Androgen-Enhancing Gene Mutation Reduces Prostate Cancer Survival

Prostate cancer patients with an inherited gene variant that enhances androgen synthesis are highly likely to develop tumors with more rapid resistance to androgen deprivation therapy (ADT) and have faster cancer progression and significantly reduced survival, a Cleveland Clinic/Mayo Clinic study has found.

The results suggest that the variant of the HSD3B1 steroidogenic enzyme gene could be a powerful new biomarker capable of identifying patients with aggressive disease who warrant early escalated therapy, says Cleveland Clinic oncologist and principal investigator Nima Sharifi, MD.

The findings also could guide future treatment strategies for patients with the variant allele. “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,” Dr. Sharifi says.

A clinical trial is underway at Cleveland Clinic to test alternate treatments in prostate cancer patients with the inherited HSD3B1 mutation, says co-investigator Eric A. Klein, MD, Chairman of the Glickman Urological & Kidney Institute.

Dr. Sharifi’s previous research had mechanistically linked the HSD3B1 somatic mutation present in prostate cancer cell lines to castration resistance, but this study is the first to confirm that patients who possess the inherited germline variation actually fare worse clinically than those without it.

Probing the mechanics of CRPC

For more than 70 years, ADT has been the gold standard for systemic treatment of prostate cancer. Prostate cancer cells’ growth depends on androgen stimulation of the cells’ androgen receptor (AR), which drives expression of AR-induced oncogenes. The most potent androgen, dihydrotestosterone, normally is synthesized in the prostate from gonadally-secreted testosterone. With gonadal suppression, ADT dramatically reduces serum testosterone level, resulting in AR deactivation and inhibition of tumor growth.

After one to two years, however, most patients evolve from castration-sensitive to castration-resistant prostate cancer (CRPC). This happens in large part because tumors acquire the ability to synthesize their own supply of testosterone and/or 5α-dihydrotestosterone (DHT) from nongonadal sources, particularly adrenal precursors, promoting AR reactivation and enabling tumor progression and metastasis.

Dr. Sharifi, a staff member of Cleveland Clinic Cancer Center, the Glickman Urological & Kidney Institute and the Lerner Research Institute, has spent years investigating androgen metabolism and the development and mechanisms of CRPC. In a landmark 2013 study, he identified the first example of a gene mutation present in human metastatic CRPC tumors that increases the conversion of precursor steroids to DHT, permitting tumors to resume growth in the absence of gonadal testosterone.

The mutation is in the gene HSD3B1, which encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1).

3βHSD1 catalyzes the initial, rate-limiting step in the conversion of adrenal precursors to DHT and is necessary for all pathways of DHT synthesis. Dr. Sharifi found that a single nucleotide polymorphism of HSD3B1 at position 1245, converting A to C, causes a gain of function in 3βHSD1, enabling the enzyme to resist proteasomal degradation. The resulting enzymatic accumulation increases androgen synthesis, enhances AR activation and accelerates tumor proliferation.

The HSD3B1(1245C) allele can be acquired either by somatic mutation in CRPC tumors (probably due to selection pressure from ADT), or by loss of heterozygosity of the wild-type allele in patients with germline heterozygous inheritance. While Dr. Sharifi’s previous research had demonstrated the selection and expression of the mutant enzyme in a mouse xenograft model of CRPC tumors, the clinical relevance of inheritance of the variant allele in prostate cancer had not been examined in a large, representative cohort.

The current study set out to retrospectively evaluate ADT resistance, disease progression and survival in prostate cancer patients who had inherited the variant HSD3B1(1245C) allele.

HSD3B1 variant relatively common

The primary cohort consisted of prostate cancer patients who underwent prostatectomy at Cleveland Clinic prior to 2010 and who were treated with ADT for biochemical failure. Two validation cohorts at Mayo Clinic consisted of men who had undergone ADT for biochemical and/or nonmetastatic clinical failure after prostatectomy, and men with metastatic prostate cancer treated with ADT.

Germline DNA from each patient (either prostatectomy specimens or peripheral blood mononuclear cells) was obtained and genotyped for the variant HSD3B1(1245C) sequence using a high-resolution assay that Dr. Sharifi and colleagues developed to differentiate HSD3B1 from its homolog and four pseudogenes.

A total of 443 men were successfully genotyped at the targeted locus and their outcomes were analyzed using clinical data for progression-free survival, distant metastasis-free survival and overall survival.

Frequency of the variant HSD3B1(1245C) allele in the pooled cohort was 29 percent, indicating that the polymorphism is relatively common. Pooled genotype distribution was 49 percent homozygous wild-type, 43 percent heterozygous and 7 percent homozygous variant.

Number of variant alleles affects survival

The researchers found that inheritance of the variant HSD3B1(1245C) allele strongly correlated with reduced survival (progression-free, distant metastasis-free, and overall).

They also found that the number of variant alleles patients inherited was a major factor in their survival. Among heterozygotes in the primary study cohort, median progression-free survival from ADT initiation was 4.1 years compared with 2.5 years for homozygous variant men. Median distant metastasis-free survival was 6.8 years and 3.6 years, respectively. Thirty-five percent of heterozygote patients were alive at 10 years post-ADT initiation, while none of the homozygous variant men lived to that point. This correlation suggests that the extra copy of the polymorphism leads to increased intratumoral androgen synthesis.

Overall survival according to HSD3B1 genotype in (A) the primary study cohort and (B) the metastatic validation cohort.
Reprinted from The Lancet Oncology. In Press. Hearn JWD, AbuAli G, Reichard CA, Reddy CA, Magi-Galluzzi C, Chang K, Carlson R, Rangel L, Reagan K, Davis BJ, Karnes RJ, Kohli M, Tindall D, Klein EA, Sharifi N. , M.D. HSD3B1 and Resistance to Androgen-Deprivation Therapy in Prostate Cancer: A Retrospective, Multicohort Study. ©2016 used with permission from Elsevier.

Implications for treatment, surveillance

The results indicate that the presence of inherited HSD3B1(1245C) is a strong predictor of which patients will develop resistance to ADT. It could help guide decisions about whether early escalated treatment is warranted and what type of treatment may have the best chance of success.

“A simple blood test could allow us to personalize therapy by telling us which patients need to be treated more aggressively, such as with more intensive hormonal therapy,” says Dr. Sharifi. “On the contrary, patients with metastatic cancer who do not carry the polymorphism may fare as well with ADT alone.”

The researchers speculate that prostate cancer patients with the HSD3B1(1245C) genotype might be insufficiently treated with ADT alone and would benefit from further androgen axis inhibition with drugs such as enzalutamide or abiraterone acetate or chemohormonal therapy. The new clinical trial at Cleveland Clinic will test whether sustained androgen signaling conferred by inheritance of the HSD3B1(1245C) genotype is reversible with a potent AR antagonist.

Furthermore, an HSD3B1(1245C)-based blood test could help inform active surveillance (AS) selection; men with the inherited genotype may be higher-risk AS candidates since they are unlikely to respond to ADT if the opportunity to cure localized cancer is missed.

In an accompanying commentary, oncologist Emmanuel S. Antonarakis, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said the results of Dr. Sharifi and colleagues’ study “add to the accumulating evidence that germline and somatic biomarker information can and should be used in the future to help direct therapy in men with recurrent and advanced prostate cancer.”