Patterns of HER2 expression and genomic correlates in lung cancer, with a focus on preanalytical variables impacting immunohistochemical staining results

Aims Fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved for advanced stage or metastatic solid tumours with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) 3+ staining. Data on HER2 IHC testing and knowledge of genomic correlates in lung cancer are scarce. This study analyses genomic characteristics of HER2-expressing tumours and addresses issues with preanalytical variables for lung cancer specimens. Methods HER2 IHC staining was performed on selected archival cytology and surgical pathology lung cancer specimens for patients eligible for T-DXd therapy. Patient and tumour characteristics and next-generation sequencing (NGS) data were correlated with HER2 IHC results. Results 166 patients with thoracic tumour samples had HER2 expression assessed: 46% were IHC 0, 28% IHC 1+, 13% IHC 2+ and 13% IHC 3+. HER2 IHC scores were overall lower for cytology cell blocks as compared with surgical pathology specimens; 79% of cases with paired specimens had a decrease in their HER2 IHC score from their surgical specimen to their paired cytology specimen. Of specimens with HER2 IHC 3+ and NGS available, only 14% (3/21) had concomitant ERBB2 alterations. Among all specimens, ERBB2 point mutations were noted in 4% (4/110) and ERBB2 amplification in 3% (3/110). The majority of HER2 3+ cases with paired NGS (17/21, 81%) had non- ERBB2 genomic alterations, including: KRAS , TP53, and STK11 mutations. Conclusions HER2 IHC 3+ is seen in a small but clinically significant proportion of samples and is associated with a variety of co-occurring non-ERBB2 genomic alterations. Preanalytical variables including specimen fixation can significantly impact the assessment of HER2 expression via immunohistochemistry.