Gene Variant Seen to Promote Castration-resistant Disease in Whites

Gene Variant Seen to Promote Castration-resistant Disease in Whites

A variant in a gene that promotes the production of testosterone by prostate cancer cells is linked to poorer survival and the development of castration-resistant disease in Caucasians with metastatic prostate cancer, a study suggests.

Its researchers recommend that genetic testing be part of routine care for patients, as those with this variant may need more aggressive treatment.

The study, “HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer,” was published in the journal JAMA Oncology.

The growth of many prostate cancers is driven by signaling from male hormones, most notably testosterone. Treatment with androgen deprivation therapy (ADT), where testosterone levels are lowered by means of surgical or chemical castration, is often effective.

But some tumors become castration-resistant, and no longer respond to ADT.

One common way castration resistance develops is when tumor cells start making their own testosterone, and are no longer dependent on testosterone from elsewhere. This process is heavily reliant on an enzyme coded by the gene HSD3B1.

A variant in this gene, HSD3B1(1245C) is associated with higher testosterone production. As such, it has been proposed that HSD3B1(1245C) could predispose certain individuals to castration-resistant cancer that is harder to treat.

Researchers at the Cleveland Clinic and colleagues tested this idea using data from the Phase 3 trial (NCT00309985), called CHAARTED, in which men with metastatic prostate cancer who still responded to ADT were randomly assigned to ADT with or without the chemotherapy agent docetaxel.

They looked at data for 475 patients — all white, average age of 63. Of them, 270 had at least one copy of the HSD3B1(1245C) variant (each person inherits one copy from each biological parent).

Caucasians were chosen as the focus because HSD3B1(1245C) is more common in this population. Though this specificity limits the extent to which study findings can be generalized, it also eliminates potential confounding effects, the scientists said.

Patients were grouped based on the size of their tumors: those with low-volume (174 men) or high-volume (301). Generally, high-volume cancer, defined as having visceral metastases or at least four bone metastases, is associated with worse clinical outcomes.

Among men with low-volume disease, significantly more patients with at least one copy of HSD3B1(1245C) acquired resistance to ADT — meaning they developed castration-resistant cancer — after two years, compared to those without this variant (51.0% vs. 70.5%).

Statistical models that accounted for other known risk factors suggested an 89% increased risk for castration-resistant cancer in people with this variant. (A gene variant describes any change — benign or disease-causing — in the DNA sequences that compose a gene.)

Patients in the low-volume group also had poorer five-year overall survival rates if they carried the HSD3B1(1245C) variant — 57.5% vs. 70.8%. The variant increased the risk of death by 74%, according to statistical models.

In contrast, no significant associations between HSD3B1(1245C) status and survival or the development of castration-resistant cancer were found among those with high-volume disease.

In both low- and high-volume patient groups, the presence of the HSD3B1(1245C) variant was not associated with significantly different responses to docetaxel.

“Taken together,” the researchers wrote, “our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume metastatic prostate cancer.”

“These findings lay the groundwork for more personalized and effective treatments for prostate cancer,” Nima Sharifi, MD, the study’s senior author with the Cleveland Clinic, said in a press release.

For instance, the researchers suggest that people with low-volume prostate cancer who carry HSD3B1(1245C) might derive more benefit from early use of aggressive therapies, before castration resistance is acquired. Future studies will be needed to test this idea.

“As the team has shown here, incorporating genetic testing in prostate cancer as part of routine care has significant potential to improve treatment success and quality and length of life for men with prostate cancer who carry the HSD3B1(1245C) variant. This work is another step in that direction,” Sharifi added.