Distinct Clinicopathological Features and Prognostic Values of High-, Low-, or Non-Expressing HER2 Status in Colorectal Cancer

SIMPLE SUMMARY: In recent years, the antibody-drug conjugate (ADC) of Human Epidermal Growth Factor Receptor 2 (HER2) has been found to play an important role in some HER2-negative cancers as in it did in HER2-positive patients. Therefore, a more detailed and suitable classification of HER2 is needed. Our study revealed that HER2-low colorectal cancer tumors did not show an intermediate state of HER2 expression in clinicopathology and prognosis. HER2-low colorectal cancer tumors are like HER2-zero tumors, with a lower proportion of perineural invasion, lower tumor stage and more RAS/BRAF mutation, compared with HER2-high tumors. Multivariate analysis and propensity score matching also revealed that HER2-high expression was an independent prognostic factor of disease-free survival. Our study indicated that the routine examination of HER2 status is needed in early-stage colorectal cancer. ABSTRACT: The encouraging effects of HER2-ADC in patients with HER2-low expression cancers indicated the classical classifications based on positive and negative HER2 might no longer be suitable. However, the biology and prognosis of colorectal cancer patients with different HER2 expression status were still not clear. This is a multi-center retrospective study that included patients with histologically confirmed colorectal cancer and determined HER2 status who received radical surgical resection. HER2 immunohistochemistry (IHC) 1+ and IHC 2+ groups were combined and defined as a HER2-low group because of the concordance of clinicopathological characteristics. As compared with the HER2-high group, both the HER2-zero and the HER2-low group had less tumor with perineural invasion (14.3%, 13.1% vs. 31.6%, p = 0.001 and p < 0.001), less stage III disease (41.8%, 39.9% vs. 56.1%, p = 0.044 and p = 0.022), more RAS/BRAF mutation (52.1%, 49.9% vs. 19.5%, p < 0.001 and p < 0.001) and better disease-free survival (DFS) (3y-DFS rate of 78.7%, 82.4% vs. 59.3%, p < 0.001 and p < 0.001). Multivariate analysis and propensity score matching also revealed that HER2-high expression was an independent prognostic factor of DFS. In conclusion, our study revealed that HER2-low colorectal cancer tumors are close to HER2-zero tumors, but different from HER2-high tumors. The routine examination of HER2 IHC is needed in early-stage colorectal cancer.