Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with HER-2-positive tumors, the HER-2͞chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 ؎ 2.72 vs. 2.8 ؎ 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the HER-2 gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was HER-2-negative each acquired HER-2 gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8 -59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.
Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.
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