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Preprint WatchModerateSeptember 19th, 2026

Spatial/molecular heterogeneity and treatment response in HER2+ early breast cancer: Translational analyses from the DAPHNe trial

Chen, E.; Schlam, I.; Shimada, K.; Li, T.; Ogayo, E. R.; Patel, A.; Davis, J.; Lin, J.-R.; Schultz, A.; Townsend, M. G.; Zheng, K. F.; Wanderley, C. W.; Pastorello, R.; New, F.; Metzger, E.; Sinclair, N.; Spring, L. M.; Faggen, M.; Constantine, M.; Desai, N.; Tung, N.; Tayob, N.; Krop, I. E.; Tolaney, S. M.; Winer, E. P.; Guerriero, J. L.; Mittendorf, E. A.; Waks, A. G.

In translational analyses of the DAPHNe trial, a high ERBB2 gene signature and HER2 protein expression predicted favorable pathologic response to neoadjuvant paclitaxel, trastuzumab and pertuzumab, while estrogen receptor signaling signatures predicted unfavorable response.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The claim is that ERBB2 dependence, measured as signature strength rather than as binary receptor positivity, separates responders from non-responders to HER2-directed therapy in early breast cancer. That is directly relevant to the two ERBB2 failures on file. Poziotinib in HER2 exon 20 insertion non-small cell lung carcinoma (poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch) is recorded as a translational mismatch, and XMT-2056 in HER2-expressing advanced solid tumors (xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation) was discontinued for strategic reasons after a safety hold. If quantitative ERBB2 dependence predicts benefit within a population already selected as HER2-positive, then trials that enroll on expression alone are diluting their own effect size, which is the failure shape poziotinib showed. The finding is retrospective, single-trial, and derived from 98 patients, so it is hypothesis-generating rather than a selection rule.

Abstract excerpt

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.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.