Jame Abraham, MD, FACP on the Phase III ZEST Trial

Speaker 1: I am going to talk about the Zest trial, which was presented by Dr. Turner at the San Antonio Breast Cancer Symposium in 2024. So this is a circulating tumor DNA surveillance in Zest. It's a randomized phase three double-blind study of Niraparib or placebo in patients with triple negative breast cancer for HER2-negative BRCA mutated breast cancer with molecular residual disease after the definitive treatment. So as all of us know, about 20 to 30% of early breast cancer will relapse. At this point, we don't have a good test to predict who will relapse in the later follow-up. So ctDNA testing has been in use for many tumor types. In breast cancer, we don't have really a validated test or study to prove that the ctDNA testing will improve long-term outcome. So this is the first phase three randomized double-blind clinical trial of MRD detected treatment in breast cancer to assess whether Niraparib could improve this survivor. So it's a large study, ctDNA and randomized between the ctDNA positive and then intervention with Niraparib. So in conclusion, it was terminated early on because the low randomization rate, and there is a broad criteria, entry criteria including low risk patients in this thing that resulted in low rate of ctDNA positivity. High rate of metastatic disease at the time of ctDNA positivity. So for patients with triple negative breast cancer, ctDNA positivity occurred most frequently as expected in the first six months from the end of treatment. And that's, of course, consistent with earlier occurrence in typical triple negative breast cancer. There was a high rate of radiographic recurrence at time of ctDNA positivity, providing support for strategies to start ctDNA testing earlier in the disease trajectory of triple negative breast cancer. This trial was not powered to evaluate the effect of Niraparib versus placebo given early termination, but the recurrence freeze interval was numerically longer with Niraparib. So the bottom line is ctDNA ready for primetime. My answer today, no. I don't think we should reduce using ctDNA in a clinical setting outside of a clinical trial, because we have a lot of unanswered questions in the ctDNA space. I'm sure this will change in the future when we have more data of what's the right type of ctDNA we should be doing, what's the right type of patients we should be testing, what diagnostic tests we can do once the ctDNA is found to be positive, and how we can intervene once the test is positive. So at this point, I know patients are anxious, I can clearly understand that. But at this point, ctDNA is not ready for a primetime.