Considering Real-World Applications With ctDNA


Shared insight on how circulating tumor DNA may be used in real-world clinical practice to improve the value of cancer care.


John H. Strickler, MD:Now I’m going to move on to future directions and start first with you, Dr Dietrich. Based on the data, in what cases would you or are you currently using circulating tumor DNA [ctDNA] and in what cases are you not currently using it, specifically for breast cancer?

Martin Dietrich, MD, PhD: Well, I do not routinely use ctDNA on any patients, so I think this has to be tailored to individual situations. I think breast [cancer] is not at the level of utility beyond the actual tumor DNA analysis in a biopsy. We’ve kind of supplanted ctDNA, the tissue analysis with the ctDNA analysis for sequencing, and especially at the last ASCO [American Society of Clinical Oncology annual meeting]. We’ve seen that some of the markers that are both dynamic and non-graspable by ctDNA, in particular, HER2 expression in the low and intermediate settings, still need the complementary analysis of tumor tissue. That kind of sets ctDNA analysis a step back now that we basically have the use of anti–HER-2 directed antibody-drug conjugates across the entire spectrum of breast cancer. That issue has certainly been pushed back to the forefront. In terms of monitoring, it is a difficult question to answer. I think the answer isn’t sure, but the clinical setting is not yet defined. So, I want to say I use it in cases of judgment where I think it might be helpful to identify additional lesions that help me monitor difficult to assess disease-bone only is one. Peritoneal… and lobular cancer is another one where I think we have always the fine line between bowel obstruction and need for switch of therapy. I think an early detection there is helpful. So, I use it in the metastatic space in select cases. In the adjuvant setting, I feel like we have such good randomized prospective data from tens of thousands of patients using genomic assays. It will be very hard to replace that with prognostic data. So, I would complement this. I think this may sometimes be a decision-making point for patients that are on the fence about chemotherapy where the additional positivity of chemotherapy would be an additional incentive to do chemotherapy. The predicament comes with, what if I have a discordance between a high genomic score of recurrence and concern for MRD negativity? There are certain aspects that ctDNA does not address. It addresses obviously the sensitivity threshold, tumor dormancy, and latency of recurrence. So, we always have to advise patients, and while this assay is highly deployable, the question is where is it actually applicable yet? I think this will take a lot of time. I think Dr Bardia gave a very good prediction that hopefully within this decade we’re going to have this information available, but that’s still a long time. I want to say routinely, I’m currently not using it, preferably doing it in the context of a clinical trial to create more than an anecdote and really try to see if we can capture this data prospectively. Certainly, a great number of prospective data pieces, and then, obviously, a big interest here is patients that have abnormal imaging findings after initial diagnosis with biopsy may be more challenging. I think more to come but currently, for me, not a routine use. Modality in most cases. Certainly, different from what the colleagues in GI [gastrointestinal] malignancies are doing.

John H. Strickler, MD: Speaking from the perspective of a GI oncologist who manages colorectal cancer patients, we have seen broad adoption of ctDNA in the clinic. The most common utilization of it is of course, where tumor tissue is not readily accessible or we feel like the tumor has changed. For example, if the tumor genomic profile has changed under the selective pressure of usually targeted therapies. That’s where it’s come into some use and has been practical as a complement to our current tools. MRD [minimal residual disease] is a newer assay and many of us are just now grasping the evidence we have which is compelling, both at a prognostic level but also compelling that we can potentially use this data in certain clinical scenarios to guide our management. So, we’ve seen results from the dynamic trial which suggested that you could use circulating tumor DNA to potentially deescalate treatment in cases of lower-risk disease and escalate treatment in higher-risk disease, and it sounds like that data is not quite there yet for breast cancer, but those studies are ongoing currently. Dr Bardia, what do you think is next for this field, both in breast cancer and beyond? What should we look forward to in the next five or ten years?

Aditya Bardia, MD, MPH: I agree with what’s been said before. The current application of ctDNA is in metastatic breast cancer but a lot of excitement in the adjuvant setting and over the next 3 to 5 years we are likely to see demonstration of clinical utility of the use of ctDNA in the breast cancer setting. Moving forward, in breast cancer and other cancers, there’s also interest in early detection. Can we even detect cancer before we can see it on a mammogram or colonoscopy? There are ongoing studies looking at ctDNA as a screening tool for early detection of cancer. It’s a very high bar and you really need a very sensitive assay, and the concern also is if you see something that’s present in the blood, you also have to figure out the tissue of origin. If you’re seeing a certain alteration, is it coming from the colon or the breast or the lung, for example with KRAS mutation, but I think all of those things would need to be worked out. If it demonstrates promise, blood tests for cancers that just sounds like sci-fi at this time but could be reality five to ten years from now.

John H. Strickler, MD:Yes, and certainly those studies are ongoing and could be a helpful adjunct, both for early detection of breast cancer, colon cancer, and many other diseases where detecting that disease at an earlier stage substantially increases the cure rate with surgery. So, that’s an exciting development, and certainly in the area of colorectal cancer while we have some very interesting data from our initial retrospective and prospective studies there are practice-changing studies still ongoing that we hope to see read out in the next 3 to 5 years. CIRCULATE-Japan, CIRCULATE-US, and cooperative group studies are ongoing both to understand whether the test has utility, not just prognostically but also with the use of chemotherapy to guide our adjuvant decision-making. Then also to help us understand whether we should be escalating treatment and what to do when that test is positive, and how best to manage it and there are exciting studies still going on in the field.

Transcript edited for clarity.

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