Dynamic HER2 reassessment and precision sequencing after trastuzumab in HER2-positive advanced gastric cancer
A Ooki1, K Shimozaki1, K Yamaguchi1
1Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Abstract:
Human epidermal growth factor receptor 2 (HER2)-targeted therapy has transformed the treatment of HER2-positive advanced gastric cancer. Trastuzumab-based chemotherapy has been established as the first effective biomarker-defined approach for this disease; however, the frequent loss of HER2 expression after treatment has limited the benefits of continued HER2 targeting beyond progression. This biological instability may explain why earlier attempts to extend HER2-targeted therapy after trastuzumab did not consistently produce clinical benefits. In the phase III DESTINY-Gastric04 trial, trastuzumab deruxtecan emerged as the preferred second-line treatment for patients with persistent HER2-positive disease on repeat biopsy, highlighting the importance of contemporaneous tumor biology over archival HER2 status. Key challenges remain, particularly in decision making when repeat biopsy is not feasible and when managing tumors that convert to nonactionable HER2 states after trastuzumab treatment. In this review, we examine the biological and clinical implications of dynamic HER2 reassessment and outline a practical framework for treatment sequencing in advanced gastric cancer.
Insights
Human epidermal growth factor receptor 2 (HER2) targeted therapy is crucial for advanced gastric cancer. Trastuzumab deruxtecan is a preferred second-line option for HER2-positive patients, emphasizing updated tumor biology assessments.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Human epidermal growth factor receptor 2 (HER2)-targeted therapy revolutionized HER2-positive advanced gastric cancer treatment.
- Trastuzumab-based chemotherapy is the established first-line biomarker-defined approach.
- Loss of HER2 expression post-treatment limits sustained HER2 targeting benefits.
Purpose of the Study:
- To review the biological and clinical implications of dynamic HER2 reassessment in advanced gastric cancer.
- To outline a practical framework for treatment sequencing considering HER2 status changes.
- To address challenges in decision-making when repeat biopsies are not feasible.
Main Methods:
- Review of clinical trial data, focusing on the DESTINY-Gastric04 trial.
- Analysis of biological mechanisms underlying HER2 expression instability.
- Examination of treatment strategies for advanced gastric cancer with dynamic HER2 status.
Main Results:
- Trastuzumab deruxtecan is the preferred second-line treatment for persistent HER2-positive disease on repeat biopsy.
- Contemporaneous tumor HER2 status is more critical than archival status for treatment decisions.
- HER2 expression can dynamically change, posing challenges for continued targeted therapy.
Conclusions:
- Dynamic HER2 reassessment is vital for optimizing treatment sequencing in advanced gastric cancer.
- Managing tumors with nonactionable HER2 states after trastuzumab requires careful consideration.
- A practical framework is needed to guide clinical decisions regarding HER2-targeted therapies.
