Tumor fraction in cell-free DNA as a biomarker in prostate cancer

JCI Insight. 2018 Nov 2;3(21):e122109. doi: 10.1172/jci.insight.122109.


Background: Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non-tumor-derived cfDNA through multiple courses of therapy have not been well described.

Methods: CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy.

Results: TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1-3 bone metastases, 0.190 for 4+ bone metastases; P < 0.0001) and with visceral metastases (P < 0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P < 0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non-tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was >7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic.

Conclusion: TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response.

Trial registration: Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135.

Funding: Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).

Keywords: Oncology; Prostate cancer.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / blood
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Biomarkers, Tumor / blood
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary*
  • Cell-Free Nucleic Acids / drug effects
  • Cell-Free Nucleic Acids / genetics*
  • Chemoradiotherapy / methods
  • Circulating Tumor DNA / drug effects
  • Circulating Tumor DNA / genetics*
  • Hemoglobins / analysis
  • Humans
  • Male
  • Multivariate Analysis
  • Neoplasm Metastasis
  • Prospective Studies
  • Prostate-Specific Antigen
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / mortality
  • Survival Analysis
  • Whole Genome Sequencing / methods


  • Antineoplastic Agents, Hormonal
  • Biomarkers, Tumor
  • Cell-Free Nucleic Acids
  • Circulating Tumor DNA
  • Hemoglobins
  • Alkaline Phosphatase
  • Prostate-Specific Antigen