Circulating 11-oxygenated androgens predict survival in localized prostate cancer

In men with localized prostate cancer undergoing radical prostatectomy and treated with 5α-reductase inhibitor (5-ARI), preoperative levels of circulating 11-oxygenated androgens can indicate either disease progression or improved survival, a recent study has found.

Specifically, “11-oxygenated adrenal androgen precursors were associated with progressive disease, while bioactive 11-oxygenated androgen 11-ketotestosterone (11KT) and its metabolite 11-ketoandrosterone (11KAST) were associated with improved metastasis-free survival outcomes,” the researchers said.

A total of 1,793 treatment-naïve patients and 155 who received preoperative treatment in the prospective PROCURE cohort, for which preoperative plasma samples were collected before undergoing radical prostatectomy, were included in the analysis.

The researchers used liquid chromatography-tandem mass spectrometry to quantify adrenal 11-oxygenated precursors, potent 11-oxygenated androgens, and their metabolites. They also examined circulating levels in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models.

Of the patients, 583 had biochemical recurrence, 104 developed metastatic disease, and 168 died at a median follow-up of 93.8 months after surgery. Men with prostate-specific antigen >20 ng/mL and positive nodal status showed higher levels of 11-hydroxytestosterone and 11-ketotestosterone (p<0.05). [J Urol 2023;209:337-346]

Multivariable analyses revealed no significant association between 11-oxygenated androgens and disease-free survival. However, the predominant androgenic 11KT adrenal 11β-hydroxyandrostenedione and its metabolite 11KAST, modeled as quartiles, showed a connection with metastasis-free survival (p=0.06, p=0.03, and p=0.008, respectively).

Notably, patients on 5-ARI presented a significant accumulation of 11-oxygenated androgen precursors and bioactive androgens but reduced levels of metabolites (p<0.001).

Adrenal hormones

“Our study establishes the potential prognostic value of plasma levels of adrenal-derived 11-oxygenated androgens in localized prostate cancer and highlights significant changes in circulating levels of 11-oxygenated androgens at radical prostatectomy associated with preoperative 5-ARI treatment,” the researchers said.

“Adrenal androgen precursor 11β-hydroxyandrostenedione was associated with poorer metastasis-free survival, whereas androgenic 11KT and its metabolite 11KAST were associated with better metastasis-free survival outcomes,” they added.

Previous studies supported the present finding on the association between higher levels of the full agonist 11KT and better outcomes, according to the researchers. Moreover, the link between high levels of the 11KAST metabolite and fewer metastatic events indicated that hepatic and peripheral androgen biotransformation might predict clinical outcomes after surgery even before treatment initiation.

In patients with localized prostate cancer, metastasis development was significantly associated with shorter overall survival. [J Clin Oncol 2017;35:3097-3104]

“These adrenal hormones are associated herein with progression to the metastatic stage and, based on previous data generated in castration-resistant disease, 11-oxygenated androgens may thus sustain progression before and after androgen deprivation therapy initiation,” the researchers said. [JCI Insight 2021;6:2021]

“Additional studies focusing on this class of adrenal-derived 11-oxygenated androgens are required to help capture the impact of these additional circulating hormones on disease progression in localized and metastatic castration-sensitive and castration-resistant diseases,” they noted.