Genetic Variant Predicts Faster Time to Prostate Cancer Metastasis

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The variant HSD3B1 allele increases the likelihood of metastasis in men receiving androgen-deprivation therapy for biochemically recurrent disease after radiotherapy for localized PCa.
The variant HSD3B1 allele increases the likelihood of metastasis in men receiving androgen-deprivation therapy for biochemically recurrent disease after radiotherapy for localized PCa.

Men who receive androgen-deprivation therapy (ADT) for biochemical recurrent disease after primary radiotherapy for localized prostate cancer (PCa) experience more rapid development of metastasis if they have a certain variant allele, according to a new study.

In a study of 213 patients, the median time to metastasis was 7.4, 5.8, and 4.4 years for those with 0, 1, and 2 variant HSD3B1 (1245C) alleles, respectively, Nima Sharifi, MD, of Cleveland Clinic in Ohio, and colleagues reported online ahead of print in JAMA Oncology. During a median follow-up of 7.9 years, the median time to progression was 2.3 years. Compared with patients who had no variant alleles, those with 2 variant alleles had a 2-fold increased risk of metastasis on multivariate analysis. Of the 213 men, 97 (46%), 96 (45%), and 20 (9%) inherited 0, 1, and 2 variant alleles, respectively.

The study found no significant association between the variant allele and time to progression (TTP) or overall survival (OS).

The variant HSD3B1 (1245C) allele enhances dihydrotestosterone synthesis and predicts resistance to ADT for biochemically recurrent PCa following radical prostatectomy, the authors explained. They believe their study is the first to analyze the association between the variant HSD3B1 (1245C) allele and response to ADT following radiotherapy for PCa.

Dr Sharifi's team pointed to some notable differences between their study and studies looking at men receiving ADT for biochemically recurrent PCa following radical prostatectomy. In the current study, 105 (49%) of the 213 patients had received prior ADT along with radiotherapy. In the RP cohorts, few men had previously received ADT, they noted. “This is relevant, since the selective pressure from ADT ultimately leads to emergence of multiple somatic resistance mechanisms, which could dilute the impact of germline HSD3B1 genotype.”

In addition, in the current study, 119 (56%) men received an androgen receptor (AR) antagonist during ADT, whereas the vast majority of patients in the previously published cohorts did not.

“Although the HSD3B1 (1245C) allele increases the rate at which adrenal androgen precursors are converted to dihydrotestosterone within tumor cells, AR antagonists compete with intratumoral androgens and may attenuate the effect of the variant allele,” the investigators speculated. “Thus, it is possible that the high rates of prior ADT exposure and frequent use of AR antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS.”

Reference

Hearn JWD, Xie W, Nakabayashi M, et al. Association of HSD3B1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol 2017; published online ahead of print. doi: 10.1001/jamaoncol.2017.3164

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