Understanding the Mechanisms and Use of ctDNA and MRD Testing


Expert panelists elucidate the mechanisms of ctDNA and MRD testing, providing a broad perspective on how they are used in cancer care.


John H. Strickler, MD: Briefly, Dr Dietrich, what is CT [circulating tumor] or cell-free DNA?

Martin Dietrich, MD, PhD: Cell-free DNA is a waste product that is circulating in plasma. It’s a product of tumor cell turnover, and it can be captured and then analyzed on plasma samples. We’ve seen a long discussion about circulating tumor DNA, and regarding the genomic characterization of disease, we’ve been using it for liquid biopsies for a long time. We’ve really extended its use into molecular disease monitoring, or MRD [minimal residual disease] where we can not only use descriptive analysis of sequencing approaches, but really semi-quantitative measurements of presence or absence, and then relative titers of circulating tumor DNA assessment. Obviously, those don’t correlate necessarily with the amount of tumor volume. There are many factors that go into this current treatment, and the amount of proliferation, the amount of cell turnover, cell death in the tumor DNA, and obviously certain chronological factors that may play a role as well.

In summary, basically, it is a surrogate marker of tumor cell presence that can be utilized in a plethora of ways for analysis in the setting of disease treatments. This can be tailored in multiple ways. We’ve looked at MRD monitoring in two larger compartments. One is the noninformed one where we basically use an agnostic, broad capture next-generation sequencing platform. The alternative is the informed part where we basically sequence the tumor, and then design specific primers that are looking at tumor-specific mutations that may help us guide and detect this in a more sensitive manner. I think this is currently the more commonly used modality. We don’t have as much head-to-head data between those 2 technologies. Though it’s one of the exciting tools that we’re trying to develop to help us gauge responses to cancer better, and help us to design trials and treatments that are more specific and hopefully in the avoidance of unnecessary treatments.

John H. Strickler, MD: That’s wonderful. So, one of the terms that we’ve heard used is so-called MRD. What does that term mean, and what does ctDNA have to do with MRD?

Martin Dietrich, MD, PhD: There’s a difference between the hematologic and the oncological use of MRD. In our world, I think this has been used as both minimally residual disease as well as molecular residual disease for treatment. I’m not sure which terminology is eventually going to take the lead, but the idea is to have a layer deeper into the classical imaging modalities or tumor markers that we’re using and to help us guide the presence or absence of both the presence of disease or monitoring of disease response. So MRD is a measure that’s supposed to help us steer treatment on a much more sensitive level, and due to its non-invasive nature, also on a more real-time level, where we don’t have to have repeat scans as frequently. Though maybe using blood as a surrogate for the establishment of these markers. There are certainly several settings where this can be utilized, in the active treatment setting, and in the surveillance setting. Then also, obviously, in the metastatic disease course, where the rising and dropping titers of MRD may be helpful to guide the next treatment decision, so maybe prepare us to think about the next line of therapy. There’s a lot of investigation in the space, and certainly with the versatility and the non-invasive nature, there’s certainly an amount of excitement at every meeting that we’re going to.

Transcript edited for clarity.

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