Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial

Abstract

Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer. Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence postradiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable Cox regression analyses adjusted for baseline prognostic factors assessed time to castration-resistant prostate cancer (CRPC), prostate cancer survival, and overall survival according to tertile of sex steroid measured by mass spectrometry. Post-ADT initiation, we measured samples in 219 patients as well as two subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and DHT, while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA), and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone (E) and estradiol (E) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups. Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E and E and rising DHEA and AST levels, which predict a shorter time to CRPC. .

Plasma extracellular vesicles as phenotypic biomarkers in prostate cancer patients

“…Our previous work demonstrated the sex steroids, including testosterone and estrogens, predict time to castration resistance in patients on androgen deprivation therapy (ADT) with LHRH agonizts . Therefore, with detailed LC‐MS measurements available from 26 of the same blood samples from patients with CRPC analyzed in this study, we next sought to compare if a relationship exists between AR‐V7 status and castrate levels of sex steroids.…”

Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer

“…Importantly, the observation that lower androgen levels in CRPC associate with worse outcomes is not incompatible with data linking the achievement of lower T levels with improved time to progression in men with CSPC treated with ADT (28,29). While time to development of CRPC may be delayed, CRPC tumors that emerge n patients with lower T levels (due to low adrenal contribution and/or optimally suppressed T levels while on ADT) are likely to represent a more aggressive, less androgen-dependent phenotype vs tumors that emerge with more rapid kinetics in context of higher androgen levels (due to more robust adrenal contribution and/or suboptimally suppressed T levels).…”

Impact of estrogens in males and androgens in females

“…ERβ isoform switching has been observed in castration-resistant and metastatic prostate cancer in men, perhaps explaining the dichotomy of ERβ actions in various types of this malignancy. Interestingly, recent studies in humans show that a high expression of ERβ occurs in many prostate cancers and correlates to a favorable prognosis (56), whereas high levels of estradiol or estrone are significantly associated with a shorter time to the development of castration-resistant prostate cancer, presumably through actions at ERα (57). In aromatase-KO mice, an ERβ agonist induces apoptosis of stromal, luminal, and epithelial cells within the prostate.…”