Clinical Impact of Sex Steroid Hormones and HSD3B1 Genotype in Metastatic Prostate Cancer
Akram, Sadia (2025-05-16)
Clinical Impact of Sex Steroid Hormones and HSD3B1 Genotype in Metastatic Prostate Cancer
(16.05.2025)
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
suljettu
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2025061972086
https://urn.fi/URN:NBN:fi-fe2025061972086
Tiivistelmä
Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men, with approximately 1.4 million annual new cases, globally. Androgen deprivation therapy (ADT) remains the golden standard for treatment of advanced and metastatic PCa. Despite this most patients develop castration-resistant prostate cancer (CRPC). Understanding the role of androgens involved in steroidogenesis pathway and genetic variations in particular HSD3B1 (1245C) allele linked to resistance is crucial for optimizing treatment strategies and improving clinical outcomes.
Objective: To determine the effect of steroid levels and HSD3B1 genotype in response to ADT and progression to CRPC.
Materials and Methods: This study analysed samples of 32 patients with metastatic PCa from ADTPSMA2 clinical trial. Blood samples were collected at baseline and every 3 months for up to 33 months to measure serum steroid concentrations using liquid chromatography-tandem mass spectrometry. The samples were genotyped for HSD3B1 polymorphisms (rs1047303) using Sanger sequencing. Unsupervised clustering and non-parametric rank statistical testing were performed to determine the impact of HSD3B1 genotype in relation to ADT and CRPC status.
Results: A total of 84.4% of patients had high-risk metastatic PCa with Gleason score 9 – 10. Of the 30 patients successfully genotyped, 20 had AA genotype, 9 had AC genotype, and only 1 had CC genotype. Following ADT treatment, steroid analysis showed that mean concentration of 11-ketotestosterone was significantly higher (p < 0.001) than concentrations of 11- ketodihydrotestosterone, testosterone, and dihydrotestosterone.
The baseline-to-ADT ratio of 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and 11-oxygenated androgens in AA genotype is significantly higher (p < 0.05) as compared to AC genotype. This shows that patients with AC genotype had higher levels of these steroids post ADT as compared to baseline which suggests that ADT response depends on HSD3B1 genotype. Unsupervised clustering of the baseline-to-ADT steroid ratios revealed two distinct clusters which were defined by response to ADT. While both clusters had similar baseline levels, the first cluster exhibited significantly higher steroid concentrations in comparison to the second cluster following ADT. However, these relatively different high and low concentration steroid clusters were not associated with CRPC status.
Conclusion: This study suggests that the HSD3B1 (1245C) allele is associated with resistance to ADT. Additionally, 11-ketotestosterone is the most active androgen in circulation of metastatic PCa patients after castration, holding potential in clinical diagnostics.
Objective: To determine the effect of steroid levels and HSD3B1 genotype in response to ADT and progression to CRPC.
Materials and Methods: This study analysed samples of 32 patients with metastatic PCa from ADTPSMA2 clinical trial. Blood samples were collected at baseline and every 3 months for up to 33 months to measure serum steroid concentrations using liquid chromatography-tandem mass spectrometry. The samples were genotyped for HSD3B1 polymorphisms (rs1047303) using Sanger sequencing. Unsupervised clustering and non-parametric rank statistical testing were performed to determine the impact of HSD3B1 genotype in relation to ADT and CRPC status.
Results: A total of 84.4% of patients had high-risk metastatic PCa with Gleason score 9 – 10. Of the 30 patients successfully genotyped, 20 had AA genotype, 9 had AC genotype, and only 1 had CC genotype. Following ADT treatment, steroid analysis showed that mean concentration of 11-ketotestosterone was significantly higher (p < 0.001) than concentrations of 11- ketodihydrotestosterone, testosterone, and dihydrotestosterone.
The baseline-to-ADT ratio of 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and 11-oxygenated androgens in AA genotype is significantly higher (p < 0.05) as compared to AC genotype. This shows that patients with AC genotype had higher levels of these steroids post ADT as compared to baseline which suggests that ADT response depends on HSD3B1 genotype. Unsupervised clustering of the baseline-to-ADT steroid ratios revealed two distinct clusters which were defined by response to ADT. While both clusters had similar baseline levels, the first cluster exhibited significantly higher steroid concentrations in comparison to the second cluster following ADT. However, these relatively different high and low concentration steroid clusters were not associated with CRPC status.
Conclusion: This study suggests that the HSD3B1 (1245C) allele is associated with resistance to ADT. Additionally, 11-ketotestosterone is the most active androgen in circulation of metastatic PCa patients after castration, holding potential in clinical diagnostics.