The Evolution of Circulating Tumor DNA in Oncology

Jason Starr, DO: There’s an evolution of how we’ve used these, what we would call liquid biopsy or blood tests. So, as I alluded to before, circulating tumor DNA is this encompassing term. One utility is you have a patient that comes to clinic, and they have metastatic colon cancer and you want to figure out if they have certain mutations, for example, in colorectal cancer. You want to know do they have a RAS mutation or a BRAF mutation or HER2 amplification. This blood test will have almost equal concordance, maybe better than actually getting tissue. A lot of times you’ll end up getting the tissue sample because you want to confirm obviously the diagnosis, but the turnaround time on a liquid biopsy is maybe 7 days or so and for genomic, analysis from the tissue could take anywhere from 2 to 3 weeks. So you get quicker answers for the patient to make treatment decisions.

In lung cancer, for example, the FDA [Food and Drug Administration] approved a circulating tumor DNA assay. They are more widely being used in the clinic. As my practices evolved, I use them more and more. I get a tissue diagnosis in addition to the liquid biopsy. The other nice thing about the liquid biopsy is you can follow the evolution of the variants of interest, where they would call it variant allele frequency, or VAF. And if the treatment is effective, almost invariably, you’ll see that the variant allele fraction of that specific mutation will go down. It can be helpful to determine “is my treatment effective?”, in addition to treatment selection.

Let’s pivot to molecular residual disease [MRD]. Again, this isn’t necessarily targeting mutations. It’s more detecting or determining “is there measurable disease that we can’t see on imaging, CT, MRI?” So on and so forth. And this can be very helpful in many different facets. One could be determining whether or not treatment is indicated. So if the patient still has disease left behind after colon cancer resection, and you’re trying to determine whether or not the patient needs adjuvant treatment, the molecular residual disease, if it’s positive, may push you into the direction of giving adjuvant therapy, which would make good sense because that’s the role of adjuvant therapy to destroy micrometastatic disease.

Also, molecular residual disease is being more helpful also with following effectiveness of treatment, particularly immunotherapy. With immunotherapy, sometimes it can be hard after the first 2 or 3 cycles to determine if the treatment’s working because sometimes you get something called pseudoprogression, where the immune system essentially gets in there and causes inflammation around where the tumor is. So it looks there’s growth, but it’s actually effective therapy. If you were watching the molecular residual disease, you would actually see the mean tumor molecules going down, which would give you more confidence that the therapy is working.

Another area where MRD is being explored, or there was a recent paper on this, where the patient has metastatic disease and has a surgery to remove the metastatic lesion and deciding on treatment after that. And so, measuring the MRD to see whether or not there are situations with stage IV, where we can cure patients, but at least deciding on when to initiate treatment is equally important. Sometimes you can really delay systemic therapy, and this would be 1 proof, 1 piece of evidence that could push you in the direction of not giving treatment, at least at that moment.

And then with cancer detection, that’s evolving. There was a new assay that was introduced by a company referred to as GRAIL. And what they’re trying to do is they’re trying to detect cancer earlier to help improve outcomes. Now I think that the technology is still a bit early for cancer detection in the general population, but in high-risk individuals who have a strong family history or have a longstanding history of smoking or other environmental factors, or genetic for that matter, this may be of utility and it may be more of utility once the technology is more refined and we have more data. What you don’t want to do is you don’t want to test the general population and get false positives. Because one, you go on a wild goose chase looking for cancer, and two you’re going to cause a lot of anxiety for the patient. And so those things we have to be careful with.

This transcript has been edited for clarity.

EP: 1.Explaining Molecular Residual Disease

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EP: 2.The Evolution of Circulating Tumor DNA in Oncology

EP: 3.MRD Assessments

EP: 4.MRD Results and Guiding Treatment Decisions

EP: 5.MRD and Value-Based Care Models

EP: 6.Supporting MRD Availability

EP: 7.INSPIRE and IMvigor011 Trials

EP: 8.Potential Changes for MRD in the Future