A testosterone-related genetic variant appears to be a potent biomarker for men with androgen-resistant prostate cancer because men who inherit one or two versions of the allele die sooner than patients who do not, researchers at Cleveland and Mayo Clinics have found.
It is the first time the variant on chromosome 1, a single nucleotide polymorphism (SNP), has been linked to poorer progression-free survival, distant metastasis-free survival, and overall survival, according to the study, published online in The Lancet Oncology (DOI: http://dx.doi.org/10.1016/S1470-2045(16)30227-3).
HSD3B1 encodes for an altered enzyme that enhances dihydrotestosterone synthesis and results in resistance to androgen deprivation therapy (ADT), also known as medical castration. The altered enzyme allows prostate cancer cells to self-generate androgens during treatment.
The discovery may lead to a blood test for the polymorphism, according to co-author Nima Sharifi, MD, a cancer biology researcher at the Cleveland Clinic's Lerner Research Institute.
"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," said Sharifi, who holds the Kendrick Family Endowed Chair for Prostate Cancer Research at Cleveland Clinic.
Sharifi was part of the team that first identified the HSD3B1 variant and its potential role in treatment-resistant prostate cancer in 2013.
"HSD3B1 could potentially be a powerful genetic biomarker to differentiate men who will benefit from ADT and who might require earlier escalated therapy," he told Oncology Times. "Unlike some other types of cancer, genetic data has not been used to stratify patients for treatment purposes, but these findings have the potential to change this."
He said the researchers are in the early stages launching a clinical trial testing possible alternative treatments for individuals with the HSD3B1 mutation.
Methods, Results
Using data and samples from prospectively maintained prostate cancer registries at the two clinics, the team examined survival in post-prostatectomy and metastatic validation cohorts to assess the independent predictive value of HSD3B1.
They genotyped 443 patients, including 118 prostatectomy patients in the primary group, 137 in the post-prostatectomy validation cohort, and 188 subjects in the metastatic validation arm.
In the primary outcomes group, the median progression-free survival rate fell depending on the number of inherited variants. Rates were 6.6 years for men with a homozygous wild-type genotype, 4.1 years for those with a heterozygous variant genotype, and 2.5 years for subjects with homozygous variant genotype.
In the homozygous wild-type group, inheritance of two copies of the variant allele was predictive of decreased progression-free survival (hazard ratio 2.4), as was inheritance of one copy (HR 1.7). There was little difference in distant metastasis-free survival and overall survival, and the findings were then independently validated.
Overall survival was significantly associated with the HSD3B1 genotype in both cohorts. At 5 years, overall survival was 82 percent homozygous wild-type men, 74 percent in the heterozygous group, and 58 percent among homozygous variant men, while 10-year overall survival was 55 percent in homozygous the wild-type group, 35 percent in heterozygous men, and 0 percent in the homozygous variant arm.
"Our findings suggest HSD3B1 genotype could distinguish men with disease likely to respond favorably to ADT from those with disease prone to behave more aggressively, and who, therefore, might merit escalated therapy," the authors said.
Treatment Possibilities
In terms of potential treatment for men with the variant, they said that clinical trials using combined androgen blockade and an androgen receptor antagonist have indicated the clinical benefit of combined androgen blockade in unselected patients is small.
"Although speculative, a differential benefit might be possible from use of combined androgen blockade, with little incremental gain for those with homozygous wild-type variants, but more meaningful gains if they have the variant allele," said Sharifi.
Moreover, the HSD3B1 (1245C) genotype could be used to guide future studies of selective early use of highly potent androgen inhibitors such as enzalutamide or abiraterone acetate.
"Men with the HSD3B1 (1245C) allele, especially two copies, could potentially benefit greatly if one of these drugs were started with ADT rather than waiting until development of castration-resistant prostate cancer," Sharifi noted.
The HSD3B1 genotype could also help in decisions on the use of chemohormonal therapy, according to the study.
Two trials, the Eastern Cooperative Oncology Group E3805 (CHAARTED) and STAMPEDE, showed that use of chemohormonal therapy before development of castration-resistant prostate cancer substantially improved survival outcomes compared with ADT alone. Cytotoxic therapy would probably be most beneficial in men who are least likely to have a durable response to ADT, whereas men who are likely to have a sustained response to ADT might benefit to a lesser extent. HSD3B1 genotype could, therefore, help guide patient management, especially for men with a marginal ability to tolerate chemotherapy.
Benefit of Genetics
Commenting on the study, Jong Park, PhD, Associate Professor at the University of South Florida H. Lee Moffitt Cancer Center and Research Institute, Tampa, told Oncology Times that the findings add to the growing body of evidence on the importance of precision medicine in managing prostate cancer patients.
"This was a promising study although there were a few weaknesses in my mind. As prostate cancer researchers we want to predict patients' prognosis and treatment outcomes," he said. "Although we have a prediction model for prognosis, it is not accurate as we would like. This genetic information can enhance an accuracy of prediction with additional genetic profile."
In 2013, Park and colleagues at Moffitt Cancer Center and Louisiana State University developed a technique for identifying aggressive prostate cancers using genetic interactions between SNPs. He noted there have been numerous studies on genetic variations of HSD3B1, including a 2007 study that linked polymorphisms in HSD3B1 and prostate cancer risk.
"In that study, we didn't find any role in prostate cancer risk, but our question was different. We did not evaluate its possible role in progression, recurrence, or metastasis."
The major weaknesses in the current study were that the sample size was small and there was no connection between genotype and physiological function. "To make this information translational, we need validated results in a larger independent population," Park noted.
Finding a Better Biomarker
Prostate cancer lags behind breast cancer, lymphoma, and others in having any biomarker that can be used to drive prognosis and treatment decisions, noted Edwin M. Posadas, MD, Director of the Translational Oncology Program at Cedars-Sinai Medical Center, Los Angeles.
"Prostate cancer is the most common cancer in men, and the second most common in terms of cancer deaths, but unlike a number of other cancers we haven't had a new risk or prognostic classification scheme since the 1950s," he said. Posadas is also Clinical Associate Professor at UCLA's David Geffen School of Medicine.
"Based on this study and other research, HSD3B1 is potentially a biomarker that can be used for stratification, and this is especially important because the field in rapidly expanding."
While androgen deprivation therapy has been around since the 1940s, it is becoming clear that the treatment is not uniformly effective in all men with prostate cancer, according to Posadas.
"We have known that some men are at increased risk of more aggressive, androgen-resistant prostate cancer, but until now we have not had any way to identify such patients," he told Oncology Times. "ADT has a lot of side effects, and patients always want to know how long they will have to continue therapy. Now we may have a way to answer them. We can begin breaking this cancer into pockets, and this brings us closer to being able to personalize treatment. This is a field that has sorely needed this."
Kurt Samson is a contributing writer.