Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

We performed whole genome sequencing and whole-exome sequencing of cell-free DNA (cfDNA) and whole-exome sequencing of matched tumor biopsies and germline DNA from patients with metastatic cancer. Using ichorCNA, a software tool that quantifies tumor content in ultra-low pass whole genome sequencing (~0.1x) of cfDNA without prior genomic characterization of the tumor, we show genome-wide concordance between cfDNA and tumor biopsies and detectability of high tumor fractions (>0.1) in the cfDNA of many patients with metastatic cancer. We then established that whole-exome sequencing of cfDNA can enable comprehensive profiling of tumors from blood, with high tumor-content cfDNA samples demonstrating concordance of clonal somatic mutations, copy number alterations, mutational signatures, and neoantigens with matched tumor biopsies. This study introduces a new method to identify patients that could be eligible for tumor profiling from cfDNA and sheds light on the concordance between metastatic tissue and blood biopsies.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Longitudinal Cohort
• Subject Sample Telemetry Report (SSTR)

Patients with metastatic cancer were prospectively identified for enrollment into tissue analysis and banking cohorts (Dana-Farber Cancer Institute). Eligible patients included those with known metastatic as well as those with newly diagnosed cancer (de novo metastatic disease). After obtaining informed consent for genomic analysis of their blood and/or tumor tissue, an initial blood draw was collected. Accessible metastatic, non-bone sites (e.g. breast, skin, lymph node, etc) were preferentially identified for biopsy. When feasible, a corresponding blood draw for plasma was performed within seven days of a metastatic tumor biopsy. A subset of patients underwent subsequent blood draws at the time of treatment switch, 4-6 weeks after treatment switch, and every 3 months if on stable treatment.

Eligible metastatic prostate cancer patients were identified through the Clinical Research Information System (CRIS) database at Dana-Farber Cancer Institute. The CRIS system comprises data-entry software, a central data repository, collection of patient data including comprehensive follow-up of all patients, and tightly integrated security measures. All patients provided written informed consent to allow the collection of tissue and blood and analysis of clinical and genetic data for research purposes (Dana-Farber Cancer Institute). The cohorts accrued to this study were patients who either 1) were identified based on prospective chart review to have PSA >20 ng/ml, progressive disease based on rising PSA, and scan progression; 2) were participants in a Phase I study of crizotinib in combination with enzalutamide or a Phase Ib study of abiraterone in combination with ARN-509; or 3) were eligible for metastasis biopsy after progression on enzalutamide or abiraterone through the Stand Up 2 Cancer/PCF Dream Team Effort based on participation in one of the following protocols: a Phase II study of abiraterone in combination with dutasteride, a Phase II trial of enzalutamide with correlative assessment of AR, a Phase II trial of abiraterone without exogenous, and a tumor biopsy protocol to assess tissue correlates of therapeutic response. Blood specimens were prospectively collected from eligible patients.

• Primary Phenotype: Neoplasms
• Neoplasm Metastasis

• BioSample

• Principal Investigator
  • Viktor A. Adalsteinsson. Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
• Co-Investigators
  • Gad Getz. Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MA, USA.
  • J. Christopher Love. Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
  • Matthew Meyerson. Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.