This Article Full Text Full Text (PDF) Erratum (v25,p3790) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Loi, S. Articles by Sotiriou, C. Search for Related Content PubMed PubMed Citation Articles by Loi, S. Articles by Sotiriou, C. Related Articles Related Correspondence Social Bookmarking                            What's this?

Definition of Clinically Distinct Molecular Subtypes in Estrogen Receptor–Positive Breast Carcinomas Through Genomic Grade

Sherene Loi, Benjamin Haibe-Kains, Christine Desmedt, Françoise Lallemand, Andrew M. Tutt, Cheryl Gillet, Paul Ellis, Adrian Harris, Jonas Bergh, John A. Foekens, Jan G.M. Klijn, Denis Larsimont, Marc Buyse, Gianluca Bontempi, Mauro Delorenzi, Martine J. Piccart, Christos Sotiriou

From the Jules Bordet Institute; Machine Learning Group, Université Libre de Bruxelles; International Drug and Development Institute, Brussels, Belgium; Peter MacCallum Cancer Center, Melbourne, Australia; Guys Hospital, London; John Radcliffe Hospital, Oxford, United Kingdom; Karolinska Institute, Stockholm, Sweden; Erasmus Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; National Center of Competence in Research Molecular Oncology, Swiss Institute of Cancer Research and Swiss Institute of Bioinformatics, Epalinges, Switzerland

Address reprint requests to Christos Sotiriou, MD, PhD, Translational Research Unit, Jules Bordet Institute, Université Libre de Bruxelles, 121 Blvd de Waterloo, 1000 Brussels, Belgium; e-mail: christos.sotiriou{at}bordet.be

Purpose A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) –positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed.

Materials and Methods We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high–or low–genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome.

Results Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations.

Conclusion The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.

Supported by grants from the Jean-Claude Heuson Breast Cancer Foundation (S.L., C.S.), the Belgian National Foundation for Research (FNRS; B.H.-K., C.D., C.S.), the E. Lauder Breast Cancer Foundation (C.S.), and the MEDIC Foundation (C.S.).

S.L., B.H.-K., and C.D. contributed equally to this article.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Correspondence

• Expression Profiling in Breast Carcinoma: New Insights on Old Prognostic Factors?
  Marc Debled, Gaëtan MacGrogan, Isabelle de Mascarel, Véronique Brouste, Hervé Bonnefoi, and Louis Mauriac
  JCO 2007 25: 4316-4317 [Full Text]

This article has been cited by other articles:

				G. Frasci, G. D'Aiuto, P. Comella, M. D'Aiuto, M. Di Bonito, P. Ruffolo, G. Iodice, A. Petrillo, S. Lastoria, P. Oliviero, et al. Preoperative weekly cisplatin, epirubicin, and paclitaxel (PET) improves prognosis in locally advanced breast cancer patients: an update of the Southern Italy Cooperative Oncology Group (SICOG) randomised trial 9908 Ann. Onc., October 8, 2009; (2009) mdp356v1. [Abstract] [Full Text] [PDF]

				S. H. Dairkee, A. Sayeed, G. Luciani, S. Champion, Z. Meng, L. R. Jakkula, H. S. Feiler, J. W. Gray, and D. H. Moore Immutable Functional Attributes of Histologic Grade Revealed by Context-Independent Gene Expression in Primary Breast Cancer Cells Cancer Res., October 1, 2009; 69(19): 7826 - 7834. [Abstract] [Full Text] [PDF]

				A. Torkamani and N. J. Schork Prestige centrality-based functional outlier detection in gene expression analysis Bioinformatics, September 1, 2009; 25(17): 2222 - 2228. [Abstract] [Full Text] [PDF]

				H. J. Burstein, I. Souter, H. A. D'Alessandro, and D. C. Sgroi Case 25-2009 -- A 36-Year-Old Woman with Hormone-Receptor-Positive Breast Cancer N. Engl. J. Med., August 13, 2009; 361(7): 699 - 707. [Full Text] [PDF]

				F. Correa Geyer and J. S. Reis-Filho Microarray-based Gene Expression Profiling as a Clinical Tool for Breast Cancer Management: Are We There Yet? International Journal of Surgical Pathology, August 1, 2009; 17(4): 285 - 302. [Abstract] [PDF]

				C. Liedtke, C. Hatzis, W. F. Symmans, C. Desmedt, B. Haibe-Kains, V. Valero, H. Kuerer, G. N. Hortobagyi, M. Piccart-Gebhart, C. Sotiriou, et al. Genomic Grade Index Is Associated With Response to Chemotherapy in Patients With Breast Cancer J. Clin. Oncol., July 1, 2009; 27(19): 3185 - 3191. [Abstract] [Full Text] [PDF]

