Prostate cancer. -Amplification of the androgen receptor (AR) detected by ctDNA analysis is associated with poor response to anti-androgen therapy
Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis
DOI: 10.1200/PO.19.00123 JCO Precision Oncology - published online September 24, 2019
Amplification of the androgen receptor (AR) detected by ctDNA analysis is associated with poor response to anti-androgen therapy
Increases in androgen receptor (AR) copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer. We aim to evaluate the association between AR CN as a continuous variable and clinical outcome.
Using multivariable fractional polynomials analysis using Cox regression models, a nonlinear relationship between plasma AR CN and outcome was identified for overall survival, where initially for small incremental gains in CN there was a large added hazard ratio that plateaued at higher CN. The CN cut point associated with the highest local hazard ratio was 1.92. A similar nonlinear association was observed with progression-free survival. In an exploratory analysis of PCR2023, the time from start of long-term androgen-deprivation therapy to start of AAP or abiraterone acetate plus dexamethasone was significantly shorter in patients with plasma AR CN of 1.92 or greater than patients with plasma AR CN of less than 1.92 (43 v 130 weeks, respectively; P = .005). This was confirmed in cohort A (P = .003), the PREMIERE cohort (P = .03), and the British Colombia cohort (P = .003).
Patients with metastatic castration-resistant prostate cancer can be dichotomized by a plasma AR CN cut point of 1.92. Plasma AR CN value of 1.92 or greater identifies aggressive disease that is poorly responsive to AR targeting and is associated with a prior short response to primary androgen-deprivation therapy.