Beyond ERBB2 amplification: RNA and proteomic HER2 assessment for pan-tumor treatment stratification
- 1Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Abstract
HER2-directed therapies are expanding across solid tumors, but ERBB2 amplification incompletely captures HER2 expression and pan-tumor IHC lacks standardization. We developed ERBB2 mRNA, bulk HER2 protein and RNA-signature screening benchmarked against IHC/FISH. Screening identified HER2-enriched populations beyond amplification in a pan-tumor discovery cohort of 1,331 tumor biopsies and validated RNA-based screening in an external cohort of 3,898 tumor biopsies. All six objective responses among 51 treated patients in the discovery cohort occurred in tumors positive by ERBB2 mRNA and the combined RNA-signature. In the external dataset (n=102), ERBB2 mRNA positivity was associated with longer time on treatment (hazard ratio 0.42, 95% confidence interval 0.27-0.64) and overall survival (0.41, 0.25-0.65), with concordant associations for the combined RNA signature. Spatial proteomics comprising 2,721 tiles across 88 samples captured HER2 heterogeneity and identified HER2-enriched profiles below bulk thresholds. These findings support prospective evaluation of RNA and proteomic screening for treatment selection.
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BibTeX
@misc{egebjerg2026beyond,
title = {{Beyond ERBB2 amplification: RNA and proteomic HER2 assessment for pan-tumor treatment stratification}},
author = {K. Egebjerg and K. S. Rohrberg and F. O. Bagger and A.-V. Laenkholm and M.-L. M. Talman and A. B. Nielsen and J. Wang and E. Chelebian and M. T. Strauss and A. Mund and X. Zheng and R. S. Garbyal and M. K. Nedergaard and B. H. Conlon and L. Robinson and T. Kringelbach and M. Hoejgaard and A. Y. Schmidt and M. F. Larsen and D. Alosi and A. R. Kodahl and R. L. Eefsen and M. Ladekarl and L. Soendergaard and L. H. Jensen and U. N. Lassen and M. Mau-Soerensen},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.11.26365242},
url = {https://www.medrxiv.org/content/10.64898/2026.10.11.26365242v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Beyond ERBB2 amplification: RNA and proteomic HER2 assessment for pan-tumor treatment stratification
AU - K. Egebjerg
AU - K. S. Rohrberg
AU - F. O. Bagger
AU - A.-V. Laenkholm
AU - M.-L. M. Talman
AU - A. B. Nielsen
AU - J. Wang
AU - E. Chelebian
AU - M. T. Strauss
AU - A. Mund
AU - X. Zheng
AU - R. S. Garbyal
AU - M. K. Nedergaard
AU - B. H. Conlon
AU - L. Robinson
AU - T. Kringelbach
AU - M. Hoejgaard
AU - A. Y. Schmidt
AU - M. F. Larsen
AU - D. Alosi
AU - A. R. Kodahl
AU - R. L. Eefsen
AU - M. Ladekarl
AU - L. Soendergaard
AU - L. H. Jensen
AU - U. N. Lassen
AU - M. Mau-Soerensen
PY - 2026
DA - 2026/10/11
PB - medRxiv
DO - 10.64898/2026.10.11.26365242
UR - https://www.medrxiv.org/content/10.64898/2026.10.11.26365242v1
AB - HER2-directed therapies are expanding across solid tumors, but ERBB2 amplification incompletely captures HER2 expression and pan-tumor IHC lacks standardization. We developed ERBB2 mRNA, bulk HER2 protein and RNA-signature screening benchmarked against IHC/FISH. Screening identified HER2-enriched populations beyond amplification in a pan-tumor discovery cohort of 1,331 tumor biopsies and validated RNA-based screening in an external cohort of 3,898 tumor biopsies. All six objective responses among 51 treated patients in the discovery cohort occurred in tumors positive by ERBB2 mRNA and the combined RNA-signature. In the external dataset (n=102), ERBB2 mRNA positivity was associated with longer time on treatment (hazard ratio 0.42, 95% confidence interval 0.27-0.64) and overall survival (0.41, 0.25-0.65), with concordant associations for the combined RNA signature. Spatial proteomics comprising 2,721 tiles across 88 samples captured HER2 heterogeneity and identified HER2-enriched profiles below bulk thresholds. These findings support prospective evaluation of RNA and proteomic screening for treatment selection.
ER -