Martin Gleave, MD
Alexander Wyatt, DPhil
In a study reported in the Journal of the National Cancer Institute, Wyatt et al found high agreement between driver mutations in plasma circulating tumor DNA (ctDNA) and metastatic tissue biopsy in castration-resistant prostate cancer. Martin Gleave, MD, and Alexander Wyatt, DPhil, of Vancouver Prostate Centre, University of British Columbia, are the corresponding authors of the Journal of the National Cancer Institute article.
Mutations Identified in ctDNA
In the study, targeted sequencing for 72 clinically relevant genes was performed in 45 plasma cell–free DNA (cfDNA) samples obtained at biopsy of metastatic tissue. Among cfDNA samples, 34 (75.6%) had a ctDNA proportion greater than 2% of total cfDNA. Among these 34 patients, all somatic mutations in the matched metastatic tissue biopsies were present in ctDNA. Alterations in the 34 samples included AR amplification in 22 (64.7%); SPOP mutation in 3 (8.8%); and inactivating alterations in the tumor suppressors TP53, PTEN, RB1, APC, CDKN1B, BRCA2, and PIK3R1.
Copy number profiles of the matched liquid and solid biopsies were highly correlated, with a concordance of 88.9% being observed for individual gene copy number calls across clinically actionable genes (AR, BRCA2, ATM, PTEN, PIK3CA, PIK3CB, PIK3R1, TP53, and RB1). ctDNA sequencing robustly identified seven somatic mutations not found in solid biopsy; all were protein-altering mutations, and four were known cancer drivers, consisting of TP53 missense, RB1 frameshift, PTEN frameshift, and APC stopgain mutations.
The investigators concluded: “Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide [metastatic castration-resistant prostate cancer] patient management based on ctDNA alone.”
The study was supported by a Stand Up to Cancer Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant, Prostate Cancer Canada, and others.