Influence of ischemia on tissue androgens in eugonadal and androgen-deprived men treated with prostatectomy.
118 Background: Optimizing tissue androgen suppression may provide a higher rate of complete pathologic response in patients with localized prostate cancer (PCa). The ability to accurately assess tissue androgens may be influenced by ischemic time and catabolism after devascularization. This study was performed to determine if ischemia influences tissue androgen in eugonadal men and in men treated with various types of neoadjuvant androgen deprivation (ADT). Methods: Eugonadal men (n=12) or men treated with neoadjuvant ADT using LHRH agonist and Casodex or LHRH agonist with Dutasteride, Casodex or all three with Ketoconazole (n=34) underwent prostatectomy for localized PCa. Tissue was acquired by needle biopsy at the time of ligation of the vascular pedicles, at prostate removal and at 30 minutes after prostate removal. Prostate tissue was flash-frozen and tissue dihydrotestosterone (DHT) and testosterone (T) were determined by LC/MS/MS. Change in tissue androgens from clamp was assessed at each time point. Trends in androgen levels were assessed by ANOVA for eugonadal men and within each treatment group Results: Average time from clamp to removal was 23 minutes (± 8) and from removal to subsequent biopsy 32 minutes (± 2). There was no evidence for a significant change in T or DHT over the time intervals tested (one way ANOVA p>0.05 for all measures) except in patients treated with LHRH agonist and Casodex alone. In this group of patients, T declined by 34%by the time of prostate removal, and by 83% at 30 minutes after removal when compared to levels at clamp (one way ANOVA p=0.017, test for linear trend =0.007). In all other treatment groups, both T and DHT were stable for 60 minutes. Conclusions: Assessment of DHT levels in prostate tissue at prostatectomy is not compromised by ischemia. Tissue sampling from 30-60 minutes after vascular clamping yields a stable measure of tissue DHT in the majority of patients. In the absence of SRD5A blockade, testosterone sampling in castrate men is sensitive to ischemia, and delayed sampling underestimates tissue androgen levels due to ischemia-related metabolism. These results lend important insight into clinical trial design and translational endpoints.