could significantly affect future clinical trials in this patient population. HSD3B1 should be tested in all men presenting with metastatic prostate cancer. Those harboring HSD3B1 variants are predicted to have inferior response to standard therapy, and should be offered more aggressive treatment options such a chemotherapy or participation in the clinical trials. Is there anything else you would like to add?

Response: I would like to thank Drs. Andrew Hahn, David Gill, and Lisa Cannon-Albright, along with other authors for their integral help with this research project and manuscript preparation. There are no relevant disclosures. Thank you for your contribution to the community.

Citation: ASCO abstract February 2017 and published in

Agarwal N, Hahn AW, Gill DM, Farnham JM, Poole AI, Cannon-Albright L. Independent Validation of Effect of HSD3B1 Genotype on Response to Androgen-Deprivation Therapy in Prostate Cancer. JAMA Oncol. Published online February 16, 2017. doi:10.1001/jamaoncol.2017.0147

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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