Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Activating point mutations in the human epidermal growth factor receptor 2 (HER2) gene (ERBB2) are known drivers of breast cancer signaling.
• The prevalence and clinical significance of ERBB2/HER2 mutations in breast cancer bone metastases remain largely unknown.

Purpose of the Study:

• To investigate the frequency and characteristics of ERBB2/HER2 mutations in bone metastases from breast cancer patients.
• To determine the association of these mutations with specific breast cancer subtypes and clinical phenotypes.

Main Methods:

• Analysis of ERBB2/HER2 mutations in bone metastasis samples from 231 breast cancer patients.
• Genotyping for ERBB2/HER2 mutations, including assessment of HER2 protein expression and gene amplification.
• Correlation of mutation status with breast cancer subtypes (lobular, pleomorphic lobular, luminal, triple-negative) and estrogen receptor gene (ESR1) mutations.

Main Results:

• Activating ERBB2/HER2 mutations were detected in 3% of bone metastases (7 out of 231 patients).
• The most common mutations were p.L755S (71%) and p.V777L (29%).
• Mutations were significantly more frequent in the pleomorphic subtype of lobular breast cancer (17.4% vs. 4.4% in general lobular).
• All mutated cases tested negative for HER2 protein expression and gene amplification.
• No concomitant ERBB2/HER2 and ESR1 mutations were observed in metastatic luminal cancers.

Conclusions:

• Activating HER2 mutations are present in approximately 3% of breast cancer bone metastases, particularly in the pleomorphic lobular subtype.
• These mutations confer a HER2-negative status by conventional assays, potentially leading to missed opportunities for targeted anti-HER2 therapy.
• Further investigation is warranted to identify and treat patients with HER2-mutated bone metastases.