Targeting HER2 expression in cancer: New drugs and new indications

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Functional activation of human epidermal growth factor receptor 2 (HER2) promotes carcinogenesis.
• HER2 alterations, particularly gene amplification, are well-established in breast and gastric cancers, with targeted therapies available.
• Somatic HER2 gene mutations are emerging as a novel biomarker for HER2-directed therapies.

Purpose of the Study:

• To investigate the role of HER2 mutations in cancer development and their potential as predictive biomarkers for HER2-targeted therapies.
• To explore the clinical significance of HER2 mutations in various cancer types.

Main Methods:

• Review of preclinical data on HER2 mutations as oncogenic drivers.
• Analysis of clinical trial data, including a Phase II trial of trastuzumab deruxtecan in non-small cell lung carcinoma patients with HER2 alterations.

Main Results:

• Preclinical data suggest activating HER2 mutations are potent oncogenic drivers, analogous to HER2 amplification.
• A Phase II trial demonstrated clinical sensitivity to the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma harboring HER2 mutations.

Conclusions:

• HER2 mutations represent a significant oncogenic event and a potential predictive biomarker for HER2-directed treatments.
• Targeted therapies against HER2, including antibody-drug conjugates, show promise in cancers with HER2 mutations, expanding treatment options beyond HER2 amplification.