Fighting HER2 in Gastric Cancer: Current Approaches and Future Landscapes

Area of Science:

• Oncology
• Gastroenterology
• Pharmacology

Background:

• Gastric cancer (GC) is a leading cause of cancer mortality globally.
• HER2-positive GC is a significant subset, with trastuzumab-based chemotherapy as standard first-line care.
• Trastuzumab resistance limits treatment efficacy, necessitating novel therapeutic strategies.

Purpose of the Study:

• To review current and emerging HER2-directed therapies for gastric cancer.
• To highlight the efficacy of trastuzumab deruxtecan in trastuzumab-refractory HER2-positive GC.
• To discuss strategies for overcoming resistance and expanding treatment to HER2-low populations.

Main Methods:

• Review of clinical trials and scientific literature on HER2-targeted therapies in gastric cancer.
• Analysis of antibody-drug conjugates (ADCs), immune-based therapies, and pathway inhibitors.
• Focus on trastuzumab deruxtecan and its role in overcoming resistance.

Main Results:

• Trastuzumab deruxtecan demonstrates significant efficacy in HER2-positive GC, including cases with heterogeneous HER2 expression and trastuzumab resistance.
• Other HER2-targeted ADCs are under investigation, showing potential as alternative treatments.
• Novel strategies including immunotherapy and pathway inhibitors are being explored to enhance efficacy in both HER2-high and HER2-low GC.

Conclusions:

• Trastuzumab deruxtecan represents a promising advancement for HER2-positive gastric cancer, particularly in refractory settings.
• Addressing resistance mechanisms and exploring novel HER2-directed therapies are crucial for improving patient outcomes.
• Future research should focus on optimizing treatment strategies for broader patient populations, including those with HER2-low expression.