Abstract Background: ctDNA dynamics are emerging as a promising biomarker for predicting treatment response. In the I-SPY2 trial, early clearance of ctDNA during neoadjuvant therapy (NAT) has been shown to predict treatment response across receptor subtypes (Magbanua et al., Cancer Cell, 2023). Separately, transcriptional profiling of pretreatment tumors has enabled the classification of breast cancers into Response Predictive Subtypes (RPS), incorporating immune, DNA repair deficiency (DRD), and Luminal expression biomarkers in addition to HR and HER2, which, if used to allocate treatment decisions, are predicted to improve response and outcome (Wolf et al., Cancer Cell, 2022). However, ctDNA dynamics in RPS and its association with treatment response have yet to be explored. Methods: The study involved 719 patients (pts) with high-risk early-stage breast cancer who received NAT in I-SPY2. ctDNA levels were measured in blood collected at baseline and on-treatment at weeks (wk) 3 and 12 (post-paclitaxel before anthracycline) using a personalized tumor-informed 16-plex PCR-NGS assay (Signatera, Natera, Inc.). RPS were grouped into treatment-sensitive, i.e., those with high pathological complete response (pCR) rates HER2-Immune+ (n=207, 29%), HER2-Immune-DRD+ (n=80, 11%), and HER2+Non-luminal (n=131, 18.%) when treated with the best matched therapeutic option (e.g., immunotherapy for HER2-Immune+) vs. treatment-resistant, i.e., those that have shown low pCR rates to nearly every class of agent/combination tested in I-SPY2 to date HR+HER2-Immune-DRD- (n=211, 29%), HR-HER2-Immune-DRD- (n=35, 5%), and HER2+Luminal (n=55, 8%). We evaluated the association between ctDNA dynamics and treatment response as measured by residual cancer burden (RCB) after NAT. ctDNA dynamics were defined as persistently ctDNA-negative, clearance at wk 3 (early clearance) or wk 12 (clearance), or no clearance at wk 12. Results: Baseline ctDNA positivity rates varied significantly across RPS Fisher’s exact (FE) p0.001, ranging from 56% (HER2+Luminal) to 95% (HER2-Immune-DRD+). There were significant differences in the median ctDNA concentration across RPS Kruskal-Wallis (KW) p0.001, with the lowest and highest median values observed in the HER2+Luminal and HER2-Immune-DRD+ groups, respectively. The proportion of pts who cleared ctDNA early varied significantly across subtypes (FE p0.001), ranging from 21% (HR-HER2-Immune-DRD-) to 67% (HER2+Non-luminal). In the treatment-sensitive RPS, we observed a strong association between early ctDNA clearance and treatment response. In the HER2-Immune+ subtype, early ctDNA clearance was associated with significantly higher proportions of pts who eventually had no (RCB-0/pCR) or limited (RCB-I) residual cancer (86% vs. late clearance=57%, no clearance=32%, FE p0.001). Early ctDNA clearance significantly improved the odds of achieving an RCB-0/RCB-I (OR=12.6, 95% CI 5.2-33.4). In addition, early clearance also markedly shifted the distributions toward lower RCB scores, with pts who cleared ctDNA early showing significantly lower median RCB scores compared to those who remained ctDNA-positive (KW p0.001). Similar results were observed in other treatment-sensitive RPS (HER2-Immune-DRD+ and HER2+NonLuminal). These significant associations between ctDNA dynamics and treatment response were not observed in the treatment-resistant subtypes. Conclusions: Early ctDNA clearance is a strong predictor of favorable response in treatment-sensitive RPS. ctDNA monitoring and classifying tumors by RPS are being tested as part of an algorithm for treatment decisions in the neoadjuvant setting. These results offer insights into the potential contributions of RPS and ctDNA to imaging in optimizing therapy in the I-SPY2 trial. Citation Format: M. Magbanua, D. Wolf, N. Manon, R. Sayaman, L. Brown Swigart, G. Hirst, C. Yau, W. Li, C. Isaacs, R. Shatsky, A. Clark, A. Zimmer, A. Delson, J. Perlmutter, M. Liu, P. Pohlmann, N. Hylton, R. Nanda, D. Yee, W. Symmans, L. Esserman, H. Rugo, A. DeMichele, L. van 't Veer. Ctdna dynamics is most predictive of response in treatment-sensitive response-predictive subtypes of breast cancer: results from the I-SPY2 trial 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 PD6-07.
Magbanua et al. (Tue,) studied this question.