				C. H. Barrios, C. Sampaio, J. Vinholes, and R. Caponero What is the role of chemotherapy in estrogen receptor-positive, advanced breast cancer? Ann. Onc., July 1, 2009; 20(7): 1157 - 1162. [Abstract] [Full Text] [PDF]

				A. M. Sieuwerts, J. Kraan, J. Bolt-De Vries, P. Van Der Spoel, F. Elstrodt, M. Smid, M. Timmermans, B. Mostert, M. Schutte, J. W. M. Martens, et al. Response: Re: Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal-Like Breast Tumor Cells J Natl Cancer Inst, June 16, 2009; 101(12): 896 - 897. [Full Text] [PDF]

				S. P. Pitroda, N. N. Khodarev, M. A. Beckett, D. W. Kufe, and R. R. Weichselbaum From the Cover: MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment PNAS, April 7, 2009; 106(14): 5837 - 5841. [Abstract] [Full Text] [PDF]

				M. Schmidt, J. G. Hengstler, C. von Torne, H. Koelbl, and M. C. Gehrmann Coordinates in the Universe of Node-Negative Breast Cancer Revisited Cancer Res., April 1, 2009; 69(7): 2695 - 2698. [Abstract] [Full Text] [PDF]

				J. S. Parker, M. Mullins, M. C.U. Cheang, S. Leung, D. Voduc, T. Vickery, S. Davies, C. Fauron, X. He, Z. Hu, et al. Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes J. Clin. Oncol., March 10, 2009; 27(8): 1160 - 1167. [Abstract] [Full Text] [PDF]

				C. Sotiriou and L. Pusztai Gene-Expression Signatures in Breast Cancer N. Engl. J. Med., February 19, 2009; 360(8): 790 - 800. [Full Text] [PDF]

				S Badve and H Nakshatri Oestrogen-receptor-positive breast cancer: towards bridging histopathological and molecular classifications J. Clin. Pathol., January 1, 2009; 62(1): 6 - 12. [Abstract] [Full Text] [PDF]

				P. Bhat-Nakshatri, G. Wang, H. Appaiah, N. Luktuke, J. S. Carroll, T. R. Geistlinger, M. Brown, S. Badve, Y. Liu, and H. Nakshatri AKT Alters Genome-Wide Estrogen Receptor {alpha} Binding and Impacts Estrogen Signaling in Breast Cancer Mol. Cell. Biol., December 15, 2008; 28(24): 7487 - 7503. [Abstract] [Full Text] [PDF]

				M. Dowsett and A. K. Dunbier Emerging Biomarkers and New Understanding of Traditional Markers in Personalized Therapy for Breast Cancer Clin. Cancer Res., December 15, 2008; 14(24): 8019 - 8026. [Abstract] [Full Text] [PDF]

				D. T. Ross, C.-y. Kim, G. Tang, O. L. Bohn, R. A. Beck, B. Z. Ring, R. S. Seitz, S. Paik, J. P. Costantino, and N. Wolmark Chemosensitivity and Stratification by a Five Monoclonal Antibody Immunohistochemistry Test in the NSABP B14 and B20 Trials Clin. Cancer Res., October 15, 2008; 14(20): 6602 - 6609. [Abstract] [Full Text] [PDF]

				L. R. Webster, S.-F. Lee, C. Ringland, A. L. Morey, A. M. Hanby, G. Morgan, K. Byth, P. A. Mote, P. J. Provan, I. O. Ellis, et al. Poor-Prognosis Estrogen Receptor-Positive Breast Cancer Identified by Histopathologic Subclassification Clin. Cancer Res., October 15, 2008; 14(20): 6625 - 6633. [Abstract] [Full Text] [PDF]

				B. Haibe-Kains, C. Desmedt, C. Sotiriou, and G. Bontempi A comparative study of survival models for breast cancer prognostication based on microarray data: does a single gene beat them all? Bioinformatics, October 1, 2008; 24(19): 2200 - 2208. [Abstract] [Full Text] [PDF]

				M. P. Goetz, V. J. Suman, F. J. Couch, M. M. Ames, J. M. Rae, M. G. Erlander, X.-J. Ma, D. C. Sgroi, C. A. Reynolds, W. L. Lingle, et al. Cytochrome P450 2D6 and Homeobox 13/Interleukin-17B Receptor: Combining Inherited and Tumor Gene Markers for Prediction of Tamoxifen Resistance Clin. Cancer Res., September 15, 2008; 14(18): 5864 - 5868. [Abstract] [Full Text] [PDF]

				C. Desmedt, B. Haibe-Kains, P. Wirapati, M. Buyse, D. Larsimont, G. Bontempi, M. Delorenzi, M. Piccart, and C. Sotiriou Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes Clin. Cancer Res., August 15, 2008; 14(16): 5158 - 5165. [Abstract] [Full Text] [PDF]

				C. R. Acharya and A. Potti Documenting Biospecimen Conditions in Reports of Studies--Reply JAMA, August 13, 2008; 300(6): 651 - 651. [Full Text] [PDF]

