The authors used droplet digital (dd) PCR to assess AR copy number (CN) and mutations (2105T > A (p.L702H) and 2632A > G (p.T878A) status in plasma DNA from 171 patients treated with abiraterone (abi)/enzalutamide (enza) in biomarker protocols at 2 institutions. The aim was to evaluate plasma AR after sample collection but prior to analysis.
We first optimized multiplex ddPCR to accurately define AR status and identified an AR CN cutpoint = 2.01 as having the greatest likelihood to split patients into 2 prognostic groups. We confirmed a strong agreement between ddPCR and NGS for quantitating AR CN and mutation allelic frequency (Bland-Altman test: mean difference -0.02 95%CI -2.45 to 2.41; mean difference -0.01 95%CI -0.015 to 0.016 respectively). AR CN gain was observed in 10 (14%) pre- and 33 (34%) post-doc patients and associated with a worse overall survival (OS) (HR 3.98 95%CI 1.74-9.10 p < 0.001; HR 3.81 95%CI 2.28-6.37 p < 0.001 respectively), progression-free survival (PFS) (HR 2.18 95%CI 1.08-4.39 p = 0.03; HR 1.95 95%CI 1.23-3.11 p = 0.01 respectively) and PSA decline ≥50% (OR 4.7 95%CI 1.17-19.17 p = 0.035; OR 5.0 95%CI 1.70-14.91 p = 0.003 respectively). AR mutations were observed in 8 (11%) post-doc, but no pre-doc abi-treated patients and also associated with worse OS (HR 3.26 95%CI 1.47-not reached p = 0.004). There was no interaction between AR and doc status (p = 0.83 for OS, p = 0.99 for PFS). Multivariable analysis, adjusting for AR CN and mutations, previous doc, double stranded DNA concentration, LDH, confirmed AR status was independently associated with OS (HR 3.77 95%CI 2.42-5.88 p < 0.001 and HR 2.76 95%CI 1.26-6.07 p = 0.011 for AR CN and mutation respectively) and PFS (HR 1.96 95% CI 1.32-2.93 p = 0.001).
In summary, plasma AR status assessment using multiplex ddPCR identifies CRPC with worse outcome to enza/abi in pre-/post-doc CRPC. Additional clinical qualification is available from the PREMIERE study. Prospective evaluation of treatment decisions based on plasma AR is now required.
Presented By: Vincenza Conteduca, MD, PhD, Centre for Evolution and Cancer, The Institute of Cancer Research, London SW7 3RP, UK, London, United Kingdom
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA