Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

Eur Urol. 2019 Apr;75(4):667-675. doi: 10.1016/j.eururo.2018.12.042. Epub 2019 Jan 10.

Abstract

Background: Several systemic therapeutic options exist for metastatic castrate-sensitive prostate cancer (mCSPC). Circulating tumor DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer and can influence decision-making, but remains untested in mCSPC.

Objective: To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy.

Design, setting, and participants: We collected plasma cell-free DNA (cfDNA) from 53 patients newly diagnosed with mCSPC and, where possible, during treatment. Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue.

Results and limitations: The median ctDNA fraction was 11% (range 0-84%) among untreated patients but was lower (1.0%, range 0-51%) among patients after short-term (median 22d) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. The concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.

Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either is suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically relevant somatic alterations in all patients.

Patient summary: In men with advanced prostate cancer, tumor DNA shed into the bloodstream can be measured via a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies. Sequencing data were deposited in the European Genome-phenome Archive (EGA) under study identifier EGAS00001003351.

Keywords: Androgen deprivation therapy; Castration-sensitive; Cell-free DNA; Circulating tumor DNA; DNA repair; Liquid biopsy; Precision oncology; Sequencing; Tissue biopsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Androgen Antagonists / therapeutic use
  • Biomarkers, Tumor / blood*
  • Biomarkers, Tumor / genetics
  • Circulating Tumor DNA / blood*
  • Circulating Tumor DNA / genetics
  • Clinical Decision-Making
  • DNA Mutational Analysis
  • DNA Repair
  • Genetic Predisposition to Disease
  • Humans
  • Liquid Biopsy
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Phenotype
  • Predictive Value of Tests
  • Prospective Studies
  • Prostatic Neoplasms / blood*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Time Factors
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Androgen Antagonists
  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • TP53 protein, human
  • Tumor Suppressor Protein p53

Grant support