Dr Jones on the Application of ctDNA Testing in CRC

Jeremy C. Jones, MD, vice chair, assistant professor, medical oncologist, hematologist, Division of Hematology and Oncology, Mayo Clinic, discusses the applications of circulating tumor DNA (ctDNA) testing in colorectal cancer (CRC).

ctDNA tests are typically engineered to achieve a high level of specificity, Jones begins. When such a test yields a positive result, it strongly suggests the presence of residual disease, specifically molecular residual disease, he highlights, adding that these tests excel in this regard. However, the development of such tests involves a balance between sensitivity and specificity. Specificity pertains to the likelihood of disease presence when the test is positive; a positive test result is generally trusted to signify the presence of disease, Jones emphasizes. To achieve this level of trust, there may be a trade-off with sensitivity, and a negative test result may not effectively rule out the presence of residual cancer, he adds. 

Understanding this dynamic in these testing platforms is essential for determining how to integrate these tests effectively into clinical practice, Jones expands. For example, in stage II CRC, there hasn't been a definitive prospective adjuvant trial demonstrating a universal benefit of ctDNA testing, therefore, oncologists often rely on post hoc analyses to identify high-risk features, such as lymphovascular invasion, perineural invasion, or primary tumor disruption, to guide adjuvant chemotherapy decisions, Jones explains. However, if a patient with stage II disease were to test positive for ctDNA, a strong indicator of high risk, even without these established high-risk features, the positive result would warrant a discussion about the potential benefits and risks of adjuvant chemotherapy, Jones says. Furthermore, Jones emphasizes the current lack of conclusive data in all stage II CRC cases within this landscape.

Conversely, for stage III colon cancer, where robust randomized data support the use of adjuvant chemotherapy, it would be unwise to withhold chemotherapy solely based on a ctDNAtest result, he continues. These tests are reliable when positive, but in isolation, a negative result may not provide sufficient information, Jones says. In practice, these considerations inform how these tests are used. They may serve as tools to enhance post-adjuvant treatment monitoring in stage III cases, although the precise effect on patient outcomes remains uncertain, he adds. Furthermore, ctDNA test results can be a valuable entry point for clinical trial enrollment, enriching the trial population with patients at the highest risk for unfavorableoutcomes, Jones concludes.