Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification prior to commencing a new treatment. We hypothesized that a second sample collected after one cycle treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment.
Plasma DNA (128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression) from 151 chemotherapy-naïve metastatic castration resistant prostate cancer (mCRPC) patients in a phase 2 study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes:TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2, and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS).
Plasma tumor DNA was associated with shorter OS (hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, p=<0.0001) and PFS (HR: 2.05; 95% CI: 1.36-3.11, p<0.001). Using a multivariable model, including plasma tumor DNA, patients who had a TP53 or RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53, HR 7.13, 95% CI 2.37-21.47, p<0.001; RB1, HR 6.24, 95% CI 1.97-19.73, p=0.002; PTEN, HR 11.9, 95% CI 3.6-39.34, p<0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared to those who were undetectable pre-treatment (respectively p=0.48, p=0.43, p=0.5). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients.
Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.
Annals of oncology : official journal of the European Society for Medical Oncology. 2021 Mar 29 [Epub ahead of print]
A Jayaram, A Wingate, D Wetterskog, G Wheeler, C N Sternberg, R Jones, A Berruti, F Lefresne, M Lahaye, S Thomas, M Gormley, F Meacham, K Garg, L P Lim, A S Merseburger, B Tombal, D Ricci, G Attard
University College London Cancer Institute, London, United Kingdom., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York-Presbyterian, New York, USA., University of Glasgow, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom., University of Brescia, Spedali Civili Hospital, Brescia, Italy., Janssen-Cilag, France., Janssen Research and Development, LLC, Spring House, Pennsylvania, USA., Resolution BioScience, Inc., Kirkland, Washington, USA., Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany., Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium., University College London Cancer Institute, London, United Kingdom. Electronic address: .