The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results
1Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan.
Abstract:
Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene ERBB, is known to be mutated or amplified in various malignant diseases, and many HER2-targeted therapies (including monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors) have been investigated. HER2 overexpression is observed in ~30% of patients with osteosarcoma, and HER2-targeted therapy for osteosarcoma has also been investigated, along with the prognostic and/or predictive value of HER2. An effective HER2-targeted therapy for osteosarcoma has not been established, however. An antibody-drug conjugate (ADC), i.e., trastuzumab deruxtecan (T-DXd), has been approved for the treatment of HER2-positive malignant diseases such as breast cancer and gastric cancer. T-DXd showed promising efficacy in a tumor-agnostic clinical trial, but even T-DXd did not demonstrate sufficient efficacy against HER2-positive osteosarcoma. In this review, the underlying reasons/mechanisms for the failure of HER2-targeted treatments for osteosarcoma (including T-DXd) are discussed, and the potential and future direction of HER2-targeted therapy is described.
Insights
Human epidermal growth factor receptor 2 (HER2) targeted therapies show limited efficacy in osteosarcoma. This review explores reasons for treatment failure and future directions for HER2-targeted therapy in osteosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Human epidermal growth factor receptor 2 (HER2) is implicated in various cancers.
- HER2 overexpression occurs in approximately 30% of osteosarcoma patients.
- Existing HER2-targeted therapies have not yet proven effective for osteosarcoma.
Purpose of the Study:
- To review the mechanisms underlying the limited efficacy of HER2-targeted therapies in osteosarcoma.
- To discuss the potential and future directions for HER2-targeted treatment strategies in osteosarcoma.
Main Methods:
- Literature review of HER2-targeted therapies in osteosarcoma.
- Analysis of clinical trial data for HER2-targeted agents, including trastuzumab deruxtecan (T-DXd).
- Exploration of resistance mechanisms and novel therapeutic approaches.
Main Results:
- HER2-targeted therapies, including T-DXd, have shown insufficient efficacy in HER2-positive osteosarcoma.
- Specific reasons for treatment failure in osteosarcoma are discussed.
- The prognostic and predictive value of HER2 in osteosarcoma requires further investigation.
Conclusions:
- Effective HER2-targeted therapy for osteosarcoma remains an unmet clinical need.
- Understanding resistance mechanisms is crucial for developing future strategies.
- Further research into novel HER2-targeted approaches is warranted for osteosarcoma treatment.
