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Background  The impact of HER2 somatic mutations in colorectal carcinoma (CRC) has not been well studied and its relationship with microsatellite instability‐high (MSI‐H) is yet to be fully elucidated.    Materials and Methods  From February 2017 to February 2020, the data of patients with CRC who underwent next‐generation sequencing and had detailed record of clinicopathological information were investigated. HER2 alteration and its relationship with MSI‐H were analyzed.    Results  Among 731 patients who underwent sequencing, 55 patients (7.5%) had HER2 alteration, including 29 (4.0%) with HER2 somatic mutations, 24 (3.3%) with HER2 gene amplification, and 2 patients (0.2%) with both HER2 mutations and amplification. R678Q was the most common mutated kinase domain, and no HER2 kinase domain in‐frame insertions/deletions were found in HER2 mutated cases. MSI‐H was found in 5.2% of our cohort and 36.8% of MSI‐H patients had HER2 mutation. For HER2 mutated cases, 48.3% were MSI‐H, whereas none of the HER2 amplification cases were MSI‐H. MSI‐H patients with HER2 mutation had significantly worse median progression‐free survival for programmed death‐1 (PD‐1) antibody than those without HER2 alteration ( p  = .036).    Conclusion  High MSI‐H rate was found in HER2 mutated cases, but no MSI‐H was found in HER2 amplification cases. MSI‐H patients with HER2 mutated had worse progression‐free survival for PD‐1 antibody than those without.    Implications for Practice  This study highlights the high microsatellite instability‐high (MSI‐H) rate in HER2 mutated cases but no MSI‐H in HER2 amplification cases. Moreover MSI‐H patients with HER2 mutated had worse progression‐free survival for programmed death‐1 antibody than those without. Further research to explore the internal relationship between HER2 alteration and MSI‐H is needed.

Relationship of HER2 Alteration and Microsatellite Instability Status in Colorectal Adenocarcinoma