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A Paper to Circulate

This paper is one of a number published over the last year that examine the potential for liquid biopsy in colorectal cancer. That’s a clear indication of a subject worthy of study – but there are several reasons I like this piece in particular. For one, it’s open-access, which makes it available to a much larger readership than one published in a traditional, subscribers-only journal. For another, it’s an example of careful research – the authors assembled a good population, used control groups wisely, conducted a well-defined study, and reported on the limitations as well as the results of their research.

Circulating free DNA (cfDNA) has been put forward as a potential tool for early diagnosis, monitoring of disease burden, and as an alternative to tissue biopsy for determining the RAS mutation status of a patient. In the paper I’ve chosen, the authors use a series of Phase II clinical trials to obtain plasma from 229 well-documented metastatic colorectal cancer patients and 100 controls, using the REMARK guidance (REporting recommendations for tumor MARKer prognostic studies, available at DNA was quantified using qPCR for the peptidylprolyl isomerase A (cyclophilin A) gene, and a laboratory-developed amplification-refractory mutation system assay for RAS gene alterations was used to determine the presence of KRAS mutations.

The paper has some limitations. For instance, it was not clear what product sizes were identified by the authors’ PCR methods, which is important as fragmentation of DNA in plasma will affect the sensitivity of the assay. The colorectal cancer cases were mainly advanced, but no analysis based on tumor load by radiology or another tumor marker like carcinoembryonic antigen (CEA) was given. Nevertheless, the authors should be congratulated on performing a meticulous study with reasonable patient numbers and a control group. They are quite right in saying that “differences in investigational methodologies make direct comparisons (between studies) difficult” – although personally I think “impossible” might be a better term!

The authors should be congratulated on performing a meticulous study with reasonable patient numbers and a control group.

That issue does, however, call attention to a gap in our current work. There is a strong need for the community involved in this type of research to use well-defined comparators in their papers. A tumor marker like CEA is the obvious solution for colorectal cancer, though this is more difficult for many other tumor types.  The authors call for “combined efforts to compare, validate and prospectively investigate the role of cfDNA quantification in cancer, with the overall perspective of translating results into clinical care.” Based on the results of several such studies, this is clearly the next step – we need large, multicenter studies to provide the analytical and clinical validation necessary for this technology to enter routine clinical practice.

Variations on a Drop by James Nichols

A Paper to Circulate by Ian Cree

Hyperspectral Disease Diagnosis by Peter Griffiths

Diagnosis: Digital by Liron Pantanowitz

Collagen and the Colon by Miguel Reyes-Múgica

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About the Author
Ian Cree

Ian Cree is Head of the World Health Organization Classification of Tumors Group, International Agency for Research on Cancer, Lyon, France.

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