Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer

Purpose: Exceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC. Patients and Methods: We identified exceptional (real-world progression-free survival [rwPFS] [&ge;]3 years) and conventional (rwPFS <3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS. Results: Of 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx <100 ppm. MRD was associated with outcomes: 0/27 [0%] exceptional versus 9/12 [75%] conventional responders (p<0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative. Conclusions: MRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.