SRD5A2 Expression is a Predictor of Response to Finasteride in the MTOPS Trial
Ra'ad Al-Faouri, MD MMSc, Christina Sharkey, MS, Zongwei Wang, PHD, Aria F. Olumi, MD.
Beth Israel Deaconess Medical Center, Boston, MA, USA.
BACKGROUND: The Medical Therapy Of Prostatic Symptoms (MTOPS) study was a multi-center, randomized, controlled clinical trial conducted between 1995 and 2001 aiming to evaluate the effect of finasteride, doxazosin, or a combination of both drugs on the progression of urinary symptoms in men with benign prostatic hyperplasia (BPH). We have demonstrated that 30% of adult prostates do not express SRD5A2 through epigenetic regulation, enabling us to postulate that expression of SRD5A2 may be related to response to finasteride. Prostate biopsies and clinical data from 82 MTOPS trial participants were obtained to test the correlation between baseline expression of SRD5A2 and the response to medical treatment with finasteride. METHODS: We classified men based on changing their AUA symptom score (AUA SS) into good responders (change of AUASS ≤ -12) and poor responders (change of AUASS ≥ -2). Using immunoreactive score system (IRS score), we quantified the expression of SRD5A2 in the biopsies. We compared baseline age, demographics, AUA SS, BMI, serum dihydrotestosterone (DHT) between men in the two groups.RESULTS: There was no significant difference in TPV between the two groups. Men in the 5ARI good response group were found to have higher expression of SRD5A2 compared to men in the 5ARI poor response group (p-value <0.007). In addition, there was a statistically significant correlation between the expression of SRD5A2 and the 5-year change in AUASS (Pearson's correlation coefficient: -0.4279, p-value: 0.02). In a multiple linear regression model that adjusted for baseline AUA SS, baseline total prostate volume, baseline serum DHT level, age, and BMI, men with higher expression of SRD5A2 still had better response to finasteride with better improvement of urinary symptoms as reflected by AUA symptoms scores. CONCLUSIONS: The MTOPS study was a significant milestone in the curation BPH medical management. Since expression of SRD5A2 is epigenetically regulated during adulthood, our analysis of the biopsies and clinical data provided from the trial shines a light on the importance of SRD5A2 activity and response to 5-ARI therapy. The level of response to 5-ARI therapy correlated to higher SRD5A2 expression. This may contribute to precision medicine by predicting men that are most likely to benefit from tailored therapy by 5-ARI.
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