NeoCircle: pre- and post-operative circulating tumor DNA dynamics predicts survival in neoadjuvant-treated early breast cancer

Persistent circulating tumor DNA (ctDNA) during neoadjuvant treatment (NAT) of early breast cancer (EBC) indicates high-risk disease. Similarly, detection of ctDNA post-resection indicates molecular residual disease (MRD) and impending relapse. For ctDNA to be integrated into EBC management, accessible and scalable diagnostics are required. Here we apply an ultrasensitive, personalized tumor-informed approach to ctDNA evaluation predicated on analyses of structural variants (SVs) using a novel digital PCR (dPCR) multiplex SV technology. 136 patients eligible for NAT (29.4% TNBC, 44.9% HR+ /HER2- and 24.3% HER2+), enrolled between December 2014 and March 2019, were analyzed from the prospective SCAN-B study (NCT02306096, substudy NeoCircle). ctDNA detection at baseline was 89.7%; end-NAT ctDNA-positivity (21.4%) and NAT ctDNA-non-response (13.1%) were significant predictors of disease recurrence and death, and both superior to pathologic complete response. Detection of ctDNA post-operatively or during adjuvant monitoring was significantly associated with distant recurrence (median lead-time 13.8 months, range 0-47.7 months). These findings validate SVs as an MRD analyte and provide evidence for clinical use of this approach in EBC.