Tejpar, Bertagnolli, Bosman et al. from a specific treatment. Despite more than two de- cades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive mo- lecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared iri- notecan in combination with 5-fluorouracil and leu- covorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of puta- tive prognostic and predictive markers in a large co- INTRODUCTION Colorectal cancer (CRC) is a major cause of cancer mortal- ity worldwide, with approximately 500,000 recorded deaths from the disease in 2002 [1]. A significant propor- tion of patients presenting with stage I, II, or III disease (75% of patients) can be cured by surgical intervention, with U.S. 5-year survival rate figures of 93.2%, 82.5%, and 59.5%, respectively, compared with only 8.1% for stage IV disease [2]. Following resection, there is a considerable risk for tumor recurrence in patients with stage III and high-risk stage II disease, which can be significantly reduced by treating with 5-fluorouracil (5-FU)-based adjuvant chemo- therapy [3–5]. The addition of oxaliplatin to 5-FU– based chemotherapy (5-FU, leucovorin, and oxaliplatin—the FOLFOX-4 regimen) is now a standard adjuvant treatment for colon cancer, with a higher 5-year disease-free survival (DFS) rate (73.3% versus 67.4%) and significantly higher overall survival (OS) rate at 6 years in stage III patients (78.5% versus 76%), compared with 5-FU– based treatment alone [6]. The combination of irinotecan with 5-FU failed to result in a higher DFS rate than with 5-FU– based therapy alone in the Pan European Trials in Adjuvant Colon Cancer (PETACC)-3 and Cancer and Leukemia Group B (CALGB) 89803 trials [7, 8]. In the absence of adjuvant therapy, approximately 50% of colon cancer patients with resectable disease are cured by surgery alone, whereas 50% relapse. Using adjuvant che- motherapy following surgery rescues approximately 15% of patients from the relapsing group. In current practice, the majority of colon cancer patients receive treatment unnec- essarily, either because they were cured or because they will relapse despite treatment. It is therefore essential to identify patients who will benefit from adjuvant therapy, sparing others needless toxicity and the financial burden of chemotherapy that will not work. The availability and ap- plication of various treatment modalities in colon cancer has resulted in intense interest in the elucidation of prog- nostic and predictive biomarkers that will improve outcome www.TheOncologist.com 391 lon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investi- gated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are co- investigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for bio- marker discovery in the postgenomic era. The Oncolo- gist 2010;15:390 – 404 through patient classification and selection for specific therapies. A prognostic biomarker provides information about the patient’s overall outcome, regardless of therapy, whereas a predictive biomarker gives information about the effect of a particular therapeutic intervention. Currently, the tumor–node–metastasis stage is the only proven prognostic marker to aid in the identification of patients with aggres- sive disease [3, 9]. Thus, there is an urgent need for prog- nostic and predictive biomarkers to guide adjuvant therapy for colon cancer and a need for large cohorts of randomized patients in which to test and validate biomarkers in this set- ting. A secondary objective of the PETACC-3 trial was to un- dertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort [10]. The preliminary findings of that study and the status of other large randomized adjuvant tri- als, including the CALGB 89803 trial, were reviewed and placed in the context of biomarker discovery for adjuvant treatment of colon cancer at a meeting of a panel of experts held in Boston (U.S.) in May 2008 sponsored by Pfizer. In this article, we review the current status of biomarkers for the adjuvant treatment of colon cancer and consider future strategies for biomarker discovery and development in the postgenomic era. BIOMARKERS IN COLON CANCER: PRESENT STATUS Molecular Genetics of Colon Cancer Our knowledge of the molecular etiology of colon cancer has facilitated the identification of a number of promising prognostic and/or predictive biomarkers. A simplified model of tumor progression from adenoma to carcinoma has been proposed, which includes the stepwise accumula- tion of genetic events to several key genes and genetic loci: disruption to WNT signaling, activation of the KRAS proto- oncogene, allelic imbalance (AI) on chromosome 18q, re- duced expression of SMAD4, and mutation of the TP53