Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer

J Natl Cancer Inst. 2017 Dec 1;109(12):djx118. doi: 10.1093/jnci/djx118.

Abstract

Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling.

Methods: We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations.

Results: Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways.

Conclusions: 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 mCRPC patient management based on ctDNA alone.

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • BRCA2 Protein / genetics
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Circulating Tumor DNA / blood*
  • Class Ia Phosphatidylinositol 3-Kinase
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • DNA Copy Number Variations
  • Humans
  • Liquid Biopsy
  • Male
  • Mutation
  • Neoplasm Metastasis
  • Nuclear Proteins / genetics
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology*
  • Receptors, Androgen / genetics
  • Repressor Proteins / genetics
  • Retinoblastoma Binding Proteins / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Wnt Signaling Pathway / genetics

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • BRCA2 Protein
  • BRCA2 protein, human
  • Biomarkers, Tumor
  • CDKN1B protein, human
  • Circulating Tumor DNA
  • Nuclear Proteins
  • RB1 protein, human
  • Receptors, Androgen
  • Repressor Proteins
  • Retinoblastoma Binding Proteins
  • SPOP protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Cyclin-Dependent Kinase Inhibitor p27
  • Ubiquitin-Protein Ligases
  • PIK3R1 protein, human
  • Class Ia Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase
  • PTEN protein, human