A Comprehensive Analysis of Steroid Hormones and Progression of Localized High-Risk Prostate Cancer

Abstract

Background: In men with localized prostate cancer who are undergoing radical prostatectomy (RP), it is uncertain whether their systemic hormonal environment is associated with outcomes. The objective of the study was to examine the association between the circulating steroid metabolome with prognostic factors and progression.Methods: The prospective PROCURE cohort was recruited from 2007 to 2012, and comprises 1,766 patients with localized prostate cancer who provided blood samples prior to RP. The levels of 15 steroids were measured in plasma using mass spectrometry, and their association with prognostic factors and disease-free survival (DFS) was established with logistic regression and multivariable Cox proportional hazard models.Results: The median follow-up time after surgery was 73.2 months. Overall, 524 patients experienced biochemical failure and 75 developed metastatic disease. Testosterone and andros-terone levels were higher in low-risk disease. Associations were observed between adrenal precursors and risk of cancer progression. In high-risk patients, a one-unit increment in logtransformed androstenediol (A5diol) and dehydroepiandrosterone-sulfate (DHEA-S) levels were linked to DFS with HR of 1.47 (P ¼ 0.0017; q ¼ 0.026) and 1.24 (P ¼ 0.043; q ¼ 0.323), respectively. Although the number of metastatic events was limited, trends with metastasis-free survival were observed for A5diol (HR ¼ 1.51; P ¼ 0.057) and DHEA-S levels (HR ¼ 1.43; P ¼ 0.054).Conclusions: In men with localized prostate cancer, our data suggest that the preoperative steroid metabolome is associated with the risk of recurrence of high-risk disease.Impact: The associations of adrenal androgens with progression of localized high-risk disease could help refine hormonal strategies for these patients.

Preoperative Circulating 11-Oxygenated Androgens Are Associated With Metastasis-free Survival in Localized Prostate Cancer

“…16 In this study, baseline preoperative circulating androstenediol and DHEA-sulfate levels were independent predictors of outcome in high-risk patients undergoing RP. 16…”

“…Biochemical recurrence (BCR) following RP was defined as the occurrence of a first PSA of >0.2 ng/mL at any time after surgery or a detectable PSA of <0.2 ng/mL with initiation of radiotherapy or androgen deprivation therapy (ADT). 16 Disease-free survival (DFS) was defined as the time from RP and the occurrence of BCR, metastasis, and/or death (all causes), whichever occurred first. Metastasis-free survival (MFS) was defined as the time from RP to the first detection of distant metastasis on imaging, or death from any cause, whichever occurred first.…”

“…For associations between 11-oxygenated androgen preoperative levels and clinical outcomes (BCR, DFS, and MFS), Cox proportional hazard ratios (HRs) and CI were estimated using multivariable analyses. The statistical model was adjusted for age, PSA level (continuous), pathological GS, pT, margin, and nodal status (pN), 16 and a P value of less than .05 was deemed statistically significant. The proportional hazard assumption was checked by Supremum test.…”

ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer

“…The androgen receptor (AR) is expressed by luminal prostate cells [19]. However, PCa cells express high levels of the AR with excess activation of AR signaling pathways, which enhances cellular proliferation and tumor formation [20,21,22]. Androgens are steroidal hormones that are produced at high levels in males and at low levels in females.…”

Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level

“…Lower preoperative testosterone levels were found to be associated with higher pathological stage and extra-prostatic disease, but not with biochemical recurrence. 6-8 Nonetheless, our group has shown that in patients treated with ADT for recurrent PCa, lower levels of testosterone or estrogens (estrone [E1], estradiol [E2]) were associated with longer time to CRPC. 9,10 Finally, higher baseline levels of androgens were associated with a better response to second-line antiandrogen therapy (abiraterone acetate [AA] and enzalutamide) in CRPC patients.…”