This study systematically analyzed 1604 patients with RAS/BRAF wild-type metastatic colorectal cancer from eight randomized controlled trials (RCTs), revealing that both HER2 amplification/overexpression and HER2 mutations are associated with worse prognosis. However, no predictive value was observed for bevacizumab or anti-EGFR therapies.
Literature Overview
This article titled 'Impact of Human Epidermal Growth Factor Receptor 2 in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab or Anti-EGFRs: Exploratory Analysis of Eight Randomized Trials', published in the Journal of Clinical Oncology, reviews the relationship between HER2 amplification/overexpression, HER2 mutations, and treatment responses to anti-EGFR or bevacizumab in RAS/BRAF wild-type metastatic colorectal cancer patients. Based on data from multiple RCTs, it investigates whether HER2 can serve as a prognostic or predictive biomarker in metastatic colorectal cancer.
Background Knowledge
Colorectal cancer is one of the most common malignant tumors globally, with approximately 5% of RAS/BRAF wild-type patients harboring HER2 amplification or overexpression, while HER2 mutations are rarer (about 2%). HER2 belongs to the EGFR receptor family; its amplification or overexpression activates downstream signaling pathways, promoting tumor growth and anti-apoptosis. Although existing studies suggest HER2 may contribute to anti-EGFR treatment resistance, its predictive value in first-line therapies remains controversial. Additionally, the clinical significance of HER2 mutations remains unclear, particularly as they often coexist with HER2 amplification, complicating interpretation. This study aims to clarify HER2's biomarker value in metastatic colorectal cancer (mCRC) using large-scale RCT data.
Research Methods and Experiments
The research team integrated data from 1604 patients across eight randomized clinical trials: TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405. All patients had RAS/BRAF wild-type and pMMR/MSS status, receiving first-line chemotherapy combined with bevacizumab or anti-EGFR therapy. HER2 status was evaluated using immunohistochemistry (IHC), in situ hybridization (ISH), and next-generation sequencing (NGS). Primary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the largest analysis of HER2 status in RAS/BRAF wild-type metastatic colorectal cancer to date, reinforcing HER2 as an independent prognostic factor rather than a predictive marker. While no interactions were found between HER2 status and anti-EGFR or bevacizumab responses, future research should focus on evaluating HER2-targeted therapeutic strategies in this population.
Conclusion
Basing on data from eight randomized controlled trials, this study systematically assessed the impact of HER2 amplification/overexpression and HER2 mutations on prognosis and treatment response in RAS/BRAF wild-type metastatic colorectal cancer patients. Results demonstrate that HER2 amplification/overexpression correlates with shorter progression-free and overall survival, retaining statistical significance after adjusting for confounding factors. However, it showed no predictive value for first-line anti-EGFR or bevacizumab therapies. HER2 mutations were also linked to poorer overall survival, though specific treatment strategies remain lacking. These findings suggest HER2 should be regarded as a negative prognostic factor, not a biomarker for guiding treatment decisions, while highlighting the need for clinical validation of HER2-targeted therapies to improve outcomes.
