From breast and gastric to beyond: Expanding HER2 detection in solid tumors using quantitative RNA and protein analysis

BackgroundAdvances in HER2-targeted therapies show potential for treating various solid tumors, but identifying HER2-positive patients across tumor types is challenging. Methods like immunohistochemistry (IHC) and in situ hybridization (ISH) are validated in breast and gastric cancers but become impractical in a pan-tumor setting due to low HER2 positivity rates, requiring extensive patient screening. Additionally, high observer disagreement in HER2 IHC and the need for tumor-specific scoring systems further complicate the IHC approach in this context. There is a crucial need for efficient and accurate methods to identify HER2-positive patients across solid tumors.MethodsPatients in this study were part of the pan-tumor trial, COPPO. HER2-RNA and protein levels were quantified across 46 tumor types using RNA-seq in 1330 patients and a mass spectrometer in 1298 patients; 882 patients had both RNA and protein data. HER2 status was determined in 229 breast/gastric cancer patients using HER2 IHC and FISH. A HER2-RNA and protein cutoff based on HER2 positivity was identified in breast/gastric samples and then applied to non-breast/gastric pan-tumor patients. ERBB2 amplifications and mutations were assessed using SNP array and whole-exome sequencing. ANOVA, Pearson's correlation, and ROC analysis were used to evaluate associations and cutoff performance.ResultsHER2 RNA and protein levels showed significant associations with IHC and FISH breast/gastric cancers, with AUCs of 0.84 and 0.83, respectively. In non-breast/gastric pan-tumor patients, 6.2% (65/1047) and 9.7% (89/918) tested positive for HER2 via RNA and protein cut-offs, respectively. A significant correlation (0.66, 95% CI 0.61-0.70, p < 2.2e-16) was observed, yet only 25% tested positive for both. In the HER2-RNA positive group, 13% had ERBB2 mutations and 36% had amplifications; in the protein-positive group, 3.7% had mutations and 44% had amplifications.ConclusionsThis study highlights the utility of HER2 RNA and protein quantification in identifying HER2-positive patients across various tumors. The findings encourage consideration for adoption of these biomarkers in trials aimed to identify and select patients for HER2-targeted treatments.Clinical trial identificationNCT0229052.Legal entity responsible for the studyK. Egebjerg.FundingThe study was supported by Harboefonden, Independent Research Fund, the Dannish Cancer society, and the Capital Region of Denmark. IHC and FISH was conducted by Agilent Technologies.DisclosureK. Egebjerg: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Astellas Pharma; Financial Interests, Institutional, Other, Travel: AstraZeneca, Daiichi Sankyo. All other authors have declared no conflicts of interest.