11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration
Gido Snaterse, Lisanne F. van Dessel, Job van Riet, Angela E. Taylor, Michelle van der Vlugt-Daane, Paul Hamberg, Ronald de Wit, Jenny A. Visser, Wiebke Arlt, Martijn P. Lolkema, Johannes Hofland
Gido Snaterse, Lisanne F. van Dessel, Job van Riet, Angela E. Taylor, Michelle van der Vlugt-Daane, Paul Hamberg, Ronald de Wit, Jenny A. Visser, Wiebke Arlt, Martijn P. Lolkema, Johannes Hofland
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Clinical Research and Public Health Endocrinology Oncology

11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration

Abstract

BACKGROUND Continued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically relevant concentrations in patients with CRPC to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in patients with CRPC.METHODS Patients with metastatic CRPC (n = 29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multisteroid profiling employing liquid chromatography–tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing.RESULTS 11KT was the most abundant circulating active androgen in 97% of patients with CRPC (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43%–79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49%–89%) and testosterone by 68% (38%–79%). Circulating TA concentrations at baseline were associated with a distinct intratumor gene expression signature comprising AR-regulated genes.CONCLUSION The potent AR agonist 11KT is the predominant circulating active androgen in patients with CRPC and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in patients with CRPC.TRIAL REGISTRATION Netherlands Trial Register: NL5625 (NTR5732).FUNDING Daniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/Z/17/Z).

Authors

Gido Snaterse, Lisanne F. van Dessel, Job van Riet, Angela E. Taylor, Michelle van der Vlugt-Daane, Paul Hamberg, Ronald de Wit, Jenny A. Visser, Wiebke Arlt, Martijn P. Lolkema, Johannes Hofland

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Figure 3

11-KT is the most abundant circulating active androgen in CRPC patients at baseline.

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11-KT is the most abundant circulating active androgen in CRPC patients ...
(A) Active androgen concentrations of all patients with CRPC before the start of the first treatment after enrollment (n = 29). Box plot depicts the upper and lower quartiles, with the median shown as a solid line; whiskers indicate the range. Dots indicate individual data points. Statistical analysis was performed by 1-way ANOVA (P < 0.0001) with Tukey’s multiple-comparison test. *P < 0.05, ***P < 0.001. (B) The relative abundance of each androgen is shown as a percentage of the total androgen pool. Box plot depicts the upper and lower quartiles, with the median shown as a solid line; whiskers indicate the range. Dots indicate individual data points. (C) Active androgen concentrations are shown for all baseline samples (n = 34). Values below the analytical limit of quantification are shown if relevant calibrator and spiked quality control samples were accurate and reproducible with signal-to-noise ratio greater than 10:1. Samples with undetectable concentrations were set to 0.5 times the lowest accurate calibration sample for statistical purposes. Conventional clinical cutoff values for castrate testosterone levels (0.69 and 1.74 nmol/L, or 20 and 50 ng/dL, testosterone) are indicated on the y axis for reference. OT, on treatment; PD, progressive disease.