The emerging HER2 landscape in colorectal cancer: the key to unveil the future treatment algorithm?

Colorectal cancer (CRC) represents a global health threat, standing as the second leading cause of cancer-related death worldwide. Targeted therapies brought new hope for the metastatic stage, which historically bore a very poor prognosis. Human epidermal growth receptor 2 (HER2) overexpression concerns about 5 % of the metastatic CRC (mCRC) patients, including both gene amplifications and point mutations. Albeit its controversial prognostic role, preclinical and clinical data indicate HER2 as a negative predictive biomarker of response to anti-EGFR therapies. Tissue and plasma-based NGS testing, could permit a precise identification of this resistance mechanism both at baseline and during treatment, thus guiding decision-making. Furthermore, promising results come from completed and ongoing randomized trials, testing HER2 as an actionable target. In this review, we discuss the available evidence on HER2 targeting in advanced CRC, analyzing its possible future role in the treatment algorithm.