Genetic Variant in Prostate Cancer Patients May Predict ADT Failure

Men with 1 or 2 copies of the HSD3B1 (1245C) allele are more likely to experience disease progression.
Men with 1 or 2 copies of the HSD3B1 (1245C) allele are more likely to experience disease progression.

Prostate cancer (PCa) patients with a certain variant genotype are more likely to experience resistance to androgen-deprivation therapy (ADT) following recurrence after radical prostatectomy, new study findings suggest.

The genotype, HSD3B1 (1245C), could potentially be a powerful genetic biomarker for distinguishing PCa patients who will respond favorably to ADT from those who have cancer that is more likely to behave aggressively, investigators concluded.

The HSD3B1 (1245C) allele encodes an altered enzyme that augments dihydrotestosterone synthesis from non-gonadal precursors.

“Overall, these data suggest that there may be a genetically defined subgroup of patients with prostate cancer who might benefit from upfront treatment with a next-generation anti-androgen along with standard medical or surgical castration,” principal investigator Nima Sharifi, MD, of the Glickman Urological and Kidney Institute at Cleveland Clinic, told Renal & Urology News.

Dr Sharifi and his colleagues genotyped 443 PCa patients who received ADT for biochemical failure after radical prostatectomy (RP), then correlated genotype with long-term clinical outcomes. Of these, 118 were in the primary cohort (those who underwent RP), 137 were in a post-RP validation cohort, and 188 were in a metastatic validation cohort. The primary endpoint was progression-free survival according to HSD3B1 (1245C) genotype.

Of the 118 men in the primary cohort, 44 were homozygous wild-type (37%), 62 (53%) were heterozygous (had 1 copy of the variant allele) and 12 (10%) were homozygous (had 2 copies of the variant allele).

In the primary cohort, median progression-free survival diminished as a function of the number of variant alleles inherited, the investigators reported online ahead of print in The Lancet Oncology. It was 6.6 years for homozygous wild-type men, 4.1 years for heterozygous men, and 2.5 years for homozygous variant men.

Relative to the homozygous wild-type genotype, inheritance of 1 copy or 2 copies of the variant allele predicted a 1.7-fold and 2.4-fold increased likelihood of disease progression, respectively, according to the investigators.

Median progression-free survival in the metastatic validation cohort was 1.8 years for homozygous wild-type men compared with 0.8 years for homozygous variant men, a significant difference that corresponded to a 2-fold increased risk for progression among homozygous variant men. Heterozygous men had a median progression-free survival of 1.4 years, which did not differ significantly from homozygous wild-type men.

Dr Sharifi's team examined distant metastasis-free survival only in the primary study cohort. It was 9.1 years for homozygous wild-type men, 6.8 years for heterozygous men, and 3.6 years for homozygous variant men. Compared with homozygous wild-type men, homozygous variant men had a significant 2.7-fold increased likelihood of distant metastasis. Heterozygous men had a non-significant 1.7-fold increase risk of distant metastasis.

The investigators stated that their results are biologically credible because tumor cells carrying the variant allele are able to produce their own dihydrotestosterone more efficiently.

“The next step is to determine if the adverse biology and outcomes associated with inheritance of the HSD3B1(1245C) variant are pharmacologically reversible, and how we should use these data to individualize patient therapy based on their genetics,” said Dr Sharifi, co-leader of the Cleveland Clinic's Prostate Cancer Research Center of Excellence. “The first step will be a neoadjuvant clinical trial that we are about to initiate at Cleveland Clinic.” 

Source

1. Hearn JWD et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol 2016. [Epub ahead of print].

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