Molecular classification and molecular forecasting of breast cancer: ready for clinical application? James D. Brenton, Lisa A. Carey, Ahmed Ashour Ahmed, and Carlos Caldas From the Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom; and Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC. Submitted July 6, 2005; accepted July 19, 2005. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Carlos Caldas, MD, Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom CB22XZ; e-mail: cc234@cam.ac.uk. 0732-183X/05/2329-7350/$20.00 DOI: 10.1200/JCO.2005.03.3845 Abstract Expression profiling of breast cancer has become common, and it has been suggested that the results from early studies will lead to understanding of the molecular differences between clinical cases and allow individualization of care. We critically review two main applications of expression profiling; studies unraveling novel breast cancer classifications and those that aim to identify novel markers for prediction of clinical outcome. Breast cancer may now be subclassified into luminal, basal, and HER2 subtypes with distinct differences in prognosis and response to therapy. However, profiling studies to identify predictive markers have suffered from methodologic problems that prevent general application of their results. Future work will need to reanalyze existing microarray data sets to identify more representative sets of candidate genes for use as prognostic signatures and will need to take into account the new knowledge of molecular subtypes of breast cancer when assessing predictive effects. J Clin Oncol 23:7350-7360. Introduction The management of breast cancer has been dramatically changed with the advent of widespread screening programs and the systematic use of adjuvant hormonal therapy and chemotherapy. Recent data have shown that these changes are having a major impact in outcome, and despite increasing incidence, breast cancer mortality is decreasing in most of the Western world. The recent overview of randomized adjuvant therapy trials has confirmed that systemic therapies (hormone therapy and chemotherapy) are producing cures; survival curves at 15 years show a greater separation, despite recurrence curves' remaining almost flat after 5 years. Moreover, the overview also confirms that tamoxifen is of benefit in only patients with estrogen receptor (ER)-positive disease, effectively representing a form of targeted therapy.Molecular classification and molecular forecasting of breast cancer: ready for clinical application? James D. Brenton, Lisa A. Carey, Ahmed Ashour Ahmed, and Carlos Caldas From the Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom; and Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC. Submitted July 6, 2005; accepted July 19, 2005. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Carlos Caldas, MD, Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom CB22XZ; e-mail: cc234@cam.ac.uk. 0732-183X/05/2329-7350/$20.00 DOI: 10.1200/JCO.2005.03.3845 Abstract Expression profiling of breast cancer has become common, and it has been suggested that the results from early studies will lead to understanding of the molecular differences between clinical cases and allow individualization of care. We critically review two main applications of expression profiling; studies unraveling novel breast cancer classifications and those that aim to identify novel markers for prediction of clinical outcome. Breast cancer may now be subclassified into luminal, basal, and HER2 subtypes with distinct differences in prognosis and response to therapy. However, profiling studies to identify predictive markers have suffered from methodologic problems that prevent general application of their results. Future work will need to reanalyze existing microarray data sets to identify more representative sets of candidate genes for use as prognostic signatures and will need to take into account the new knowledge of molecular subtypes of breast cancer when assessing predictive effects. J Clin Oncol 23:7350-7360. Introduction The management of breast cancer has been dramatically changed with the advent of widespread screening programs and the systematic use of adjuvant hormonal therapy and chemotherapy. Recent data have shown that these changes are having a major impact in outcome, and despite increasing incidence, breast cancer mortality is decreasing in most of the Western world. The recent overview of randomized adjuvant therapy trials has confirmed that systemic therapies (hormone therapy and chemotherapy) are producing cures; survival curves at 15 years show a greater separation, despite recurrence curves' remaining almost flat after 5 years. Moreover, the overview also confirms that tamoxifen is of benefit in only patients with estrogen receptor (ER)-positive disease, effectively representing a form of targeted therapy.