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New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up

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Abstract

Background HER2 gene amplification and/or protein overexpression in breast cancer is associated with a poor prognosis and predicts response to anti-HER2 therapy. We examine the natural history of breast cancers in relationship to increased HER2 copy numbers in a large population-based study. Patients and Methods HER2 status was measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in approximately 1,400 breast cancer cases with greater than 15 years of follow-up. Protein expression was evaluated with two different commercially-available antibodies. Results We looked for subgroups of breast cancer with different clinical outcomes, based on HER2 FISH amplification ratio. The current HER2 ratio cut point for classifying HER2 positive and negative cases is 2.2. However, we found an increased risk of disease-specific death associated with FISH ratios of >1.5. An ‘intermediate’ group of cases with HER2 ratios between 1.5 and 2.2 was found to have a significantly better outcome than the conventional ‘amplified’ group (HER2 ratio >2.2) but a significantly worse outcome than groups with FISH ratios less than 1.5. Conclusion Breast cancers with increased HER2 copy numbers (low level HER2 amplification), below the currently accepted positive threshold ratio of 2.2, showed a distinct, intermediate outcome when compared to HER2 unamplified tumors and tumors with HER2 ratios greater than 2.2. These findings suggest that a new cut point to determine HER2 positivity, at a ratio of 1.5 (well below the current recommended cut point of 2.2), should be evaluated.

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Acknowledgements

The British Columbia tissue microarray cohort was developed using funds from a Canadian Breast Cancer Research Alliance Translational Acceleration Grant along with an unrestricted education grant from sanofi-aventis Canada. The HER2 FISH analysis was funded in part by an educational grant from Roche Canada.

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Authors and Affiliations

  1. Stanford University, Room L235, 300 Pasteur Drive, Stanford, CA, 94305, USA

    K. C. Jensen, T. Hastie & R. B. West

  2. Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    K. C. Jensen & R. B. West

  3. Genetic Pathology Evaluation Centre of the Vancouver Coastal Research Institute, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada

    D. A. Turbin, S. Leung, M. A. Miller, K. Johnson, B. Norris, S. McKinney, T. O. Nielsen, D. G. Huntsman & C. B. Gilks

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  1. K. C. Jensen
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Correspondence to K. C. Jensen or R. B. West.

Electronic supplementary material

10549_2007_9887_MOESM1_ESM.pdf

Supplemental Figure 1. Proportional hazard for variable cut points comparing P-value and HER2 amplification ratio (PDF 14 kb)

10549_2007_9887_MOESM2_ESM.pdf

Supplemental Figure 2. Heatmap of likelihood values as varying with lower and higher HER2 FISH ratio cut points (PDF 26 kb)

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Jensen, K.C., Turbin, D.A., Leung, S. et al. New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up. Breast Cancer Res Treat 112, 453–459 (2008). https://doi.org/10.1007/s10549-007-9887-y

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  • DOI: https://doi.org/10.1007/s10549-007-9887-y

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