Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone

Abstract

Background: This study aimed to investigate copy number variations (CNVs) of CYP17A1 and androgen receptor (AR) genes in serum cell-free DNA collected before starting abiraterone in 53 consecutive patients with castration-resistant prostate cancer (CRPC).

Methods: Serum DNA was isolated and CNVs were analysed for AR and CYP17A1 genes using Taqman copy number assays. The association between CNVs and progression-free/overall survival (PFS/OS) was evaluated by the Kaplan-Meier method and log-rank test.

Results: Median PFS of patients with AR gene gain was 2.8 vs 9.5 months of non-gained cases (P < 0.0001). Patients with CYP17A1 gene gain had a median PFS of 2.8 months vs 9.2 months in the non-gained patients (P = 0.0014). A lower OS was reported in both cases (AR: P < 0.0001; CYP17A1: P = 0.0085). Multivariate analysis revealed that PSA decline ⩾ 50%, AR and CYP17A1 CNVs were associated with shorter PFS (P < 0.0001, P = 0.0004 and P = 0.0450, respectively), while performance status, PSA decline ⩾ 50%, AR CNV and DNA concentration were associated with OS (P = 0.0021, P = 0.0014, P = 0.0026 and P = 0.0129, respectively).

Conclusions: CNVs of AR and CYP17A1 genes would appear to be associated with outcome of CRPC patients treated with abiraterone.

Figure 1

Approach sensitivity. (A) CNV analysis of AR and CYP17A1 genes from a healthy male and CRPC patient serum DNA pool. Blue line: cutoff for AR (1.5); red line: cutoff for CYP17A1 (2.5). We tested series of different ratios of DNA from patient (gain of AR and CYP17A1 gene) and healthy males mixed together for each sample. Patient DNA percentages were 0.375, 0.75, 1.5, 3, 6, 12, 25, 50 and 100, in respect to total serum DNA. The same healthy DNA was used as a calibrator. (B) Copy number corrected for AR (sample 1) and CYP17A1 (sample 3). Note: sample 2 and sample 4 were analysed only for the points described due to insufficient DNA.

Figure 2

PFS—Kaplan Meier curves for AR (A), CYP17A1 (B) and combined AR+CYP17A1 (C). A=gene amplification; N=no gene aberration; AA=two-gene amplification; AN=only one gene amplification; NN=no aberrations for either gene.

Figure 3

OS—Kaplan Meier curves for AR (A), CYP17A1 (B) and combined AR+CYP17A1 (C). A=gene amplification; N=no aberration gene; AA=both genes amplification; AN=only one gene amplification; NN=no aberrations for either gene.