Breast Cancer Awareness: Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer

Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer — Cancer Res

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Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer Giampaolo Bianchini 1,4, Takayuki Iwamoto 2,4, Yuan Qi 3, Charles Coutant 4,6, Christine Y. Shiang 4, Bailang Wang 4, Libero Santarpia 5,7, Vicente Valero 4, Gabriel N. Hortobagyi 4, W. Fraser Symmans 5, Luca Gianni 1, and Lajos Pusztai 4

Authors' Affiliations:1Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; Departments of 3Bioinformatics, 4Breast Medical Oncology, and 5Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 6Department of Gynecology and Obstetrics, University Pierre et Marie Curie Tenon Hospital, Paris, France; and 7Translational Research Unit, Department of Medical Oncology, Hospital of Prato and Istituto Toscana Tumori, Prato, Italy Corresponding Author:
Lajos Pusztai, Department of Breast Medical Oncology, Unit 1354, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Houston, TX 77230-1439. Phone: 713-792-2817; Fax: 713-794-4385; E-mail: lpusztai{at}mdanderson.org. Abstract Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative, 7 in HER2+, and 28 in ER-/HER2- cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER-/HER2- cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER+/HER2- cancers, but not in ER-/HER2- or HER2+ cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER+/HER2- and HER2+ tumors and also predicted higher probability of pCR in HER2+ cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype. Cancer Res; 70(21); 8852–62. ©2010 AACR.

Footnotes Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).