• Ina Hohensee, Katrin Lamszus, Sabine Riethdorf, Sönke Meyer-Staeckling, Markus Glatzel, Jakob Matschke, Isabell Witzel, Manfred Westphal, Burkhard Brandt, Volkmar Müller, Klaus Pantel, and Harriet Wikman.
• Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
• Am. J. Pathol. 2013 Jul 1; 183 (1): 83-95.

AbstractCurrent 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.Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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