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Inherited Variation in the Androgen Pathway Is Associated With the Efficacy of Androgen-Deprivation Therapy in Men With Prostate Cancer

Robert W. Ross, William K. Oh, Wanling Xie, Mark Pomerantz, Mari Nakabayashi, Oliver Sartor, Mary-Ellen Taplin, Meredith M. Regan, Philip W. Kantoff, Matthew Freedman

From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Corresponding author: Matthew Freedman, MD, Dana-Farber Cancer Institute, Dana 710-C, 44 Binney St, Boston, MA 02115; e-mail: freedman{at}broad.mit.edu

Purpose Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT.

Patients and Methods A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism.

Results Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < .01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < .0001).

Conclusion This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual's response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic –genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic –these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

Supported by a Dunkin Donuts Rising Star Award (R.W.R.), the Gelb Center for Translational Research (P.W.K., W.K.O.), Bing Sound Wong Fund for Prostate Cancer Research (W.K.O.) and the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (National Cancer Institute Grant No. 5P50CA90381). The Broad Institute Center for Genotyping and Analysis is supported by Grant No. U54 RR020278-01 from the National Center for Research Resources.

P.W.K. and M.F. contributed equally to this work.

Presented in part at the American Society of Clinical Oncology Prostate Cancer Symposium, February 22-24, 2007, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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