Emerging Biomarkers and New Understandingof Traditional Markers in Personalized Therapy for Breast Cancer MitchDowsett 1,2 andAnitaK.Dunbier 1,2 Abstract The era of personalized medicine is likely to see an escalation in the use of biomarkers to ensure breast cancer patients receive optimal treatment. A combination of prognostic and predictive biomarkers should enable better quantification of the residual risk faced by patients andindicate the potential value ofadditional treatment. Establishedbiomarkers such as estrogen receptor and progesterone receptor already play a significant role in the selection of patients for endocrine therapy. Human epidermal growth factor receptor 2 (HER2) is recognized as a strong predictor of response to trastuzumab whereas, more recently, the role of estrogen receptor and HER2 as negative and positive indicators for chemotherapy has also been explored. Ki67 has traditionally been recognized as a modest prognostic factor, but recent neoadjuvant studies suggest that on-treatment measurement may be a more effective predictor of treatment efficacyforbothendocrinetreatmentandchemotherapy.Thelastdecadehasseentheemergence of numerous multigene expression profiles that aim to outdo traditional predictive and prog- nostic factors.The Oncotype DX assay and the MammaPrint profile are currently undergoing prospective clinical trials to clearly define their role. Other gene expression^based assays also show potential but are yet to be tested clinically. Rigorous comparison of these emerging markers with current treatment selection criteria will be required to determine whether they offer significant benefit to justify their use. The last 20 years have seen a substantial decline in breast cancer mortality, and a major contributor to this is the delivery of adjuvant medical therapy (1, 2). It is important, however, that decisions are made that minimize overtreatment, under- treatment, or incorrect treatment. Improved understanding and application of traditional biomarkers and the identification of new markers is increasingly providing insight into who should receive cancer therapy and what therapy they should receive, ultimately avoiding suboptimal treatment. The postgenome era has seen a deluge of reports claiming to identify factors or profiles that predict response to therapeutic agents or provide prognostic information. Only a small frac- tion has been validated to Level of Evidence I or II according to the Tumor Marker Utility Grading System endorsed by the American Society of Clinical Oncology (3, 4). Nonetheless, a subset of new markers shows substantial promise for future use. In addition, the identification and development of these markers have led to insights into their biology as well as that of existing tumor markers. Here, we review developments in the understanding of established clinical markers and examine some prominent emerging markers. We focus on characteristics of the tumor; other chapters in this issue address aspects of germ-line genetic variability that may affect clinicopathologic presentation of tumors and/or their response to therapy (5, 6). The markers discussed are summarized in Table 1. Prognosis or Prediction? The relative importance of prognostic and predictive factors has been debated for many years. Many factors show mixed prognostic and predictive associations that vary according to the treatment given. For example and as discussed below, markers of proliferation, such as Ki67, show strong prognostic effects and are also predictive of greater response to most chemotherapies but are not significantly predictive of benefit from endocrine therapy. More recently it has become increasingly accepted that the combination of the two parameters to define prognosis on a particular treatment may be of substantial value because this may allow the definition of residual risk and thereby indicate the potential value or not of additional treatment. This has been most notable in determining which estrogen receptor–positive, node-negative patients treated with endocrine therapy merit chemotherapy as well. Some traditional and a number of the newer markers or marker sets address this issue. Traditional Biomarkers A small number of single biomarkers has been used for several years in various aspects of managing breast cancer, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Their study in new Authors’Affiliations: 1 Academic Departmentof Biochemistry, Royal Marsden Hospital and 2 The Breakthrough Breast Cancer Research Centre,The Institute of Cancer Research, London, United Kingdom Received4/14/08;revised9/17/08;accepted9/30/08. Requests for reprints: AnitaK.Dunbier,AcademicDepartmentofBiochemistry, RoyalMarsdenHospital,FulhamRoad,London,SW36JJ,UnitedKingdom.Phone:44- 207-808-2883;Fax:44-207-376-3918;E-mail:anita.dunbier@icr.ac.uk. F 2008AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-08-0974 www.aacrjournals.org ClinCancerRes2008;14(24)December15,2008 8019 CCR FOCUS