This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dal Lago, L. Articles by Larsimont, D. Search for Related Content PubMed PubMed Citation Articles by Dal Lago, L. Articles by Larsimont, D.

Research Articles: Therapeutics, Targets, and Development

Correction for chromosome-17 is critical for the determination of true Her-2/neu gene amplification status in breast cancer

¹ Translational Research Unit and ² Pathology Department, Bordet Institute, Brussels, Belgium; and ³ Human Genetics Department, BioMérieux, Marcy l'Etoile, France

Requests for reprints: Denis Larsimont, Department of Pathology, Jules Bordet Institute 1, rue Heger-Bordet, 1000 Brussels, Belgium. Phone: 32-2541-3115; Fax: 32-2541-3281. E-mail: denis.larsimont{at}bordet.be

Abstract

Purpose: Trastuzumab is the cornerstone for treatment of women with HER2-overexpressing breast cancer, both in the adjuvant and in the metastatic settings. The accurate assessment of HER2 is, therefore, critical to identifying patients who may benefit from trastuzumab-based therapy. This project aimed to determine the optimal scoring method for fluorescence in situ hybridization (FISH) assay. Methods: FISH assay was done on 893 samples of breast cancer. Three scoring methods were evaluated: Her2/CEP172, Her2>4, or Her2>6. Protein and gene expression were evaluated by immunohistochemistry (n = 584) and mRNA/assay/nucleic acid sequence–based amplification (NASBA; n = 90). Results: Samples were divided into five groups based on FISH results: disomic amplified and nonamplified, polysomic amplified, nonamplified, and discordant (10.8% of cases, mostly positive with Her2>4 scoring, but negative with the others). Her2/CEP172 and Her2>6 scoring methods showed the best association (a) with regard to FISH scoring ( = 0.906, P < 10^–6) and (b) between FISH and immunohistochemistry (3+ as positive; > 0.650, P < 10^–6) or NASBA ( > 0.536, P < 10^–6). Polysomy had an effect on Her2 copy number (P < 10^–6), but had no effect on protein and mRNA content. Therefore, within the discordant subgroup, for which additive Her-2 gene copies are due to high polysomy, protein and mRNA levels were similar to those of the nonamplified samples. For this subgroup, the best concordance between FISH/immunohistochemistry/NASBA was observed with the Her2/CEP17 ratio and Her-2>6 scoring (68% and 58% perfect matches, respectively). No perfect matches were observed using the Her2>4 scoring method. Conclusion: Correction for chromosome-17 is the method of choice for clinical practice; Her-2>6, but not Her-2>4, could be used as an alternative. [Mol Cancer Ther 2006;5(10):2572–9]

Grant support: C. Desmedt was supported by a grant from the Fonds National de la Recherche Scientifique.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: L. Dal Lago, V. Durbecq, and C. Desmedt should be considered as co-first authors.

⁴ Supplementary materials for this article is available at Molecular CancerTherapeutics Online (http://mct.aacrjournals.org).

Received 3/ 8/06; revised 6/ 8/06; accepted 8/16/06.

This article has been cited by other articles:

				I. Vanden Bempt, P. Van Loo, M. Drijkoningen, P. Neven, A. Smeets, M.-R. Christiaens, R. Paridaens, and C. De Wolf-Peeters Polysomy 17 in Breast Cancer: Clinicopathologic Significance and Impact on HER-2 Testing J. Clin. Oncol., October 20, 2008; 26(30): 4869 - 4874. [Abstract] [Full Text] [PDF]

				C. L. Rosenberg Polysomy 17 and HER-2 Amplification: True, True, and Unrelated J. Clin. Oncol., October 20, 2008; 26(30): 4856 - 4858. [Full Text] [PDF]

				L. Arnould, P. Arveux, J. Couturier, M. Gelly-Marty, C. Loustalot, F. Ettore, C. Sagan, M. Antoine, F. Penault-Llorca, B. Vasseur, et al. Pathologic Complete Response to Trastuzumab-Based Neoadjuvant Therapy Is Related to the Level of HER-2 Amplification Clin. Cancer Res., November 1, 2007; 13(21): 6404 - 6409. [Abstract] [Full Text] [PDF]

				A. C. Wolff, M. E. H. Hammond, J. N. Schwartz, K. L. Hagerty, D. C. Allred, R. J. Cote, M. Dowsett, P. L. Fitzgibbons, W. M. Hanna, A. Langer, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer J. Clin. Oncol., January 1, 2007; 25(1): 118 - 145. [Abstract] [Full Text] [PDF]