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Original article
Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery
  1. Thomas Reinert1,
  2. Lone V Schøler1,
  3. Rune Thomsen1,
  4. Heidi Tobiasen1,
  5. Søren Vang1,
  6. Iver Nordentoft1,
  7. Philippe Lamy1,
  8. Anne-Sofie Kannerup2,
  9. Frank V Mortensen2,
  10. Katrine Stribolt3,
  11. Stephen Hamilton-Dutoit3,
  12. Hans J Nielsen4,
  13. Søren Laurberg5,
  14. Niels Pallisgaard6,
  15. Jakob S Pedersen1,
  16. Torben F Ørntoft1,
  17. Claus L Andersen1
  1. 1Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  2. 2Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
  3. 3Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark
  4. 4Department of Surgical Gastroenterology, University of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark
  5. 5Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark
  6. 6Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark
  1. Correspondence to Claus L Andersen, Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; cla@clin.au.dk

Abstract

Objective To develop an affordable and robust pipeline for selection of patient-specific somatic structural variants (SSVs) being informative about radicality of the primary resection, response to adjuvant therapy, incipient recurrence and response to treatment performed in relation to diagnosis of recurrence.

Design We have established efficient procedures for identification of SSVs by next-generation sequencing and subsequent quantification of 3–6 SSVs in plasma. The consequence of intratumour heterogeneity on our approach was assessed. The level of circulating tumour DNA (ctDNA) was quantified in 151 serial plasma samples from six relapsing and five non-relapsing colorectal cancer (CRC) patients by droplet digital PCR, and correlated to clinical findings.

Results Up to six personalised assays were designed for each patient. Our approach enabled efficient temporal assessment of disease status, response to surgical and oncological intervention, and early detection of incipient recurrence. Our approach provided 2–15 (mean 10) months' lead time on detection of metastatic recurrence compared to conventional follow-up. The sensitivity and specificity of the SSVs in terms of detecting postsurgery relapse were 100%.

Conclusions We show that assessment of ctDNA is a non-invasive, exquisitely specific and highly sensitive approach for monitoring disease load, which has the potential to provide clinically relevant lead times compared with conventional methods. Furthermore, we provide a low-coverage protocol optimised for identifying SSVs with excellent correlation between SSVs identified in tumours and matched metastases. Application of ctDNA analysis has the potential to change clinical practice in the management of CRC.

  • Colon cancer
  • Droplet digital PCR
  • circulating tumor DNA
  • plasma
  • mate-pair

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