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

In addition to amplification, point mutations of the human epidermal growth factor receptor 2 (HER2) gene (ERBB2) have been shown to activate the corresponding signaling pathway in breast cancer. The prevalence of ERBB2/HER2 mutation in bone metastasis of breast cancer and the associated phenotype are not known. In this study, bone metastases from breast cancer patients (n = 231) were analyzed for ERBB2/HER2 mutation. In 7 patients (3%; median age 70 years, range 50-83 years), gain-of-function mutations of ERBB2/HER2 were detected. The most frequent mutation was p.L755S (71%). In 29% of mutated cases, p.V777L was found. Lobular breast cancer was present in 71% of mutated cases (n = 5) and in 49% of all samples (n = 231; p = 0.275). Mutation frequency was 4.4% in the lobular subgroup and 17.4% in the pleomorphic subtype of lobular cancer (n = 23), respectively. All but one mutated lobular cancers were of the pleomorphic subtype (p = 0.006). Mutated cancers belonged either to the luminal (n = 4) or to the triple-negative types (n = 3). With regard to protein expression and gene amplification, HER2 was negative in all mutated cases. Among the 14% of metastatic luminal cancers with estrogen receptor gene (ESR1) mutation, conveying resistance against aromatase inhibitors, no concomitant ERBB2/HER2 mutation occurred. We conclude that activating HER2 mutation is present in about 3% of bone metastases from breast cancers, with significantly higher rates in the pleomorphic subtype of lobular cancer. Since mutated cases appear to be HER2-negative by conventional testing, the opportunity for specific anti-HER2 therapy may be missed.