Frequency of Her2-low in colorectal cancer and its relations with the tumor microenvironment.

Background: To date, little is known regarding human epithelial growth factor receptor (HER2) low-expressing colorectal cancer (CRC). Due to promising rising therapies with HER2-antibody-drug conjugates we aimed to analyze the frequency of HER2-low in patients with CRC. Additionally we characterized the clinicopathologic background of this group and its potential relationship with the tumor microenvironment represented by budding and tumor infiltrating lymphocytes (TILs).

Methods: 319 patients with CRC, stages I-IV, were enrolled. HER2-immunohistochemistry (IHC) as well as fluorescence in situ hybridization (FISH) were performed on tissue microarrays. IHC was evaluated semiquantitatively and software-assisted using the HERACLES Diagnostic Criteria for CRC. HER2-low was defined as IHC 1 + or 2 +/FISH negative. HER2-IHC results were compared with budding, TILs and their combinations.

Results: The HER2 low-expressing subset represented almost one half of all CRC (47.1 %). Assessment was highly reproducible with different methods. HER2-low cases were significantly more often lower T-, N-, and tumor stage and had less L1 compared with HER2-0. Additionally, they showed more often TILs > 5 % (p = 0.001). The difference between HER2-0 and HER2-low was highly significant between the four budding/TILs-groups (p < 0.001). Cases with low budding/high TILs were more often HER2-low. The highest difference was seen between the low budding/high TILs-group and the low budding/low TILs-group (p < 0.001).

Conclusions: HER2-low expression in CRC is frequent and involves nearly one half of all patients. We could show a relationsship between HER2-low expression and the tumor microenvironment. Special attention should be paid to the low budding/high TILs group in future research.