Dr Mouabbi on the Role of ctDNA Testing in Individualized Breast Cancer Care

“The false-negativity rate [of ctDNA tests] is low. At this point, [the false-negative rate with a] single test is approximately 6%, but if you do serial tests, such as 3 or 4 tests back-to-back, and all of them come back negative, then the negative value keeps going higher.”

Jason Aboudi Mouabbi, MD, an assistant professor in the Department of Breast Medical Oncology and the Department of General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the clinical utility of circulating tumor DNA (ctDNA) testing across the spectrum of breast cancer management, highlighting its role in refining prognosis and personalizing therapeutic intensity.

One primary application of ctDNA testing is in the neoadjuvant setting, where it has emerged as a superior tool for predicting post-surgical outcomes, Mouabbi began. Baseline assessments indicate that approximately 90% of patients have detectable ctDNA levels prior to surgical or systemic intervention, he said. Notably, the 10% of patients with undetectable baseline ctDNA levels tend to have favorable clinical outcomes regardless of the specific treatment strategy employed, he explained.

Because modern breast cancer treatment involves intensive, multi-phase regimens spanning several months of treatment, the ability to monitor real-time response via ctDNA testing provides a critical window for intervention, according to Mouabbi. Current data suggest that if a patient achieves ctDNA clearance during therapy, their long-term outcomes may match those of patients who achieve a complete pathological response, even if residual cancer cells remain, he noted.

Mouabbi cited the I-SPY trial platform as a foundational example of integrating ctDNA testing into treatment decision-making. Across these trials, in patients with hormone receptor–positive breast cancer, the administration of paclitaxel alone resulted in the clearance of ctDNA shedding in approximately 80% of patients, he reported. This finding raises the clinical question of whether most these patients should continue to receive additional intensive chemotherapy if they have already achieved the molecular markers associated with excellent long-term survival, he contextualized. In contrast, the approximately 20% of patients who maintain ctDNA shedding after initial therapy represent a cohort that definitively benefits from escalated chemotherapy prior to surgery to eliminate shedding, he stated. A similar distribution was observed in triple-negative breast cancer, where approximately 50% of patients cleared ctDNA levels after receiving half of the prescribed treatment course; the remaining 50% of patients needed further therapeutic escalation, he described.

In the adjuvant setting, ctDNA assays demonstrate extreme prognostic utility for identifying minimal residual disease, Mouabbi added. The positive predictive value of a positive ctDNA test for predicting recurrence is considered nearly absolute, reaching 100% in multiple clinical evaluations, he continued. These tests can identify molecular recurrence years before clinical symptoms or imaging findings emerge, he said. Although a single negative test currently carries a false-negative rate of approximately 6%, the diagnostic accuracy is cumulative, he explained. By employing serial testing, the negative predictive value is enhanced, offering patients greater longitudinal assurance of disease-free status, Mouabbi concluded.