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Preprint WatchModerateOctober 14th, 2026

Beyond ERBB2 amplification: RNA and proteomic HER2 assessment for pan-tumor treatment stratification

Egebjerg, K.; Rohrberg, K. S.; Bagger, F. O.; Laenkholm, A.-V.; Talman, M.-L. M.; Nielsen, A. B.; Wang, J.; Chelebian, E.; Strauss, M. T.; Mund, A.; Zheng, X.; Garbyal, R. S.; Nedergaard, M. K.; Conlon, B. H.; Robinson, L.; Kringelbach, T.; Hoejgaard, M.; Schmidt, A. Y.; Larsen, M. F.; Alosi, D.; Kodahl, A. R.; Eefsen, R. L.; Ladekarl, M.; Soendergaard, L.; Jensen, L. H.; Lassen, U. N.; Mau-Soerensen, M.

ERBB2 amplification incompletely captures HER2 expression, and RNA plus proteomic screening identifies HER2-enriched populations beyond amplification for pan-tumour treatment stratification.

Moderate contradiction

2 prior failures

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

This preprint claims that amplification-based HER2 testing misses treatable populations and proposes RNA and proteomic screening in its place. Claidex holds two ERBB2 failures that make patient selection the live variable. In poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch a precisely genotyped population still produced a translational mismatch between target engagement and clinical benefit, and xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation ended a HER2-directed payload approach before the selection question was settled. Widening the selected population without first establishing that the wider population responds risks repeating the poziotinib pattern at larger scale, so the proposal needs a response-linked validation rather than a prevalence-linked one.

Abstract excerpt

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 hetero-geneity and identified HER2-enriched profiles below bulk thresholds. These findings support prospective evaluation of RNA and proteomic screening for treatment selection.

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.