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Home » Testosterone » HSD3B1 Genotype Tied to Worse Outcomes in Low-Volume mCSPC – Renal and Urology News

Inheritingthe adrenal-permissive HSD3B1genotype may be associated with earlier development of castration resistantdisease and shorter overall survival (OS) among white men with low-volumemetastatic castration-sensitive prostate cancer (mCSPC), according to a newstudy published in JAMA Oncology.1

Thefindings suggest that the HSD3B1genotype can be used to risk stratify white men with low-volume metastatic prostatecancer, investigators concluded.

Ateam led by Nima Sharifi, MD, Director of the Genitourinary MalignanciesResearch Center at the Case Comprehensive Cancer Center in Cleveland examinedwhether the inheritance of the adrenal-permissive HSD3B1(1245C) allele is associated with probable worse clinicaloutcomes in men treated with androgen deprivation therapy (ADT) with or withoutdocetaxel for mCSPC. They examined clinical outcomes in a phase 3 clinicaltrial of castration compared with castration plus docetaxel.

Wefound that Caucasian men with low-volume metastatic prostate cancer who inheritthe adrenal-permissive HSD3B1 alleledevelop castration-resistant prostate cancer more rapidly and have shorteroverall survival from the time of castration therapy, with or withoutdocetaxel, said corresponding author.

Ina series of previous studies, investigators found that a more active inheritedversion of the adrenal-permissive HSD3B1 allelewas associated with conversion of adrenal precursor steroids to potentandrogens (testosterone and dihydrotestosterone). For the current study, Dr Sharifiand colleagues looked at 475 genotyped white men with mCSPC treated in theE3805 CHAARTED (Chemohormonal Therapy vs Androgen Ablation Randomized Trial forExtensive Disease in Prostate Cancer) trial.2

While the study showed that the adrenal-permissive genotype was associated with significantly shorter time to castration-resistant disease and significantly lower OS in men with low-volume disease, it did not show any association between genotype and outcomes in men with high-volume disease. E3805 CHAARTED was conducted from July 2006 to December 31, 2012 and included 790 men (of whom 527 had available DNA samples).All men were randomized to castration plus docetaxel 75 mg/m2 every 3 weeks for 6 cycles, or castration alone. The mean age was 63 years.

Thecurrent analysis included 475 white men with DNA samples and it showed that 270(56.8%) of them had inherited the adrenal-permissive genotype. Among men withlow-volume disease, freedom from castration-resistant prostate cancer (CRPC) at2 years was reduced in men with the adrenal-permissive genotype compared withthose who had the adrenal-restrictive genotype (51% vs 70.5%). OS at 5 yearsalso was lower among men with the adrenal-permissive genotype (57.5% vs 70.8%).The adrenal-permissive genotype was significantly associated with a nearly1.9-fold increased risk for CRPC and 1.7-fold increased risk for death.

Rightnow, we do not use genetic information to determine the time and type ofhormonal therapy used for the treatment of advanced prostate cancer, DrSharifi told Renal & Urology News.Our study, which shows a clear inherited genetic determinant of clinicaloutcomes after castration therapy and has a clearly defined mechanism, is astep toward distinguishing between different types of prostate cancer anddetermining the best treatment for each genetic group.

Themedian follow-up time was 64.4 months for the low-volume group and 42.6 monthsfor the high-volume group. As far as they are aware, the results represent thefirst prospective apparent support of the importance of the HSD3B1 genotype with respect to clinicaloutcomes, and they are concordant with previous retrospective studies, DrSharifi and colleagues noted.

MichaelWhalen, MD, Assistant Professor of Urology at the George Washington UniversitySchool of Medicine and Health Sciences in Washington, DC, said given these new findingsand the fact that an inhibitor of adrenal androgens exists in thearmamentarium, this allele should certainly continue to be examined as part ofthe germline analysis in future prospective clinical trials. Still, based on thepurported mechanism of HSD3B1, hesaid, it would have been interesting and meaningful for the authors of thecurrent study to have reported on the patients circulating levels of adrenalandrogens, DHEA,and androstenedione, or even intratumoral levels of these hormones to assesstheir impact in the tumor microenvironment.

Thefindings of the study dovetail well with the recent National ComprehensiveCancer Network Prostate Cancer Guidelines 2020 to recommend germline testing toall de novo metastatic prostatecancer patients, Dr Whalen said. Although more work has to be done, this iscertainly a step in the right direction toward precision medicine to tailortreatments based on expectations for success as derived by analysis of apatients genetic code.

HeatherH. Cheng, MD, PhD, Associate Professor of Genitourinary Medical Oncology at theUniversity of Washington in Seattle, said the new findings will need to beconfirmed in prospective trials with a much more diverse cohort. Given thepreponderance in white men, the study highlights the need for a collectiveeffort in identifying similarly promising findings in diverse populations, DrCheng said. Incorporating the HSD3B1 allele as a stratification factor forlow-volume metastatic prostate cancer in future prospective randomized trialswill be a key step in confirming these findings and in further defining its clinicalutility.

Prostatecancer is complex, and this complexity increases as the disease progresses,observed Maha Hussain, MD, Professor of Medicine in the Division of HematologyOncology at Northwestern University Feinberg School of Medicine, where she isDirector of the Robert H. Lurie Comprehensive Cancer Center. While over 90% ofmen will respond to androgen deprivation therapy, we also know that outcomesare variable in metastatic hormone sensitive prostate cancer and that diseaseburden and location clearly matter, Dr Hussain said. In addition, aside fromdisease burden and location it is still unclear what specifically impacts the magnitudeand duration of response, she said.

Theresults from this prospective study are very interesting and certainly providesome insights into the biology [of mCSPC] and why we see variable outcomes evenin patients with low-volume disease, Dr Hussain said. Nevertheless, even though the freedom fromCRPC at 2 years and OS at 5 years was lower in men with low-volume disease withthe adrenal-permissive versus adrenal-restrictive genotype, these differencesdo not justify therapy change at this time outside of clinical trials.

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HSD3B1 Genotype Tied to Worse Outcomes in Low-Volume mCSPC - Renal and Urology News

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Home » Testosterone » HSD3B1 Genotype Tied to Worse Outcomes in Low-Volume mCSPC – Renal and Urology News