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The following is a summary of “Advances and challenges in targeted therapies for HER2-amplified colorectal cancer,” published in the June 2025 issue of the European Journal of Cancer by Pizzamiglio et al.

Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality among adults in Europe. Although overall survival rates have improved over time, the prognosis for metastatic colorectal cancer (mCRC) remains poor. Historically, treatment strategies have primarily relied on standard chemotherapy regimens, often in combination with targeted therapies such as anti-epidermal growth factor receptor agents for RAS wild-type tumors, anti-vascular endothelial growth factor therapies, or immunotherapy for tumors characterized by MMR deficiency. In recent years, the advent of precision medicine has driven significant progress in oncology, leading to the development of biomarker-driven treatments that have improved outcomes for specific molecular subgroups within the mCRC population.

Among these biomarkers, amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) has been identified in approximately 6% of patients with RAS wild-type mCRC. HER2 has emerged as a clinically actionable target, although its exact prognostic and predictive value remains under investigation. Nevertheless, anti-HER2 therapies have demonstrated promising efficacy in HER2-positive mCRC, leading to their integration into treatment guidelines issued by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology. Notably, the U.S. Food and Drug Administration has recently approved two therapies for patients with previously treated HER2-positive mCRC: tucatinib in combination with trastuzumab, and trastuzumab deruxtecan as a monotherapy.

This review examines the role of HER2 as a biomarker in colorectal cancer, focusing on its molecular characteristics, the clinical profiles of patients harboring HER2 alterations, and the diagnostic strategies employed to identify HER2-positive cases. Furthermore, it highlights pivotal clinical trials that have assessed the efficacy of various HER2-targeted regimens and explores the evolving therapeutic landscape for this subset of patients with mCRC. As precision oncology continues to advance, HER2-directed therapies represent a significant step toward more individualized treatment approaches, offering new hope for improved outcomes in a historically challenging disease setting.

Source: ejcancer.com/article/S0959-8049(25)00252-7/abstract