Concordance among Gene-ExpressionBased Predictors for Breast Cancer
Cheng Fan, M.S., Daniel S. Oh, Ph.D., Lodewyk Wessels, Ph.D., Britta Weigelt, Ph.D., Dimitry S.A. Nuyten, M.D., Andrew B. Nobel, Ph.D., Laura J. van't Veer, Ph.D., and Charles M. Perou, Ph.D.
Background Gene-expressionprofiling studies of primarybreast tumors performed by different laboratories have resultedin the identification of a number of distinct prognostic profiles,or gene sets, with little overlap in terms of gene identity.
Methods To compare the predictions derived from these gene setsfor individual samples, we obtained a single data set of 295samples and applied five gene-expressionbased models:intrinsic subtypes, 70-gene profile, wound response, recurrencescore, and the two-gene ratio (for patients who had been treatedwith tamoxifen).
Results We found that most models had high rates of concordancein their outcome predictions for the individual samples. Inparticular, almost all tumors identified as having an intrinsicsubtype of basal-like, HER2-positive and estrogen-receptornegative,or luminal B (associated with a poor prognosis) were also classifiedas having a poor 70-gene profile, activated wound response,and high recurrence score. The 70-gene and recurrence-scoremodels, which are beginning to be used in the clinical setting,showed 77 to 81 percent agreement in outcome classification.
Conclusions Even though different gene sets were used for prognosticationin patients with breast cancer, four of the five tested showedsignificant agreement in the outcome predictions for individualpatients and are probably tracking a common set of biologicphenotypes.
Source Information
From the Departments of Genetics (C.F., D.S.O., C.M.P.), Statistics and Operations Research (A.B.N.), and Pathology and Laboratory Medicine (C.M.P.), University of North Carolina at Chapel Hill and Lineberger Comprehensive Cancer Center, Chapel Hill; and the Divisions of Diagnostic Oncology (L.W., B.W., L.J.V.) and Radiotherapy (D.S.A.N.), the Netherlands Cancer Institute, Amsterdam. Drs. Fan and Oh contributed equally to this article.
Address reprint requests to Dr. Perou at Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Campus Box 7295, Chapel Hill, NC 27599, or at cperou{at}med.unc.edu.
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Dyrskjot, L., Zieger, K., Real, F. X., Malats, N., Carrato, A., Hurst, C., Kotwal, S., Knowles, M., Malmstrom, P.-U., de la Torre, M., Wester, K., Allory, Y., Vordos, D., Caillault, A., Radvanyi, F., Hein, A.-M. K., Jensen, J. L., Jensen, K. M.E., Marcussen, N., Orntoft, T. F.
(2007). Gene Expression Signatures Predict Outcome in Non-Muscle-Invasive Bladder Carcinoma: A Multicenter Validation Study. Clin. Cancer Res.
13: 3545-3551
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Larsen, J. E., Pavey, S. J., Passmore, L. H., Bowman, R. V., Hayward, N. K., Fong, K. M.
(2007). Gene Expression Signature Predicts Recurrence in Lung Adenocarcinoma. Clin. Cancer Res.
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Crivellari, D., Aapro, M., Leonard, R., von Minckwitz, G., Brain, E., Goldhirsch, A., Veronesi, A., Muss, H.
(2007). Breast Cancer in the Elderly. JCO
25: 1882-1890
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Bertucci, F., Cervera, N., Birnbaum, D., Wennmalm, K., Miller, L. D., Bergh, J., Woodward, W. A., Lucci, A., Cristofanilli, M., the Advanced Research Center for Micrometastatic D, , Clarke, M. F., Liu, R., Wang, X.
(2007). A Gene Signature in Breast Cancer. NEJM
356: 1887-1888
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Saal, L. H., Johansson, P., Holm, K., Gruvberger-Saal, S. K., She, Q.-B., Maurer, M., Koujak, S., Ferrando, A. A., Malmstrom, P., Memeo, L., Isola, J., Bendahl, P.-O., Rosen, N., Hibshoosh, H., Ringner, M., Borg, A., Parsons, R.
(2007). Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc. Natl. Acad. Sci. USA
104: 7564-7569
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Minn, A. J., Gupta, G. P., Padua, D., Bos, P., Nguyen, D. X., Nuyten, D., Kreike, B., Zhang, Y., Wang, Y., Ishwaran, H., Foekens, J. A., van de Vijver, M., Massague, J.
(2007). Lung metastasis genes couple breast tumor size and metastatic spread. Proc. Natl. Acad. Sci. USA
104: 6740-6745
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Carey, L. A., Dees, E. C., Sawyer, L., Gatti, L., Moore, D. T., Collichio, F., Ollila, D. W., Sartor, C. I., Graham, M. L., Perou, C. M.
(2007). The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes. Clin. Cancer Res.
13: 2329-2334
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Shak, S., Palmer, G., Baker, J.
(2007). Re: Breast Cancer Gene Microarrays Pass Muster. JNCI J Natl Cancer Inst
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Loi, S., Haibe-Kains, B., Desmedt, C., Lallemand, F., Tutt, A. M., Gillet, C., Ellis, P., Harris, A., Bergh, J., Foekens, J. A., Klijn, J. G.M., Larsimont, D., Buyse, M., Bontempi, G., Delorenzi, M., Piccart, M. J., Sotiriou, C.
(2007). Definition of Clinically Distinct Molecular Subtypes in Estrogen Receptor-Positive Breast Carcinomas Through Genomic Grade. JCO
25: 1239-1246
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Huang, F., Reeves, K., Han, X., Fairchild, C., Platero, S., Wong, T. W., Lee, F., Shaw, P., Clark, E.
(2007). Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection. Cancer Res.
67: 2226-2238
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Ioannidis, J. P. A.
(2007). Is Molecular Profiling Ready for Use in Clinical Decision Making?. The Oncologist
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Jansen, M. P.H.M., Sieuwerts, A. M., Look, M. P., Ritstier, K., Meijer-van Gelder, M. E., van Staveren, I. L., Klijn, J. G.M., Foekens, J. A., Berns, E. M.J.J.
(2007). HOXB13-to-IL17BR Expression Ratio Is Related With Tumor Aggressiveness and Response to Tamoxifen of Recurrent Breast Cancer: A Retrospective Study. JCO
25: 662-668
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Goetz, M. P., Ingle, J. N., Couch, F. J., Fan, C., van't Veer, L. J., Perou, C. M.
(2007). Gene-Expression-Based Predictors for Breast Cancer. NEJM
356: 752-753
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Lillie, S. E., Brewer, N. T., O'Neill, S. C., Morrill, E. F., Dees, E. C., Carey, L. A., Rimer, B. K.
(2007). Retention and Use of Breast Cancer Recurrence Risk Information from Genomic Tests: The Role of Health Literacy. Cancer Epidemiol. Biomarkers Prev.
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Liu, R., Wang, X., Chen, G. Y., Dalerba, P., Gurney, A., Hoey, T., Sherlock, G., Lewicki, J., Shedden, K., Clarke, M. F.
(2007). The Prognostic Role of a Gene Signature from Tumorigenic Breast-Cancer Cells. NEJM
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Massague, J.
(2007). Sorting Out Breast-Cancer Gene Signatures. NEJM
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