Evaluation of a Tumor-Informed Molecular Residual Disease Assay in Early Triple-Negative Breast Cancer Treated With Neoadjuvant Chemotherapy, With or Without Atezolizumab.

Abstract

Detection of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) is strongly associated with recurrence risk in early triple-negative breast cancer (TNBC). Prior studies suggest that ctDNA clearance during neoadjuvant therapy (NAT) may predict pathologic complete response (pCR) and enhance the prognostic value of pCR. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-59/German Breast Group-96-GeparDouze evaluated atezolizumab added to NAT and as adjuvant therapy in 1,550 patients with stage II/III TNBC. For prospective ctDNA substudy on serial blood samples, we used whole-exome sequencing of primary tumors to generate patient-specific tumor-informed assays to correlate ctDNA status with distant recurrence and clinical outcomes. This substudy included NSABP B-59 patients with serial blood collections before NAT (baseline), after NAT before surgery, 3-6 weeks postsurgery, and 12 and 24 months after random assignment. The primary objective was to evaluate the association between ctDNA status postsurgery with distant recurrence-free interval, defined from the date of surgery to first distant metastasis or death from breast cancer. The median follow-up for the primary end point was 37 months. At baseline, ctDNA was detected in 153 of 160 patients (96%). Among 147 patients with ctDNA assessment postsurgery, ctDNA was detected in nine (6%). Distant recurrence occurred in seven of nine (77.8%) patients with ctDNA-positive status postsurgery, compared with seven of 138 (5%) with ctDNA-negative status postsurgery (log-rank <i>P</i> < 1E-16; hazard ratio, 30.3 [95% CI, 10.4 to 88.7]). Among patients with residual invasive disease after NAT and surgery, five of 42 (11.9%) with negative ctDNA status developed distant recurrence versus six of seven (85.7%) in those with positive ctDNA status. The tumor-informed MRD assay demonstrated high baseline ctDNA prevalence, marked clearance with NAT, and strong prognostic utility of post-NAT and postsurgery ctDNA-positive status for distant recurrence in early TNBC.