Molecular and clinicopathological characteristics of ERBB2 gene fusions in 32,131 Chinese patients with solid tumors

Abstract

<i>ERBB2</i> amplification is one of the most important and mature targets for HER2-targeted drug therapy. Somatic mutations of <i>ERBB2</i> in the tyrosine kinase domain have been studied extensively, and play a role in response to anti-HER2 therapy among different cancer types. However, <i>ERBB2</i> fusion has not been got attention and its relevance to HER2-targeted therapy is unclear. We comprehensively characterized <i>ERBB2</i> fusions from next-generation sequencing (NGS) data between May 2018 and October 2021 in 32,131 various solid tumors. Among the tumors, 0.28% harbored <i>ERBB2</i> fusions, which occurred more commonly in gastroesophageal junction cancer (3.12%; 3/96), breast cancer (1.89%; 8/422), urothelial carcinoma (1.72%; 1/58), and gastric cancer (1.60%; 23/1,437). Our population presented with a median age of 65 years (range 28 to 88 years), a high proportion of men (55 men vs 34 women; 61.80%). Among the patients with <i>ERBB2</i> fusions, <i>TP53</i> (82%), <i>APC</i> (18%), and <i>CDK4</i> (15%) were the top3 co-mutant genes. What's more, most patients with <i>ERBB2</i> fusion also had <i>ERBB2</i> amplification (75.28%; 67/89), which was similar to the data in the TCGA database (88.00%; 44/50). Furthermore, TCGA database shows that patients with <i>ERBB2</i> fusions in pan-cancer had a worse prognosis than those without <i>ERBB2</i> fusions, as well as in breast cancer. Besides, <i>ERBB2</i> amplification combined with <i>ERBB2</i> fusion had worse prognosis than those with only <i>ERBB2</i> amplification. <i>ERBB2</i> fusion may interfere the effect of anti-HER2-targeted antibody drugs and influence the prognosis of patients with <i>ERBB2</i> amplification. Prospective clinical trials are warranted to confirm the results in the future.