Spatial/molecular heterogeneity and treatment response in HER2+ early breast cancer: Translational analyses from the DAPHNe trial
- 1Dana-Farber Cancer Institute
Abstract
Given the heterogeneity of HER2-positive breast cancer, reliable biomarkers to guide treatment are needed. We conducted multi-platform biomarker analyses of baseline tumor tissue from the DAPHNe trial of neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) for HER2-positive early breast cancer to characterize inter- and intra-tumor heterogeneity and to identify molecular predictors of response. A total of 98 patients with stage II-III HER2-positive breast cancer received neoadjuvant THP followed by surgery. Gene expression profiling, spatial protein profiling, and single-cell imaging (cyclic immunofluorescence) were performed on pre-treatment biopsies and a subset of residual disease specimens. Pathologic response was assessed using the residual cancer burden (RCB) score. Among HER2-positive patients included in the biomarker analysis, 34% of patients had node-positive breast cancer, and 66% had hormone receptor (HR)-positive tumors. HR-positive and HR-negative tumors differed significantly across gene expression, protein expression, and single-cell profiling. High ERBB2 gene signature, p53 gene signature, and HER2 protein expression predicted favorable response (RCB 0/1), while ESR1/PGR gene, estrogen receptor (ER) signaling gene signature, and ER alpha protein expression were associated with unfavorable response (RCB 2/3). Single-cell spatial analysis revealed that cancer cells clustered by shared HER2, ER, and PR expression, suggesting local expansion of phenotypically distinct subpopulations. ER-positive cancer cells were associated with lower HLA-A and PD-L1 expression, suggesting a less immunologically active tumor cell state. Baseline HER2 and ER expression are key predictors of response to neoadjuvant HER2-targeted therapy. Single-cell spatial profiling highlights intra-tumoral heterogeneity and suggests ER-driven immune exclusion as a potential mechanism of resistance.
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BibTeX
@misc{chen2026spatialmolecular,
title = {{Spatial/molecular heterogeneity and treatment response in HER2+ early breast cancer: Translational analyses from the DAPHNe trial}},
author = {E. Chen and I. Schlam and K. Shimada and T. Li and E. R. Ogayo and A. Patel and J. Davis and J.-R. Lin and A. Schultz and M. G. Townsend and K. F. Zheng and C. W. Wanderley and R. Pastorello and F. New and E. Metzger and N. Sinclair and L. M. Spring and M. Faggen and M. Constantine and N. Desai and N. Tung and N. Tayob and I. E. Krop and S. M. Tolaney and E. P. Winer and J. L. Guerriero and E. A. Mittendorf and A. G. Waks},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752407},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752407v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Spatial/molecular heterogeneity and treatment response in HER2+ early breast cancer: Translational analyses from the DAPHNe trial
AU - E. Chen
AU - I. Schlam
AU - K. Shimada
AU - T. Li
AU - E. R. Ogayo
AU - A. Patel
AU - J. Davis
AU - J.-R. Lin
AU - A. Schultz
AU - M. G. Townsend
AU - K. F. Zheng
AU - C. W. Wanderley
AU - R. Pastorello
AU - F. New
AU - E. Metzger
AU - N. Sinclair
AU - L. M. Spring
AU - M. Faggen
AU - M. Constantine
AU - N. Desai
AU - N. Tung
AU - N. Tayob
AU - I. E. Krop
AU - S. M. Tolaney
AU - E. P. Winer
AU - J. L. Guerriero
AU - E. A. Mittendorf
AU - A. G. Waks
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752407
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752407v1
AB - Given the heterogeneity of HER2-positive breast cancer, reliable biomarkers to guide treatment are needed. We conducted multi-platform biomarker analyses of baseline tumor tissue from the DAPHNe trial of neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) for HER2-positive early breast cancer to characterize inter- and intra-tumor heterogeneity and to identify molecular predictors of response. A total of 98 patients with stage II-III HER2-positive breast cancer received neoadjuvant THP followed by surgery. Gene expression profiling, spatial protein profiling, and single-cell imaging (cyclic immunofluorescence) were performed on pre-treatment biopsies and a subset of residual disease specimens. Pathologic response was assessed using the residual cancer burden (RCB) score. Among HER2-positive patients included in the biomarker analysis, 34% of patients had node-positive breast cancer, and 66% had hormone receptor (HR)-positive tumors. HR-positive and HR-negative tumors differed significantly across gene expression, protein expression, and single-cell profiling. High ERBB2 gene signature, p53 gene signature, and HER2 protein expression predicted favorable response (RCB 0/1), while ESR1/PGR gene, estrogen receptor (ER) signaling gene signature, and ER alpha protein expression were associated with unfavorable response (RCB 2/3). Single-cell spatial analysis revealed that cancer cells clustered by shared HER2, ER, and PR expression, suggesting local expansion of phenotypically distinct subpopulations. ER-positive cancer cells were associated with lower HLA-A and PD-L1 expression, suggesting a less immunologically active tumor cell state. Baseline HER2 and ER expression are key predictors of response to neoadjuvant HER2-targeted therapy. Single-cell spatial profiling highlights intra-tumoral heterogeneity and suggests ER-driven immune exclusion as a potential mechanism of resistance.
ER -