HSD3B1 Variant Shows Biomarker Potential For Advanced Prostate Cancer

Research suggests that the HSD3B1 variant allele could help direct treatment for men with advanced prostate cancer

medwireNews: Carriage of the HSD3B1 variant allele acts as a biomarker for outcome in men with advanced prostate cancer, research suggests, predicting the timing of metastases after initiation of salvage androgen-deprivation therapy (ADT) after radiotherapy, as well as the degree of sensitivity to nonsteroidal CYP17A1 inhibition in men with castration-resistant disease.

The first of two brief reports published in JAMA Oncology showed the number of HSD3B1 1245C alleles was significantly associated with the time to metastatic disease among 213 men undergoing ADT for biochemical progression after primary radiotherapy.

The median time to progression was 2.3 years for both the 46% of men who did not have a variant allele and the 45% of men who had one copy of 1245C versus 1.4 years for those with two copies. The corresponding median times to metastases were 7.4, 5.8 and 4.4 years, and median overall survival (OS) was 7.7, 6.9 and 7.2 years, respectively.

Although time to progression and OS did not significantly differ with the number of variant alleles in multivariate analysis, the adjusted hazard ratios for metastases were a significant 1.19 and 2.01 for one and two copies versus no copies of the variant allele, respectively.

Nima Sharifi, from the Cleveland Clinic in Ohio, USA, and co-authors observe that the association between HSD3B1 genotype and outcome was weaker than previously reported for post-prostatectomy men undergoing ADT for biochemical failure.

“Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor [AR] antagonist during salvage treatment, both of which may attenuate the effect of the variant allele”, they remark.

The second study, also reported by Nima Sharifi and co-workers, demonstrated a link between the number of HSD3B1 1245C alleles and increased sensitivity to extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole in castration-resistant prostate cancer (CRPC) patients.

Median duration of ketoconazole therapy before disease progression was a median of 5.0 months for the 44 men with no variant allele, 7.5 months for the 34 men with one copy of 1245C and 12.3 months for the 12 men with two copies, a significant difference.

Median progression-free survival also lengthened significantly with an increasing number of 1245C copies at 5.4, 9.7 and 15.2 months, respectively.

“Our data indicate that the same mechanism that enables earlier CRPC by engaging extragonadal steroids more effectively may make them more dependent on these steroids”, the authors write.

“Therefore, this tumor resistance mechanism may also be exploited clinically as a tumor vulnerability to drugs that block the synthesis of potent androgens from extragonadal steroids, or possibly to AR antagonists that prevent these potent androgens from activating downstream pathways.”

The authors of an accompanying comment extrapolate: “This finding suggests that presence of inherited HSD3B1 variant alleles may predict improved response to novel androgen axis inhibitors, such as abiraterone or enzalutamide.”

Neeraj Agarwal, from the University of Utah in Salt Lake City, USA, and co-authors continue: “If that is indeed true, the inherited HSD3B1 variant allele would have the potential to become the first biomarker to aid in clinical decision making in men with [metastatic hormone-sensitive prostate cancer] choosing between abiraterone and docetaxel.”

References

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; Advance online publication 12 October 2017. doi:10.1001/jamaoncol.2017.3164

Almassi N, Reichard C, Li J, et al. HSD3B1 and response to a nonsteroidal CYP17A1 inhibitor in castration-resistant prostate cancer. JAMA Oncol; Advance online publication 12 October 2017. doi:10.1001/jamaoncol.2017.3159

Hahn AW, Pal SK, Agarwal N. HSD3B1 – A predictive biomarker in advanced prostate cancer. JAMA Oncol; Advance online publication 12 October 2017. doi:10.1001/jamaoncol.2017.3158

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