Absence of co-occurrence between HER2 amplification and dMMR/MSI in a large multicentric colorectal cancer cohort

: Mismatch repair deficiency (dMMR)/Microsatellite instability (MSI) plays a central role in colorectal cancer (CRC) as a predictive and prognostic biomarker and as a "red flag" for diagnosis of Lynch Syndrome (LS). HER2 is emerging as a therapeutic target and clinical trials are ongoing. Several reports suggested that HER2 amplification could be mutually exclusive with dMMR/MSI, which is mostly associated with HER2 mutations or other alterations. Clinical and molecular aspects in this field mostly derive from subgroup analyses of trials and real-life data are lacking. We retrospectively collected data on 350 dMMR/MSI CRC patients who underwent HER2 testing in two Italian referral centers from 2016 to 2024. HER2 amplification was evaluated with immunohistochemistry (IHC) and FISH for IHC 2+ patients. Median age was 75 years, 84% were stage II and stage III. BRAF and RAS mutation occurred in 60% and 14% of the patients with available molecular data, respectively. No patients harbored HER2 amplification, suggesting that the co-occurrence of HER2 amplification and dMMR/MSI is essentially anecdotal, making therefore HER2 testing in this subgroup less compelling.