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

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).

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.

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.

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.