Molecular Basis of HER2-Targeted Therapy for HER2-Positive Colorectal Cancer
Ayumu Yoshikawa1, Yoshiaki Nakamura1,2,3
1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa 277-0882, Japan.
Abstract:
Human epidermal growth factor receptor 2 (HER2) amplification has emerged as a biomarker in colorectal cancer (CRC), occurring in 1-4% of metastatic CRC (mCRC). In addition to conventional methods, such as immunohistochemistry and fluorescence in situ hybridization, next-generation sequencing-based tissue or circulating tumor DNA analysis has recently been used to identify HER2 amplification and assess HER2 overexpression. Prospective clinical trials have demonstrated the efficacy of HER2-targeted therapies in HER2-positive mCRC. The TRIUMPH study, a phase II study of dual HER2 antibodies, i.e., pertuzumab plus trastuzumab, demonstrated promising efficacy for patients with HER2-positive mCRC confirmed by tissue-and/or blood-based techniques, which led to the regulatory approval of this combination therapy in Japan. The mechanisms associated with efficacy and resistance have also been explored in translational studies that incorporate liquid biopsy in prospective trials. In particular, HER2 copy number and co-alterations have repeatedly been reported as biomarkers related to efficacy. To improve the therapeutic efficacy of the current strategy, many clinical trials with various HER2-targeted agents are ongoing. This review discusses the molecular basis of HER2-targeted therapeutic strategies for patients with HER2-positive mCRC.
Insights
HER2 amplification is a biomarker in metastatic colorectal cancer (mCRC). HER2-targeted therapies, like pertuzumab plus trastuzumab, show efficacy in HER2-positive mCRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Human epidermal growth factor receptor 2 (HER2) amplification is a significant biomarker in metastatic colorectal cancer (mCRC), found in 1-4% of cases.
- Conventional diagnostic methods like immunohistochemistry and fluorescence in situ hybridization are complemented by next-generation sequencing for HER2 analysis.
Purpose of the Study:
- To review the molecular basis of HER2-targeted therapeutic strategies for HER2-positive mCRC.
- To discuss the efficacy and resistance mechanisms of HER2-targeted therapies in mCRC.
Main Methods:
- Review of prospective clinical trials and translational studies.
- Analysis of tissue and circulating tumor DNA (ctDNA) for HER2 amplification and overexpression.
- Exploration of biomarkers such as HER2 copy number and co-alterations.
Main Results:
- Prospective trials demonstrate the efficacy of HER2-targeted therapies in HER2-positive mCRC.
- The TRIUMPH study showed promising results for dual HER2 antibodies (pertuzumab plus trastuzumab), leading to regulatory approval in Japan.
- Liquid biopsy in translational studies aids in understanding efficacy and resistance mechanisms.
Conclusions:
- HER2-targeted therapies are effective for a subset of mCRC patients.
- Biomarkers like HER2 copy number and co-alterations are crucial for predicting treatment response.
- Ongoing clinical trials aim to further improve therapeutic strategies for HER2-positive mCRC.
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