title: Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases.
abstract: Current standard systemic therapies for treating breast cancer patients with brain metastases are inefficient. Targeted therapies against human epidermal growth factor receptors are of clinical interest because of their alteration in a subset of breast cancers (BCs). We analyzed copy number, mutation status, and protein expression of epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), phosphatase and tensin homologue (PTEN), and PI3K catalytic subunit (PIK3CA) in 110 ductal carcinoma in situ, primary tumor, and metastatic BC samples. Alterations in EGFR, HER2, and PTEN, alone or in combination, were found in a significantly larger fraction of breast cancer brain metastases tumor tissue compared with samples from primary tumors with good prognosis, bone relapse, or other distant metastases (all P < 0.05). Primary tumor patients with a subsequent brain relapse showed almost equally high frequencies of especially EGFR and PTEN alteration as the breast cancer brain metastases patients. PIK3CA was not associated with an increased risk of brain metastases. Genetic alterations in both EGFR and PTEN were especially common in triple-negative breast cancer patients and rarely were seen among HER2-positive patients. In conclusion, we identified two independent high-risk primary BC subgroups for developing brain metastases, represented by genetic alterations in either HER2 or EGFR/PTEN-driven pathways. In contrast, none of these pathways was associated with an increased risk of bone metastasis. These findings highlight the importance of both pathways as possible targets in the treatment of brain metastases in breast cancer.
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Hohensee
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.forename: Sönke
authors.initials: S
authors.lastname: Meyer-Staeckling
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.forename: Isabell
authors.initials: I
authors.lastname: Witzel
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brandt
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human