What question did this study set out to answer?

This research aims to assess the frequency of ERBB2 alterations and their prognostic significance across different cancer types.

June 18, 2026Open Access

ERBB2/HER2 landscape and prognostic impact: large-scale, real-world analysis across solid cancers

Key Points

This research aims to assess the frequency of ERBB2 alterations and their prognostic significance across different cancer types.
Analyzed 206,750 tumors for ERBB2 alterations and 88,530 samples for HER2 immunohistochemistry.
Utilized next-generation sequencing for genomic profiling and evaluated overall survival based on real-world insurance claims.
Stratified HER2 IHC data into categories (0, 1+, 2+, or 3+) to correlate with ERBB2 mutations.
ERBB2 amplifications and mutations were identified in various cancer types, often correlating with HER2 IHC positivity.
Median overall survival was significantly higher for HER2 3+ tumors at 30.6 months (HR 0.80, 95% CI 0.77-0.83, P < 0.001).
Survival benefits were particularly evident in breast and gastric cancers that can be treated with HER2-targeted therapies.

Abstract

BACKGROUND: We evaluated the frequency and prognostic impact of human epidermal growth factor receptor 2 (HER2) protein expression immunohistochemistry (IHC) and correlations with ERBB2 genomic alterations in a large database of molecularly profiled real-world patients (Caris Life Sciences, Phoenix, AZ). MATERIALS AND METHODS: We analyzed 206 750 tumors for ERBB2 copy number alterations and pathogenic mutations (using next-generation sequencing) and 88 530 samples for HER2 IHC data (stratified as 0, 1+, 2+, or 3+). RNA (whole transcriptome) was also evaluated. Overall survival (OS) was based on real-world insurance claims. RESULTS: ERBB2 amplifications and/or mutations were found in a subset of multiple cancer types. ERBB2 amplifications were often but not always associated with higher HER2 IHC expression. ERBB2 pathogenic mutations and ERBB2 amplifications correlated significantly across cancers and in some cancer subtypes. Statistically significant associations with HER2 IHC positivity were also identified in a subgroup of tumors exhibiting mutations, even without amplifications. ERBB2 transcripts were markedly increased among HER2 IHC 3+ tumors. Median OS for HER2 (3+, 2+, 1+, and 0+) tumors were 30.6, 26.9, 26.5, and 23 months, respectively hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.77-0.83; HR 0.89, 95% CI 0.87-0.91; and HR 0.90, 95% CI 0.88-0.92, respectively (P < 0.001). However, survival advantages observed in the overall cohort appeared largely driven by breast and gastric cancers for which HER2-targeted therapies are available. CONCLUSION: Complex relationships between ERBB2 alterations and HER2 IHC expression exist, including increased expression in non-ERBB2-amplified tumors with pathogenic mutations. Importantly, ERBB2/HER2 amplification and/or mutation rates as well as transcript and protein expression varied between cancers and within cancer types, emphasizing the need for individual assessment.

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