Long-term prognostic value of ctDNA in early breast cancer: insights from the neoadjuvant ABCSG-34 Trial.

Circulating tumor DNA (ctDNA) is a promising biomarker in early breast cancer for assessing treatment response, minimal residual disease (MRD), and recurrence risk. In the ABCSG-34 phase II trial, we previously reported that persistent ctDNA during neoadjuvant therapy (NAT) was associated with higher residual cancer burden and lower rates of pathological complete response. Here, we present long-term follow-up data evaluating the prognostic relevance of ctDNA dynamics. ABCSG-34 randomized 400 patients to chemotherapy or endocrine therapy, with or without the MUC1 vaccine tecemotide. Tumor-informed SiMSen-Seq assays were used to assess ctDNA at baseline, mid-therapy, and end-of-therapy. Of 145 patients with ctDNA data, 109 had long-term follow-up (median: 7.1 years). Baseline ctDNA positivity was significantly associated with inferior overall survival (HR 2.12, p = 0.043) and shorter survival durations across all endpoints. Trends toward improved outcomes were observed in patients who cleared ctDNA during NAT, though statistical significance was not reached-likely due to limited sample size. These findings support baseline ctDNA as a prognostic marker in early breast cancer. While ctDNA clearance may reflect treatment efficacy, further validation in larger trials is needed. Ongoing studies will determine the role of ctDNA in guiding therapy and monitoring MRD.