Abstract PS5-11: Ultrasensitive ctDNA Tracking Predicts Exceptional Response in HER2+ Metastatic Breast Cancer

Abstract Background: HER2 targeted therapy (tx) has transformed the trajectory of HER2+ metastatic breast cancer (MBC), with a subgroup of pts remaining on first line (1L) tx for many years (yrs). Detection of minimal residual disease (MRD) via ctDNA to guide tx is promising but data supporting its use in HER2+ MBC are virtually absent. Methods: We identified 70 pts with HER2+ MBC treated with 1L HER2 targeted tx consented to the EMBRACE cohort study with archival tissue, buffy coat and plasma at ≥1 key timepoints while on 1L tx (baseline, first-on-tx, year Y 1 landmark L, Y2L, Y3L), or at time of disease progression (PD). We employed MAESTRO, an ultrasensitive whole-genome, tumor-informed, mutation enrichment sequencing assay, in a pooled testing format (MAESTRO-Pool). Exceptional responders were pts without PD or death for ≥3 yrs from 1L start (real-world progression-free survival rwPFS ≥3 yrs). Conventional responders were pts with PD or death within 3 yrs of 1L start (rwPFS3 yrs). Local- or brain-only PD that did not lead to tx switch were not considered events. The primary objective was the association between Y1L MRD status (plasma samples collected 1 yr from 1L start +/- 3 months) and exceptional response. Sixty-three pts (90%) (39 exceptional and 24 conventional responders) had sufficient samples and successful assay design; MAESTRO-Pool was run on 147 samples. Results: More exceptional than conventional responders had de novo MBC (69.2% vs 41.7%, p=0.03). High (3+ by IHC) HER2 expression (87.2% vs 75.0%), estrogen receptor (ER)+ status (38.5% vs 33.3%) and visceral disease (61.5% vs 62.5%) were similar between exceptional and conventional responders. Most pts in both groups had 1L chemotherapy plus trastuzumab/pertuzumab (82.1% vs 70.8%) and maintenance endocrine tx if ER+ (86.7% vs 62.5%). With 284.4 person-yrs of follow up, 6/39 exceptional responders had late PD. In a landmark analysis at Y3, the 2-yr rwPFS was 97.4% (95%CI 82.8%-99.6%) (5 yrs from 1L start); 5-yr overall survival (OS) was 91.5% (95%CI 68.7%-97.9%) (8 yrs from 1L start). For conventional responders, total follow up was 110.5 person-yrs, median rwPFS was 1.65 yrs (95%CI 1.1-2.51), median OS was 4.58 yrs (95%CI 3.78-6.95). A median of 1,370 (range 136-4,635) tumor-specific mutations were tracked per patient. MRD was detected in 50 (34%) samples (median tumor fraction (TFx) 1352.8 ppm; range 4-206,399 ppm), including 21 (42%) samples with TFx 500 ppm, the limit of detection (LOD) of tumor-agnostic MBC assays, and 14 (28%) with TFx 100 ppm, the LOD of 1st generation tumor-informed MRD tests. After excluding baseline and PD samples, MRD was detected in 7 (7.4%) and 28 (80%) samples from exceptional and conventional responders, respectively. All exceptional responders who remained progression-free were always MRD- (n=30) or cleared MRD by Y1L (n=3). Indeed, Y1L MRD status was associated with exceptional vs conventional response (0/26 0% vs 10/13 76.9%, p0.001). Four of the 6 pts who had late PD had a Y3L sample, which was MRD+ in 3 cases (lead time range 2.77-13.47 yrs) and MRD- in one case of breast-only PD. For 20/24 conventional responders, the last sample collected before PD was MRD+. Of the 4 MRD- cases, one pt had 2 primary breast cancers, one had brain-only PD. Conclusions: Here we report, to our knowledge, the first data showing a significant association between MRD detection and duration of response to 1L tx for HER2+ MBC. MRD status at Y1L was highly predictive of exceptional response. Only 2 conventional responders had distant PD without a prior MRD+ sample. All exceptional responders with late distant PD were MRD+ at Y3L. Fourteen (28%) MRD+ samples had TFx100ppm and would have been misclassified by 1st generation MRD tests, supporting the value of ultrasensitive MRD tracking to predict outcomes and its potential to guide tx de-escalation in prospective clinical trials. Citation Format: S. Morganti, C. Song, N. Zhou, K. Santos, P. Jain, L. Walsh, R. Li, J. Rhoades, K. Gilligan, G. Kirkner, C. Stever, A. Patel, M. E. Hughes, N. Priedigkeit, I. E. Krop, G. Curigliano, E. P. Winer, S. M. Tolaney, N. Tayob, H. Heiling, K. Xiong, N. U. Lin, V. A. Adalsteinsson, H. A. Parsons. Ultrasensitive ctDNA Tracking Predicts Exceptional Response in HER2+ Metastatic Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-11.