Potential Role of 11-Ketotestosterone in Castration-Resistant Prostate Cancer
Posted: Tuesday, July 20, 2021
Continued androgen receptor signaling is a key characteristic and treatment target in patients with metastatic castration-resistant prostate cancer. Studies have identified 11-ketotestosterone as a potent androgen receptor agonist, but it is unknown whether heightened levels of this agonist are present in patients with castration-resistant prostate cancer. Johannes Hofland, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, Netherlands, and colleagues investigated whether this oxidized form of testosterone persisted after castration and was a potential driver of androgen activity in patients with castration-resistant prostate cancer. Their findings, published in JCI Insight, revealed that 11-ketotestosterone was the most abundant circulating active androgen in 97% of the patients assessed. They also found that treatment with glucocorticoids reduced 11-ketotestosterone levels by 84% and testosterone levels by 68%.
“…Our results position [11-ketotestosterone] as one of the potential drivers of [androgen receptor] activation in [castration-resistant prostate cancer]. Both [testosterone] and [11-ketotestosterone] can be suppressed by glucocorticoid treatment, providing a possible explanation why glucocorticoids are beneficial in patients with [castration-resistant prostate cancer],” stated Dr. Hofland and colleagues.
A total of 29 patients with castration-resistant prostate cancer were included in this study. All patients were slated to start new lines of treatment, and sequential plasma samples were obtained from each of them. Samples were assessed for circulating steroid concentrations by multisteroid profiling employing liquid chromatography–tandem mass spectrometry. At baseline, metastatic tumor biopsy samples were obtained and subjected to RNA sequencing.
Findings revealed that 11-ketotestosterone was the most abundant circulating active androgen in 97% of patients (median 0.39 nmol/L, range = 0.03–2.39 nmol/L; P < .0001). Treatment with glucocorticoids reduced 11-ketotestosterone levels by 84% (P < .01) and testosterone levels by 68% (P < .01). A survival analysis was performed and revealed that high total active androgen concentrations (above the median) were associated with longer progression-free survival (209 vs. 133.5 days, P < .05).
Disclosure: For full disclosures of the study authors, visit insight.jci.org.