Phylogenetic ctDNA Analysis Depicts Early-Stage Lung Cancer Evolution

Nature. 2017 Apr 26;545(7655):446-451. doi: 10.1038/nature22364.

Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Trial registration: ClinicalTrials.gov NCT03004755.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy / methods
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / surgery
  • Cell Lineage / genetics*
  • Cell Tracking
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • DNA Mutational Analysis
  • DNA, Neoplasm / blood*
  • DNA, Neoplasm / genetics*
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Early Detection of Cancer / methods
  • Evolution, Molecular*
  • Humans
  • Limit of Detection
  • Lung Neoplasms / blood
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / surgery
  • Multiplex Polymerase Chain Reaction
  • Neoplasm Metastasis / diagnosis*
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Neoplasm Recurrence, Local / diagnosis*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Postoperative Care / methods
  • Reproducibility of Results
  • Tumor Burden

Substances

  • DNA, Neoplasm

Associated data

  • ClinicalTrials.gov/NCT03004755