Positive outcomes with HER2-directed ADCs in tumors showing low HER2 expression have challenged the traditional binary (positive/negative) categorization of HER2 status. However, the clinicopathological features and prognostic implications of varying HER2 expression levels in colorectal cancer remain incompletely understood. We conducted a multicenter retrospective analysis of patients with histologically confirmed colorectal cancer who underwent curative resection and had available HER2 status. Due to similar clinicopathological profiles, IHC 1+ and IHC 2+ cases were grouped as HER2-low. Relative to the HER2-high group, both HER2-zero and HER2-low tumors displayed significantly lower rates of perineural invasion (14.3% and 13.1% vs. 31.6%; P = 0.001 and P < 0.001), reduced proportion of stage III disease (41.8% and 39.9% vs. 56.1%; P = 0.044 and P = 0.022), higher prevalence of RAS/BRAF mutations (52.1% and 49.9% vs. 19.5%; P < 0.001 for both), and superior disease-free survival (3-year DFS rates: 78.7% and 82.4% vs. 59.3%; P < 0.001 for both). Multivariate analysis and propensity score matching further established HER2-high expression as an independent adverse prognostic factor for DFS. In summary, HER2-low colorectal tumors share characteristics with HER2-zero tumors and differ markedly from HER2-high tumors. Routine HER2 immunohistochemistry is warranted in early-stage colorectal cancer.
