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Original Article
Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study
  1. Jeanne Tie1,
  2. Joshua D Cohen2,
  3. Yuxuan Wang2,
  4. Lu Li2,
  5. Michael Christie3,
  6. Koen Simons4,
  7. Hany Elsaleh5,
  8. Suzanne Kosmider6,
  9. Rachel Wong7,
  10. Desmond Yip8,
  11. Margaret Lee9,
  12. Ben Tran1,
  13. David Rangiah10,
  14. Matthew Burge11,
  15. David Goldstein12,
  16. Madhu Singh13,
  17. Iain Skinner14,
  18. Ian Faragher14,
  19. Matthew Croxford14,
  20. Carolyn Bampton15,
  21. Andrew Haydon16,
  22. Ian T Jones17,
  23. Christos S Karapetis18,
  24. Timothy Price19,
  25. Mary J Schaefer2,
  26. Jeanne Ptak2,
  27. Lisa Dobbyn2,
  28. Natallie Silliman2,
  29. Isaac Kinde2,
  30. Cristian Tomasetti2,
  31. Nickolas Papadopoulos2,
  32. Kenneth Kinzler2,
  33. Bert Volgestein2,
  34. Peter Gibbs1
  1. 1Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. 2Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3Department of Pathology, Melbourne Health, Melbourne, Victoria, Australia
  4. 4Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  5. 5Department of Radiation Oncology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
  6. 6Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
  7. 7Department of Medical Oncology, Eastern Health, Melbourne, Victoria, Australia
  8. 8Department of Medical Oncology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
  9. 9Department of Medicine, Melbourne Medical School—Western Precinct, The University of Melbourne, Melbourne, Victoria, Australia
  10. 10Department of Surgery, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
  11. 11Department of Medical Oncology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  12. 12Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia
  13. 13Department of Medical Oncology, Barwon Health, Geelong, Australia
  14. 14Department of Surgery, Western Health, Melbourne, Victoria, Australia
  15. 15Department of Medical Oncology, Adelaide Cancer Centre, Adelaide, South Australia, Australia
  16. 16Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
  17. 17Department of Surgery, Melbourne Health, Melbourne, Victoria, Australia
  18. 18Flinders Centre for Innovation in Cancer, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia
  19. 19Department of Medical Oncology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia
  1. Correspondence to Associate Professor Jeanne Tie, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia; Jeanne.Tie{at}petermac.org

Abstract

Objective For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC.

Design We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4–10 weeks after surgery. Somatic mutations in individual patient’s tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results.

Results We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001).

Conclusion Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

  • tumour markers
  • colorectal cancer
  • chemotherapy
  • clinical decision making
  • molecular oncology

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Footnotes

  • BV and PG contributed equally.

  • JT and JDC contributed equally.

  • Contributors JT, BV and PG designed the study; BV, JDC, YW, MJS, JP, LD, NS, IK, KK and NP performed MPS and bioinformatic analyses; CT and LL were responsible for developing the algorithm for classifying ctDNA status; MC performed pathology assessment of the tumour tissue; HE, RW, SK, DY, ML, BT, DR, MB, DG, MS, IS, IF, CB, AH, ITJ, CSK and TP contributed to patient recruitment; JT, JDC, YW, CT, LL, KS, LD, BV and PG analysed and interpreted the data; all authors contributed to the writing and review of the manuscript.

  • Funding Australian National Health and Medical Research Council (GNT1026230), the National Institute of Health (CA62924, GM07309, and P30-CA006973), Virginia and D K Ludwig Fund for Cancer Research, The John Templeton Foundation, The Conrad R Hilton Foundation, The Sol Goldman Sequencing Facility at Johns Hopkins.

  • Competing interests KK, NP, LD and BV are founders of PapGene and Personal Genome Diagnostics and members of the Scientific Advisory Boards of Morphotek and Sysmex-Inostics. IK is an employee of PapGene. These companies and others have licensed patent applications on genetic technologies from Johns Hopkins, some of which result in royalty payments to KK, NP, LD, BV, and IK. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

  • Ethics approval Melbourne Health.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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