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

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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.

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MC, SB, UL, and HK conceived and designed the study and wrote, edited, and reviewed the manuscript. MC, SB, AL, SP, DH, and HK researched and analyzed data and wrote, edited, and reviewed the manuscript. All authors gave final approval for publication. HK takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.


The study was supported by a grant from the Deutsche Krebshilfe to HK (Grant Number 1097154).

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Correspondence to Hans Kreipe.

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Christgen, M., Bartels, S., Luft, A. et al. Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer. Virchows Arch 473, 577–582 (2018).

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