Dynamic ctDNA tracking stratifies individual relapse risk for early triple negative breast cancer patients receiving neoadjuvant chemotherapy

Background Early Triple negative breast cancer (eTNBC) is the breast cancer subtype with the least favorable outcome. Tools to identify their individual relapse risk are in great need. Circulating tumor DNA (ctDNA) analysis is shown to predict the prognosis in breast cancer, but its utility in eTNBC remains unclear. Patients and methods In this prospective study, 130 eTNBC patients receiving neoadjuvant chemotherapy (NAC) were successfully enrolled. Their blood samples were taken at the baseline, post-NAC, post-surgery and during follow-up, and were subjected to tumor-guided ctDNA analysis. Results ctDNA positivity at post-NAC and post-surgery, but not at baseline, was associated with significantly worse prognosis. A threshold of 1.1% maximum variant allele frequency (MVAF) at baseline better stratified eTNBC patients with different relapse risk, which was validated both internally and externally. A systemic tumor burden model integrating baseline and post-surgery ctDNA was highly prognostic and independent of clinical characteristics. Combining systemic tumor burden with pathologic response identified a highly curable subgroup and a subgroup of high-risk eTNBC patients that need more effective adjuvant treatments. ctDNA surveillance during follow-up showed that the patients with negative ctDNA had 100% distant recurrence free survival (DRFS), but the ones with positive ctDNA had high relapse rate with relatively short lead time. Conclusions This systemic ctDNA analysis from baseline to follow-up demonstrates the utility of baseline ctDNA with a threshold and a systemic tumor burden model in risk stratification of eTNBC patients, which may guide future treatment escalation or de-escalation trials.