Blase Polite, MD: Clinically, how would we use ctDNA [circulating tumor DNA] testing? What do the data show? In most studies in the stage II and III colon cancer setting, the Signatera assay has Medicare approval. Why did they get approval for it? There have been several studies. The [Thomas] Reinert study, published in JAMA Oncology [in 2019],is probably the first that we saw. At ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] in 2022, we saw additional data from that group, as well as data that came out of the CIRCULATE-Japan group.

If you look at a onetime circulating tumor DNA after resection, if you’re ctDNA positive, the data from Reinert and colleagues show that 75% of those patients will have a relapse. When you look at the data further at the patients who did not relapse, almost all those patients received adjuvant chemotherapy. As you extend it further and look at ctDNA positivity at any point within a 2-year period—every 3 months ctDNA testing, if anyone is positive in that period— 97% to 98% of those patients will recur. Now it’s 9% to 10%, depending on stage of patients postoperative, stage II and III, who will have positive ctDNA. For those patients, the risk of recurrence is exceedingly high.

If you look at it from a relapse standpoint, 4 to 6 weeks after surgery, patients who are positive have a chance of recurrence that’s 11 times higher than those who are ctDNA negative. When you extend the data out—patients who are negative for over 2 years vs positive at any point over the 2 years—the risk of relapse for the positive patients is 36 times higher. We have a test that has good test characteristics in terms of sensitivity and specificity, and positive and negative predictive values are in the 97%-to-98% range. If you look at patients who are ctDNA negative for 2 years, those patients have less than a 3% chance of relapsing. You can imagine how this may impact our surveillance as well as our chemotherapy decision-making.

Look at the data that came out of the GALAXY study—this is a CIRCULATE-Japan study. It’s a very large multiarm study. It’s essentially an observational cohort of patients who have ctDNA. In that population you see similar data. They did preoperative and postoperative testing. In the preoperative setting, when you look at patients by stage of disease, of patients who have stage I colon cancer, 80% have ctDNA. When you look at stages II and III, 95% to 96% of these patients have ctDNA. Compare that with CEA [carcinoembryonic antigen] stage II colon cancer. CEA is positive in about 35% to 37% of those cases. Stage III cancer CEA is positive in about 48% of those cases, compared with 96% in patients who have circulating tumor DNA. There’s no question that circulating tumor DNA is picking up cancer.

When we look at the postsurgical setting, surprisingly, 6% of patients are positive for ctDNA for stage I disease, which we would never consider giving chemotherapy to. For stage III patients, as many as 25% are positive postoperatively. We have a test that detects disease when it’s there at a very high rate. It’s detecting disease postoperatively when we don’t see disease by imaging in a high percentage of our lower-risk cancer patients and in a quarter of our stage III patients. We’re beginning to define and see a population that we may want to be more aggressive on or, alternatively, give less aggressive therapy to.

Transcript edited for clarity.