Somatic mutations of the HER2 in metastatic breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epidermal growth factor receptor (EGFR) gene mutations in lung cancer predict sensitivity to EGFR kinase inhibitors.
• HER2 (also known as NEU, EGFR2, or ERBB2), a member of the EGFR family, is crucial in various human cancers, with recent reports of mutations in lung cancers.

Purpose of the Study:

• To investigate the frequency and characteristics of HER2 mutations in metastatic breast cancer (MBC) and other epithelial cancers.
• To compare HER2 mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations.
• To assess the association between HER2 mutations and trastuzumab administration.

Main Methods:

• Full-length HER2 sequencing was performed on 198 MBC samples and 34 other epithelial cancers (bladder, prostate, colorectal).
• Mutational status was analyzed in relation to clinicopathologic features and co-occurring EGFR or KRAS mutations.
• Statistical analysis was used to determine the significance of HER2 mutations in relation to trastuzumab treatment.

Main Results:

• HER2 mutations were identified in 11.6% (23 of 198) of MBC cases and were absent in other studied epithelial cancers.
• Mutations were predominantly located in exon 15 and exon 20, with in-frame insertions similar to those in EGFR.
• HER2 mutations were significantly more frequent in patients previously treated with trastuzumab (34.8%, 8 of 23; P=0.02).
• Mutant HER2 (exons 15 and 20) demonstrated enhanced signaling, promoting survival, invasiveness, and tumorigenicity compared to wild-type HER2.

Conclusions:

• HER2 mutations are a distinct molecular event in a subset of metastatic breast cancers.
• The prevalence of HER2 mutations after trastuzumab treatment suggests a potential role in acquired resistance.
• Activated HER2 mutations confer potent oncogenic signaling, driving tumor progression and invasiveness.