Publication Year: 2000 Visited: 40

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Her-2 Gene Amplification Correlates with Higher Levels of Angiogenesis in Primary Breast Tumors. Kimberly Lynn Blackwell, V Liotcheva, Zishan A Haroon, Ken Fung, Gloria Broadwater, Steven Anderson, James Vredenburgh, Allen Proia, Charles S Greenberg, Mark W Dewhirst, Lyndsay N Harris, Duke Univ Cancer Ctr, Durham, NC; Labcorp, RTP, NC; Dana-Farber Cancer Inst, Boston, MA.

Objectives: The HER-2 (c-erb-2) oncogene is overexpressed in approximately 20-40% of human breast cancers. This study investigated the connection between HER-2 protein expression, HER-2 gene amplification, and tissue/plasma markers of angiogenesis in primary invasive breast tumors. Methods: From 1988-1995, 425 patients with metastatic breast cancer were enrolled in a study of high-dose chemotherapy with autologous transplant. Primary tumor blocks from 86 of these patients were retrospectively obtained. 59 tumors had evaluable immunohistochemical (IHC) staining of vessels with vWF antibody (Dako, CA). Mean microvessel densities (MVD) were determined by counting vWF stained cells in three separate vascular hot spots using image analysis. Maximum MVD was the hot spot with the highest counts. Tumor samples were also stained for HER-2 by IHC (CB11Ab, BioGenex, CA), HER-2 gene amplification (Ventana FISH kit, NC), and vascular endothelial growth factor (VEGF) by IHC (Neomarkers, CA). Plasma from 36 patients with primary tumor samples had VEGF (R&D, MN) and D-dimer (American Diagnostica, CT) levels determined. Results: There was a significant positive correlation between maximum MVD and HER-2 gene amplification (Spearman coefficient=0.27; p=0.038). The level of HER-2 gene amplification also correlated with plasma D-dimer levels (Spearman coefficient=0.43; p=0.021). Interestingly, tumors with HER-2 by IHC had decreased amounts of VEGF staining (Wilcoxon test; p=0.016). Of all variables examined, only average (p=0.0016) and maximum MVD (p=0.0128) predicted disease-free survival (Cox univariate model). There was no correlation between HER-2 by IHC and MVD or D-dimer. Conclusions: A significant association exists between HER-2 gene amplification and markers of tumor angiogenesis (MVD) and tumor burden (D-dimer). In addition, HER-2 appears to be associated with decreased tumor expression of VEGF. These findings warrant investigation into the physiologic and molecular mechanisms of increased angiogenesis in HER-2 overexpressing breast cancers.