				M. Schmidt, D. Bohm, C. von Torne, E. Steiner, A. Puhl, H. Pilch, H.-A. Lehr, J. G. Hengstler, H. Kolbl, and M. Gehrmann The Humoral Immune System Has a Key Prognostic Impact in Node-Negative Breast Cancer Cancer Res., July 1, 2008; 68(13): 5405 - 5413. [Abstract] [Full Text] [PDF]

				X.-J. Ma, R. Salunga, S. Dahiya, W. Wang, E. Carney, V. Durbecq, A. Harris, P. Goss, C. Sotiriou, M. Erlander, et al. A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer Clin. Cancer Res., May 1, 2008; 14(9): 2601 - 2608. [Abstract] [Full Text] [PDF]

				J. S. Ross, C. Hatzis, W. F. Symmans, L. Pusztai, and G. N. Hortobagyi Commercialized Multigene Predictors of Clinical Outcome for Breast Cancer Oncologist, May 1, 2008; 13(5): 477 - 493. [Abstract] [Full Text] [PDF]

				C. R. Acharya, D. S. Hsu, C. K. Anders, A. Anguiano, K. H. Salter, K. S. Walters, R. C. Redman, S. A. Tuchman, C. A. Moylan, S. Mukherjee, et al. Gene Expression Signatures, Clinicopathological Features, and Individualized Therapy in Breast Cancer JAMA, April 2, 2008; 299(13): 1574 - 1587. [Abstract] [Full Text] [PDF]

				S. H. Dairkee, J. Seok, S. Champion, A. Sayeed, M. Mindrinos, W. Xiao, R. W. Davis, and W. H. Goodson Bisphenol A Induces a Profile of Tumor Aggressiveness in High-Risk Cells from Breast Cancer Patients Cancer Res., April 1, 2008; 68(7): 2076 - 2080. [Abstract] [Full Text] [PDF]

				M. Chanrion, V. Negre, H. Fontaine, N. Salvetat, F. Bibeau, G. M. Grogan, L. Mauriac, D. Katsaros, F. Molina, C. Theillet, et al. A Gene Expression Signature that Can Predict the Recurrence of Tamoxifen-Treated Primary Breast Cancer Clin. Cancer Res., March 15, 2008; 14(6): 1744 - 1752. [Abstract] [Full Text] [PDF]

				I. G. Yulug and B. Gur-Dedeoglu Functional genomics in translational cancer research: focus on breast cancer Brief Funct Genomic Proteomic, March 7, 2008; (2008) eln009v1. [Abstract] [Full Text] [PDF]

				C. Camps, F. M. Buffa, S. Colella, J. Moore, C. Sotiriou, H. Sheldon, A. L. Harris, J. M. Gleadle, and J. Ragoussis hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer Clin. Cancer Res., March 1, 2008; 14(5): 1340 - 1348. [Abstract] [Full Text] [PDF]

				N. U. Lin and E. P. Winer Advances in Adjuvant Endocrine Therapy for Postmenopausal Women J. Clin. Oncol., February 10, 2008; 26(5): 798 - 805. [Abstract] [Full Text] [PDF]

				P. Finetti, N. Cervera, E. Charafe-Jauffret, C. Chabannon, C. Charpin, M. Chaffanet, J. Jacquemier, P. Viens, D. Birnbaum, and F. Bertucci Sixteen-Kinase Gene Expression Identifies Luminal Breast Cancers with Poor Prognosis Cancer Res., February 1, 2008; 68(3): 767 - 776. [Abstract] [Full Text] [PDF]

				J. Adelaide, P. Finetti, I. Bekhouche, L. Repellini, J. Geneix, F. Sircoulomb, E. Charafe-Jauffret, N. Cervera, J. Desplans, D. Parzy, et al. Integrated Profiling of Basal and Luminal Breast Cancers Cancer Res., December 15, 2007; 67(24): 11565 - 11575. [Abstract] [Full Text] [PDF]

				W. Schroth, L. Antoniadou, P. Fritz, M. Schwab, T. Muerdter, U. M. Zanger, W. Simon, M. Eichelbaum, and H. Brauch Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes J. Clin. Oncol., November 20, 2007; 25(33): 5187 - 5193. [Abstract] [Full Text] [PDF]

				M. Debled, G. MacGrogan, I. de Mascarel, V. Brouste, H. Bonnefoi, and L. Mauriac Expression Profiling in Breast Carcinoma: New Insights on Old Prognostic Factors? J. Clin. Oncol., September 20, 2007; 25(27): 4316 - 4317. [Full Text] [PDF]

				S. Loi, B. Haibe-Kains, C. Desmedt, and C. Sotiriou In Reply J. Clin. Oncol., September 20, 2007; 25(27): 4317 - 4318. [Full Text] [PDF]