HSD3B1 variant may predict treatment response in advanced prostate cancer
medwireNews: The HSD3B1 1245C variant allele could be used as a biomarker to predict treatment response in different groups of men with advanced prostate cancer, show two studies published in JAMA Oncology.
The research teams, both led by Nima Sharifi from the Cleveland Clinic in Ohio, USA, found that the HSD3B1 1245C variant allele is associated with an improved response to nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic castration-resistant prostate cancer (CRPC), but may be linked to more rapid development of metastases in men treated with androgen-deprivation therapy (ADT) for biochemical recurrence after radiotherapy.
In the first study, of 90 men with metastatic CRPC who underwent extragonadal androgen ablation with the CYP17A1 inhibitor ketoconazole, Sharifi et al found that the median duration of therapy and progression-free survival (PFS) increased significantly with increasing number of HSD3B1 1245C variant alleles inherited.
Specifically, the median duration of therapy was 5.0, 7.5, and 12.3 months for individuals with zero, one, and two variant alleles, respectively, while the median PFS was 5.4, 9.7, and 15.2 months, respectively.
The researchers say their findings indicate that the HSD3B1 1245C variant allele, which is known to increase the synthesis of potent androgens from extragonadal precursor steroids and accelerate the development of CRPC, may make the tumor more dependent on these steroids.
“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 [androgen receptor] antagonists that prevent these potent androgens from activating downstream pathways,” they write.
In a linked commentary, Neeraj Agarwal (University of Utah, Salt Lake City, USA) and co-authors note that although ketoconazole is no longer routinely used in the clinic, the study “allowed the authors to clearly demonstrate that men with variant alleles in HSD3B1 are more responsive to blockade of intratumoral androgen production.”
“This finding suggests that presence of inherited HSD3B1 variant alleles may predict improved response to novel androgen axis inhibitors, such as abiraterone or enzalutamide,” they add.
If this is proven, Agarwal et al believe that “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.”
In the second study, Sharifi and team found that increasing HSD3B1 1245C variant allele frequency was associated with a significantly decreased time to metastasis (TTM) in 213 men treated with ADT for biochemical recurrence after primary radiotherapy.
During a median follow-up of 7.9 years, the median time to metastasis was 7.4 years in individuals with no variant alleles, compared with 5.8 and 4.4 years in those with one and two variant alleles, respectively.
And on multivariate analysis, patients with two alleles had a significant twofold increased risk for metastasis compared with those with no alleles.
By contrast, median time to progression and overall survival (OS) did not vary according to allele frequency.
Noting that the authors previously found that PFS, OS, and TTM were all predicted by HSD3B1 in a group of men with progression after prostatectomy, Agarwal et al suggest that the discordance between time to metastasis and survival outcomes “could have occurred because of disease, patient, and treatment heterogeneity between these studies, such as the frequent use of [AR] antagonist with salvage irradiation in the men with postirradiation biochemical recurrence.”
“The AR antagonists compete with intratumor androgens and may have attenuated the effect of the HSD3B1 variant alleles in these men,” they remark.
By Laura Cowen
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