HER-2 gene amplification can be acquired as breast cancer progresses - PubMed (original) (raw)

. 2004 Jun 22;101(25):9393-8.

doi: 10.1073/pnas.0402993101. Epub 2004 Jun 11.

Debasish Tripathy, Sanjay Shete, Raheela Ashfaq, Barbara Haley, Steve Perkins, Peter Beitsch, Amanullah Khan, David Euhus, Cynthia Osborne, Eugene Frenkel, Susan Hoover, Marilyn Leitch, Edward Clifford, Ellen Vitetta, Larry Morrison, Dorothee Herlyn, Leon W M M Terstappen, Timothy Fleming, Tanja Fehm, Thomas Tucker, Nancy Lane, Jianqiang Wang, Jonathan Uhr

Affiliations

HER-2 gene amplification can be acquired as breast cancer progresses

Songdong Meng et al. Proc Natl Acad Sci U S A. 2004.

Abstract

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-2/chromosome 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.

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Figures

Fig. 1.

Fig. 1.

Fluorescent microscopic images of cytomorphology, immunophenotype, and FISH evaluation of CTCs of patients with metastatic breast cancer. (A) Decomposing the immunophenotype and displaying aneuploidy of a CTC from a metastatic breast patient. Single-band filters were used to block out the fluorescence of one or more fluorochromes used to stain for CTCs. Horizontally, the photos show the same cell stained for the combination of CK (green), mam (red), and nucleic acid (blue); CK only; mam only; and FISH analysis. For FISH, CEP 1 (SpectrumOrange), CEP 8 (SpectrumAqua), and CEP 17 (SpectrumGreen) were used (counts were 5, 2, and 5, respectively). The photos are taken in only one _Z_-plane, whereas the microscopist can focus on the entire range of _Z_-planes; therefore, spots that are not seen or overlap in the single _Z_-plane of the photo can be distinguished by microscopy. (B) Sequential genotyping of a CTC isolated from blood of a metastatic breast cancer patient. First photo, epithelial cell detected by an anti-CK-antibody (green) and nucleic acid (blue). Second photo, same cell hybridized with a locus-specific probe for c-myc (orange) and CEP 8 (aqua) (7, 3). Third photo, same cell hybridized with Her-2 (orange), CEP 10 (green), and CEP 17 (aqua) (6, 2, and 3). Fourth photo, same cell hybridized with CEP 1 (orange), CEP 8 (aqua), and CEP 17 (green) (6, 3, and 2). (C) Comparison of the intensity of Her-2 IF staining with HER-2 gene amplification of CTCs from metastatic breast cancer. Three rows representing Her-2 IF staining intensity of a single cell of 1+ (first row), 2+ (second row) and 3+ (third row) are shown. Photo 1 of each row shows staining for the combination of CK, Her-2, and nucleic acid. Photo 2 shows IF staining for Her-2 and nucleic acid. Photo 3 shows FISH results for HER-2 (SpectrumOrange) and CEP 17 (SpectrumGreen). Her-2 IF staining intensity (IFI) and HER-2/CEP 17 ratio (Ratio) for each cell are shown.

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