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Genetic variant predicts clinical response to prostate cancer therapy
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The presence of HSD3B1 variant predicted clinical outcomes to certain therapies among men treated for localized and metastatic castration-resistant prostate cancers, according to results of two clinical studies published in JAMA Oncology.
Men who inherit the variant may benefit from treatment that targets specific hormonal pathways, the research showed.
“If men carry a specific testosterone-related genetic abnormality, we may be able to personalize their therapy and treat specific patients more aggressively,” Nima Sharifi, MD, physician and researcher at Cleveland Clinic Lerner Research Institute, said in a press release.
Previous research showed the HSD3B1 variant is a predictive biomarker for androgen deprivation therapy. However, it is unknown whether the marker is associated with negative clinical outcomes among men treated with ADT for biochemical recurrence after primary radiotherapy, or with the development of castration-resistant prostate cancer, because extragonadal androgen synthesis is present during both.
In one study, Sharifi and colleagues examined 90 men (median age, 61.5 years) with metastatic castration-resistant prostate cancer subsequently treated with ketoconazole — a nonsteroidal CYP17A1 inhibitor — due to resistance to ADT.
Duration of ketoconazole therapy and time to disease progression — defined as first occurrence of biochemical or radiographic progression — served as the primary endpoints.
Eighty-eight patients had sufficient data to determine duration of ketoconazole therapy, and 81 patients had sufficient time-to-disease-progression data.
Researchers found the median duration of therapy increased with the number of inherited HSD3B1 variant alleles: median duration of therapy was 5 months (95% CI, 3.4-10.4) for men with zero alleles, 7.5 months (95% CI, 4.9-19.2) for one allele and 12.3 months (95% CI, 1.8-not reached) for two alleles.
The median PFS also increased with the number of inherited HSD3B1 alleles, from 5.4 months, to 9.7 months and 15.2 months (P = .03).
“We hypothesized that HSD3B1 variant tumors became resistant to ADT because they have a backup supply of androgens,” Sharifi said in the release. “However, relying on these extra-gonadal androgens makes them more sensitive to ketoconazole.”
In a second study, researchers identified men from the Prostate Clinical Research Information System at Dana-Farber Cancer Institute who underwent ADT for biochemical recurrence after radiation therapy.
The analysis included 213 men with successful genotyping for HSD3B1. Of these, 46% carried zero variant alleles (median age, 69 years), 45% carried one allele (median age, 72 years) and 9% carried two variant alleles (median age, 69 years).
Median follow-up was 7.9 years.
Median time to progression was 2.3 years (95% CI, 1.6-3.1) for men with zero alleles; 2.3 years (95% CI, 1.5-3.3) for one allele; and 1.4 years (95% CI, 0.7-3.3) for two alleles.
The median time to metastasis decreased with the number of inherited variant alleles, from 7.4 years for zero alleles, 5.8 years for one allele and 4.4 years for two alleles (P = .03.).
Median OS appeared similar across these groups (zero alleles, 7.7 years; one allele, 6.9 years; two alleles, 7.2 years).
Multivariate analysis showed an adjusted HR for metastasis of 1.19 (95% CI, 0.74-1.92) for one allele and 2.01 (95% CI, 1.02-3.97) for two alleles.
“We are hopeful that these findings will lead to more personalized and effective treatments for prostate cancer,” Sharifi said. – by Melinda Stevens
Disclosures: Sharifi is listed as co-inventor on a patent application for a treatment based on HSD3B1. Please see the full studies for lists of all other authors’ relevant financial disclosures.
Perspective
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Prostate cancer, like other malignancies, is an extremely heterogeneous disease process, and patients exhibit a wide spectrum of clinical behavior. The search for biomarkers to predict clinical destiny and, thus, provide individualized treatment strategies is a vibrant area of oncologic research. Previous work demonstrated that inheritance of the HSD3B1 (1245C) allele is associated with resistance to androgen ablation therapy among patients who undergo prostate surgery.
In this study, investigators confirm that homozygous variant HSD3B1 (1245C) allele expression is associated with adverse clinical outcomes among patients who progress following definitive radiation therapy. The signal here, however, did not appear as strong as in prostatectomy cohorts. Only time to developing metastases — and not PFS or OS — was associated with HSD3B1variant expression. The researchers hypothesize this may be due to the fact that some patients had been previously exposed to androgen deprivation therapy, that androgen receptor antagonists were used and that, overall, the radiation therapy cohorts likely included patients with more aggressive disease than those patients who underwent prostatectomy. It is unlikely that harboring homozygous variant HSD3B1 (1245C) allele is going to be a clinically actionable finding in the near future; however, it is work such as this that is likely to move the proverbial needle and get us closer to personalized and more effective cancer care.
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