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Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival

  • David H. Murray
  • Erin L. Symonds
  • Graeme P. Young
  • Susan Byrne
  • Philippa Rabbitt
  • Amitesh Roy
  • Kathryn Cornthwaite
  • Christos S. Karapetis
  • Susanne K. Pedersen
Original Article – Cancer Research
  • 24 Downloads

Abstract

Purpose

Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence.

Methods

ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival.

Results

Blood was collected from 172 CRC patients after surgery and 28 (16%) were ctDNA positive. Recurrence was diagnosed in 23 of the 138 with clinical follow-up after surgery (median follow-up 23.3 months, IQR 14.3–29.5). Multivariate modeling indicated that features suggestive of residual disease were an independent predictor of post-surgery ctDNA status: cases with any of three features (close resection margins, apical node involved, or distant metastases) were 5.3 times (95% CI 1.5–18.4, p = 0.008) more likely to be ctDNA positive. Multivariate analysis showed that post-surgery ctDNA positivity was independently associated with an increased risk of recurrence (HR 3.8, 1.5–9.5, p = 0.004).

Conclusions

CRC cases positive for methylated ctDNA after surgery are at increased risk of residual disease and subsequently recurrence. This could have implications for guiding recommendations for adjuvant therapy and surveillance strategies. Randomized studies are now indicated to determine if monitoring cases with these biomarkers leads to survival benefit.

Keywords

Colorectal cancer (CRC) Circulating tumor DNA (ctDNA) Survival Residual disease Methylated DNA 

Notes

Acknowledgements

GPY and CK are recipients of a grant funded by the financial support of Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health together with the support of the Flinders Medical Centre Foundation, its donors and partners.

Funding

This study was funded in part by the National Health and Medical Research Council (APP1006242, APP1017083) and Clinical Genomics Pty Ltd.

Compliance with ethical standards

Conflict of interest

GPY is a paid consultant of Clinical Genomics. SKP and DHM are paid employees of Clinical Genomics. All other authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • David H. Murray
    • 1
  • Erin L. Symonds
    • 2
    • 3
  • Graeme P. Young
    • 2
  • Susan Byrne
    • 2
  • Philippa Rabbitt
    • 4
  • Amitesh Roy
    • 5
  • Kathryn Cornthwaite
    • 2
  • Christos S. Karapetis
    • 5
  • Susanne K. Pedersen
    • 1
  1. 1.Clinical Genomics Pty LtdNorth RydeAustralia
  2. 2.Flinders Centre for Innovation in Cancer, College of Medicine and Public HealthFlinders University of South AustraliaBedford ParkAustralia
  3. 3.Bowel Health ServiceFlinders Medical CentreBedford ParkAustralia
  4. 4.Colorectal Surgery, Division of Surgery and Perioperative MedicineFlinders Medical CentreBedford ParkAustralia
  5. 5.Department of OncologyFlinders Medical CentreBedford ParkAustralia

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