Detection of circulating tumor DNA using a tissue-free epigenomic assay is a highly prognostic biomarker in early-stage triple negative breast cancer

Abstract Purpose: Clinical tools to monitor treatment response and metastatic risk could improve early-stage triple-negative breast cancer (TNBC) care. While molecular residual disease (MRD) assays show promise, their use in the neoadjuvant setting requires rapid turnaround times. Tissue-informed approaches may be challenging for patients with limited biopsy samples. The objectives were to determine the surveillance sensitivity for detecting metastatic recurrence and evaluate the ctDNA response to neoadjuvant therapy using a tissue-free epigenomic assay. Patients and Methods: Patients with stage II or III TNBC undergoing neoadjuvant docetaxel and carboplatin chemotherapy on a clinical trial (NCT02124902) followed by surgery with or without adjuvant therapy were included in this study. Blood samples were prospectively collected prior to, during, and after completion of neoadjuvant therapy (NAT), and after surgery at pre-specified surveillance time points. Plasma samples were analyzed by Guardant Reveal. Results: A total of 119 TNBC patients were included in the analysis. ctDNA was detected in the post-surgical setting in 8.9% (7/79) of patients, with an 83% (5/6) patient-level surveillance sensitivity for metastatic recurrence and 99.5% (197/198) sample-level specificity. Post-surgical ctDNA detection was prognostic for shorter recurrence-free interval (RFI; HR 37.7, p<0.0001). ctDNA detection at the post-NAT pre-surgical time point was also associated with shorter RFI in patients with residual disease at surgery (HR 28.2, p<0.0001). Conclusions: In early-stage TNBC patients, a tissue-free, epigenomic assay and demonstrated high specificity and sensitivity for metastatic recurrence. ctDNA detection in the neoadjuvant setting indicated poor prognosis, highlighting its potential role across breast cancer care.