Role of Rebiopsy and ctDNA Testing at Progression of mCRC



Marwan Fakih, MD: What is the role of rebiopsy—or what we call liquid biopsy as well, which is the circulating tumor DNA [ctDNA]—in the management of patients with metastatic colorectal cancer? We now know that all patients with metastatic colorectal cancer are in need of next-generation sequencing and what we call comprehensive genomic analysis at the time of diagnosis. We make decisions regarding treatment based on these data that are available to us at the time of diagnosis.

Certainly, there is heterogeneity within the 1 individual as far as the different metastatic disease foci. Not all tumors, not all metastases, have the same molecular profile. But at least for the main drivers such as RAS and BRAF, we know that those patients have considerable concordance between their primary and different sites of metastatic disease. We also know that as we integrate biological therapy and targeted therapy in the earlier lines of the treatment of patients with metastatic colorectal cancer, we are inducing more heterogeneity—we are inducing what we call clonal evolution. There are new mutations that appear in the blood and selection of less dominant clones initially that now become more dominant.

For example, when we look at patients who receive anti-EGFR therapy, we know that at the time of resistance to anti-EGFR therapy following an excellent response, more than 70% of those patients now have alterations that you can detect in the blood that activate the MAP kinase pathway. These could be, for example, RAS mutations, BRAF amplifications, KRAS amplifications, and even fusions sometimes. These alterations are associated with the emerging resistance to anti-EGFR therapy. Do I use ctDNA and do I use liquid biopsies in the management and follow-up of my patients? Of course, but not all the time.

If I am considering, for example, rechallenging somebody with anti-EGFR therapy after that patient has progressed on anti-EGFR therapy in the first-line setting—following a great response and after that patient went on a second-line treatment that does not include an anti-EGFR—after about 5 or 6 months if that patient has progressed on the second-line chemotherapy that is not anti-EGFR containing, a liquid biopsy is extremely important. It is important because it helps to figure out if the markers of resistance that were present at the time of resistant to anti-EGFR have now dissipated or disappeared.

If that is the case, we are looking at a possibility of a 20% to 30% chance of an objective response in that patient by just revisiting the first chemotherapy plus anti-EGFR, as far as a salvage rechallenge. So yes, I do use that. Do I know that there is a value in doing ctDNA in patients who have a KRAS mutation? I do not think there is any evidence that liquid biopsies in patients with RAS-mutated colon cancer in the management of patients with metastatic colorectal cancer and in directing treatment of patients with metastatic colorectal cancer has now been validated. I think the use of liquid biopsies or the concept of rebiopsy could be considered on a select basis, predominantly in the setting of resistance to targeted therapies.

Transcript Edited for Clarity

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