Abstract

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal–Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Highlights

  • Circulating tumour DNA typically constitutes a small proportion of an individual’s total circulating free DNA;

  • Multiple approaches are being explored in an attempt to design more sensitive assays; for next-generation sequencing-based multigene approaches involving the sampling of serial and/or larger plasma volumes currently provide the best level of sensitivity for the detection of minimal residual disease (MRD)

  • In the absence of results from ongoing clinical trials that include circulating tumour DNA (ctDNA)-based biomarker screening and monitoring, we propose that the collection and longterm storage of plasma samples be made mandatory for all future studies involving targeted therapies and/or immuno­therapy in order to enable retrospective assessments of possible mechanisms of treatment resistance

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Summary

Methods

A workshop was conducted under the auspices of the Colon and Rectal–Anal Task forces of the US NCI on 3 June 2018 in Chicago, IL, USA, at the ASCO Annual Meeting (co-Chairs A.D., V.M. and S.K.). Members of the Task Forces, along with selected invitees, collectively provided expertise in next-generation sequencing (NGS), ctDNA methodology and other aspects of assay development (S.R.H., M.D.), bioinformatics (M.D.), biostatistics and technical data management (Q.S., G.Y., F.S.O.) as well as in various subdisciplines of clinical care and clinical and translational research, including genomic medicine (S.K., R.B.C.) in CRC and patient advocacy. Additional invitees included select members of the NCI, the NCI’s Cancer Therapy Evaluation Program and the Gastrointestinal Steering Committee. The recommendations developed during the thematic Working Groups were discussed and voted upon individually by all members towards the development of a consensus to recognize the limitations of current knowledge and identify key gaps and to develop recommendations for future research (Box 1; Table 1). The final draft of the manuscript was reviewed by members of the Cancer Therapy Evaluation Program, whose helpful comments were incorporated. The role of ctDNA as a tool for early detection of CRC was not part of the Workshop agenda and is not covered in this manuscript but has been comprehensively reviewed elsewhere[17,18]

Clinical setting
Difficulty in establishing clinical utility and validity
Lack of clinical adoption
Management of MRD
Treatment naive
Disease relapse or recurrence
Management of rectal cancer
Monitoring metastatic disease
Error correction through consensus read
Tumour responsiveness
Findings
Conclusions
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