Tracking response to neoadjuvant systemic therapy through circulating tumor DNA analysis in breast cancer

Neoadjuvant systemic therapy (NST) is a standard treatment approach for patients with early-stage breast cancer, particularly those with stage II-III disease and aggressive subtypes such as HER2-positive and triple-negative breast cancer. While NST improves surgical outcomes and provides prognostic information, accurately assessing preoperative treatment response remains a clinical challenge. Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker for monitoring disease dynamics and guiding therapeutic decisions. In this study, we aimed to evaluate whether ctDNA analysis in patients with stage II-III breast cancer (n = 20) could serve as a surrogate for invasive biopsies in molecular profiling and as a tool for monitoring response to NST. At baseline, ctDNA was detectable in the majority of patients by droplet digital (dd)PCR (15/18, 83%) and all patients with longitudinal follow-up had ctDNA clearance after NST (13/13; 100%). A positive correlation was observed between the allele fraction in ctDNA, histologic grade and molecular subtype, suggesting that ctDNA levels may be influenced by tumor biology. None of the three patients with undetectable baseline ctDNA had distant relapse, regardless of whether they achieved pathologic complete response (pCR), compared to 5/15 (33%) with detectable baseline ctDNA. These findings suggest that ctDNA assessment at baseline may provide additional prognostic information to define the risk of patients after NST. While ctDNA shows promise in capturing tumor burden and biological characteristics, its role in predicting pCR and long-term outcomes requires further investigation.