Clinical and Genomic Features of <i>HER2</i> Exon 20 Insertion Mutations and Characterization of <i>HER2</i> Expression by Immunohistochemistry in East Asian Non-Small-Cell Lung Cancer.

Abstract

<i>HER2</i>-altered non-small-cell lung cancer (NSCLC) represents a diverse subgroup, including mutations, amplifications, and overexpression. However, <i>HER2</i> exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of <i>HER2</i>-altered NSCLC in an Asian tertiary cancer center. We identified patients with <i>HER2</i>-mutated NSCLC in our institutional database, collating clinicopathological features and treatment outcomes. The genomic landscape of human epidermal growth factor receptor 2 (<i>HER2</i>)-mutated NSCLC was further evaluated using whole-exome sequencing (WES) data from combined local and publicly available data sets. <i>HER2</i> amplification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data. Among 1,252 patients with consecutive lung adenocarcinoma undergoing routine next-generation sequencing, the prevalence of <i>HER2</i> mutations was 3.1%-exon 20 insertion mutations comprised 2.7%. We examined the clinicopathological features in 55 patients with <i>HER2</i>-mutated NSCLC comprising 40 exon 20 insertion and 15 nonexon 20 insertion mutations. The most common exon 20 insertion mutation was <i>HER2</i>^Y772_A775dup in 30 (75%), followed by <i>HER2</i>^G776delinsVC in five patients (13%). There were limited responses to HER2-directed therapies apart from trastuzumab-deruxtecan, and no responses were seen with immunotherapy monotherapy. Evaluating the genomics features of <i>HER2</i> exon 20 insertion mutations using WES data revealed low tumor mutational burden (TMB), low incidence of cancer driver comutations, and a predominance of aging mutational signature-similar to <i>EGFR</i>-mutated tumors. In contrast, uncommon (or nonexon 20 insertion) <i>HER2</i>-mutated tumors resembled <i>EGFR</i> wild-type tumors with higher TMB, higher frequency of cancer driver comutations, and greater presence of smoking and APOBEC mutational signature. Finally, in evaluating HER2 immunohistochemistry in all lung adenocarcinoma, there was significant discordance comparing different scoring systems and poor correlation with <i>HER2</i> RNA expression and <i>HER2</i> amplification. The incidence of <i>HER2</i> mutations is 3.1% in East Asian nonsquamous NSCLC. <i>HER2</i> exon 20 insertion-mutated tumors appear genomically distinct from uncommon (nonexon 20 insertion) <i>HER2</i> mutations, the latter demonstrating higher TMB, co-occurring drivers, and predominant nonaging mutational signature. The therapeutic implications of the genomic and clinical features of <i>HER2</i>-mutated NSCLC warrant further investigation.