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Despite patient selection based on ERBB2 overexpression, not all patients benefit from trastuzumab therapy. We have investigated whether a ERBB2 gene dosage effect might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Absolute ERBB2 copy numbers (“CN”) and ERBB2/centromer 17 ratios (“R”) were measured by FISH analysis in tumors of 127 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer. CN and R were both significantly associated with shorter time to first metastasis (TTM) (CN: OR: 1.099, 95% CI: 1.042–1.159; R: OR: 1.211, 95% CI: 1.080–1.357) and longer PFS (CN: OR: 0.917, 95% CI: 0.867–0.969; R: OR: 0.840, 95% CI: 0.743-0.949) in a continuous variable Cox's regression model. Tumors with ERBB2/centromer 17 ratios of <2.2 had a significantly shorter TTM (p = 0.002) and significantly longer PFS (p = 0.003) than tumors with low-level (R: 2.2–6) and high-level amplification (R: >6). Interestingly, when ERBB2 copy numbers were analyzed, a significantly shorter TTM (p = 0.001) and longer PFS (p = 0.026) were observed in the group with high-level amplified CN (CN: >13), while no difference was observed between non- and low-level amplified CN. R, but not CN, was an independent predictor of complete (CR; OR: 1.685; 95%CI: 1.122–2.532) and partial (PR; OR: 1.704; 95% CI: 1.136–2.556) response in logistic regression analysis. CR (p = 0.016) rates were significantly higher in the high-level amplification group (R > 6), but no difference existed in response rates between non- and low-level amplified tumors in Chi-square tests. High-level ERBB2 amplification is associated with shorter TTM, but improved response to trastuzumab in metastatic breast cancer.While a cut-off for HER2/ERBB2 overexpression had been well established in breast cancer prognosis, little is known about the biological behavior of tumors with very high levels of ERBB2 gene amplification. Here, ERBB2 copy number amplifications and ERBB2/centromer17 ratio were investigated in archived tumor samples of breast cancer patients with metastatic lesions who received trastuzumab-based treatment. The findings indicate that tumors with high ERBB2 copy numbers are particularly aggressive in the absence of trastuzumab but respond well to trastuzumab-based therapy in the metastatic setting.