Association of <i>HSD3B1</i> Genotype With Response to Androgen-Deprivation Therapy for Biochemical Recurrence After Radiotherapy for Localized Prostate Cancer
Authors: Jason W. D. Hearn, Wanling Xie, Mari Nakabayashi, Nima Almassi, Chad A. Reichard, Mark Pomerantz, Philip W. Kantoff, Nima Sharifi
Journal: JAMA Oncology (2017)

<h3>Importance</h3> The variant<i>HSD3B1</i>(1245C) allele enhances dihydrotestosterone synthesis and predicts resistance to androgen-deprivation therapy (ADT) for biochemically recurrent prostate cancer after prostatectomy and for metastatic disease. Whether this is true after radiotherapy is unknown. <h3>Objective</h3> To determine whether the<i>HSD3B1</i>(1245C) allele predicts worse clinical outcomes from ADT for biochemical recurrence after radiotherapy. <h3>Design, Setting, and Participants</h3> The Prostate Clinical Research Information System at Dana-Farber Cancer Institute was used to identify the study cohort, which included men treated with ADT for biochemical recurrence after primary radiotherapy between 1996 and 2013. We retrospectively determined<i>HSD3B1</i>genotype. <h3>Main Outcomes and Measures</h3> Time to progression, time to metastasis, and overall survival according to genotype. Demographic and treatment characteristics were evaluated for confounders. Multivariable analyses were performed to adjust for known prognostic factors. <h3>Results</h3> A total of 218 eligible men were identified, of whom 213 (98%) were successfully genotyped. Of these, 97 of 213 (46%), 96 of 213 (45%) and 20 of 213 (9%) carried 0, 1, and 2 variant alleles. Overall variant allele frequency was 136 of 426 alleles (32%). Median patient age (interquartile range) was 69 (63-74), 72 (65-78), and 69 (65-77) years for 0, 1, and 2 variant alleles (<i>P</i> = .03). Demographic and treatment factors were otherwise similar. During a median follow-up of 7.9 years, median time to progression was 2.3 years (95% CI, 1.6-3.1 years) with 0 variant alleles, 2.3 years (95% CI, 1.5-3.3 years) with 1 variant allele, and 1.4 years (95% CI, 0.7-3.3 years) with 2 variant alleles (<i>P</i> = .68). Median time to metastasis diminished with the number of variant alleles inherited: 7.4 (95% CI, 6.7-9.7), 5.8 (95% CI, 4.9-6.5), and 4.4 (95% CI, 3.0-5.7) years, with inheritance of 0, 1, and 2 variant alleles, respectively (<i>P</i> = .03). Median OS was 7.7 (95% CI, 6.7-10.3), 6.9 (95% CI, 5.8-8.4), and 7.2 (95% CI, 3.8-7.9) years with inheritance of 0, 1, and 2 variant alleles, respectively (<i>P</i> = .31). On multivariable analysis with 0 variant alleles as the reference, the adjusted hazard ratio for metastasis was 1.19 (95% CI, 0.74-1.92) (<i>P</i> = .48) for 1 variant allele and 2.01 (95% CI, 1.02-3.97) (<i>P</i> = .045) for 2 variant alleles. Multivariable analysis did not demonstrate significant differences in TTP or OS. <h3>Conclusions and Relevance</h3> In this study, the<i>HSD3B1</i>(1245C) allele was associated with more rapid development of metastases in men treated with ADT for biochemical recurrence after primary radiation therapy for prostate cancer. Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor antagonist during salvage treatment, both of which may attenuate the effect of the variant allele.