Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA

Ann Oncol. 2016 Oct;27(10):1959-65. doi: 10.1093/annonc/mdw278. Epub 2016 Aug 8.

Abstract

Background: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment.

Patients and methods: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy.

Results: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel.

Conclusion: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.

Keywords: circulating cell-free DNA; clonal response to therapy; next-generation sequencing; vaginal mucosal melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Pharmacological
  • Carboplatin / administration & dosage
  • Cell-Free Nucleic Acids / drug effects
  • Cell-Free Nucleic Acids / genetics*
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / genetics
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Imatinib Mesylate / administration & dosage
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Middle Aged
  • Mutation
  • Paclitaxel / administration & dosage
  • Precision Medicine
  • Proto-Oncogene Proteins c-kit / genetics*
  • Vaginal Neoplasms / drug therapy*
  • Vaginal Neoplasms / genetics
  • Vaginal Neoplasms / pathology
  • Whole Exome Sequencing

Substances

  • Biomarkers, Pharmacological
  • Cell-Free Nucleic Acids
  • DNA, Neoplasm
  • Imatinib Mesylate
  • Carboplatin
  • Proto-Oncogene Proteins c-kit
  • Paclitaxel