Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis

Abstract

PURPOSEIncreases 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.PATIENTS AND METHODSPCR2023 was an international, multi-institution, open-label, phase II study of abiraterone acetate plus prednisolone (AAP) or abiraterone acetate plus dexamethasone that included plasma AR assessment as a predefined exploratory secondary end point. Plasma AR CN data (ClinicalTrials.gov identifier: NCT01867710 ) from this study (n = 133) were pooled with data from the following three other cohorts: cohort A, which was treated with either AAP or enzalutamide (n = 73); the PREMIERE trial (ClinicalTrials.gov identifier: NCT02288936 ) of biomarkers for enzalutamide (n = 94); and a phase II trial from British Columbia (ClinicalTrials.gov identifier: NCT02125357 ) that randomly assigned men to either AAP or enzalutamide (n = 201). The primary outcome measures for the biomarker analysis were overall survival and progression-free survival.RESULTSUsing 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).CONCLUSIONPatients 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.

Multiplex Digital PCR to Detect Amplifications of Specific Androgen Receptor Loci in Cell-Free DNA for Prognosis of Metastatic Castration-Resistant Prostate Cancer

“…After normalization to the averaged combined reference control, we observed the median Log2 CN ratio, being 0.52 (range −1.42–6.00) for AR -En, 0.29 (range −1.69–5.45) for AR -E1, 0.36 (range −0.92–5.45) for AR -E8, and 0.14 (range −1.54–5.04) for OPHN1 ( Figure 2 A). We defined the amplification as the normalized CN ratio ≥ 1.92 between the targets and reference loci using a suggested threshold [ 29 ] and our previously reported observations made in an independent mCRPC cohort [ 4 ]. Among the 108 mCRPC patients, 28 (25.9%) had AR enhancer amplification; 24 (22.2%) had AR- E8 amplification; 25 (23.1%) had AR -E1 amplification; and 19 (17.6%) had OPHN1 amplification ( Figure 2 B).…”

“…Interestingly, the association of AR-E1 with OS was changed to significant from insignificant ( p value from 0.08 was changed to 0.02). However, to stay consistent with the recently published cutoff call rates on amplification status [ 29 ], we selected 1.92 as the cutoff value for amplification calls.…”

Age over 35 years is associated with increased mortality after pulmonary valve replacement in repaired tetralogy of Fallot: results from the UK National Congenital Heart Disease Audit database

“…The hazard ratio (HR) for each age bracket was calculated relative to the baseline bracket (15–20 years) using a Cox regression stratified by centre and single age cut-offs corresponding to the highest increase in HR were selected for evaluation, and the proportionality assumption tested using Schoenfeld residuals. Log-likelihood was used as a correlative measure for determining the optimal cutpoint [ 14 ]. Classification and Regression Tree Analysis (CART) was used as an alternative method for automatic identification of optimal cut-offs and the results from both approaches were compared [ 15 ].…”

Circulating Androgen Receptor for Prognosis and Treatment Selection in Prostate Cancer

“…Moreover, it is still controversial whether the level of CN gain has any impact on clinical outcomes. A recent meta-analysis [21] described a nonlinear relationship between plasma AR CN and survival, while Annala et al [22] showed a different response to abiraterone/enzalutamide for patients with high AR gain (>8 copies) compared with low AR gain (two to eight copies), indicating a possible dose-response effect in overcoming inhibition of AR signalling using AR-directed therapies.…”