400 concluded that microarray expression profiling is able to predict, to some extent, prognosis in stage B colon cancer patients and that resampling techniques should be used to objectively assess the performance of microarray-based prognosis predictors [150]. More recently, a multivariate analysis (including stage, grade, nodes, and MSI status) of four developmental studies in colon cancer patients identified 18 genes (seven prognos- tic genes and six genes predictive for 5-FU and LV benefit, and five reference genes) and separate prognostic RS and treatment predictive score (TS) algorithms [37]. In a vali- dation analysis on material from the QUASAR study, the RS was validated as an independent predictor of individu- alized recurrence risk for stage II colon cancer patients, al- though the TS was not validated as a predictor of benefit from 5-FU and LV therapy [37]. Although studies in colon cancer are promising, caution is required because investigators have yet to meet the high standards for study reproducibility and generalizability re- quired for the use of genomic profiling in the classification of cancer patients for clinical purposes (reviewed by Michiels et al. [151]). Robust prediction rules must be de- veloped in order to correlate gene-expression profiles with clinical outcome. A major question to be addressed with this approach is whether or not gene-expression profiles im- prove on existing prognostic systems. In breast cancer, clin- ical trials have been established to determine the prognostic and predictive values of gene-expression profiles. In the TAILORx study [Trial Assigning IndividuaLized Options for Treatment (Rx)], the National Cancer Institute is inves- tigating the breast cancer RS model in 10,000 women re- cruited across the U.S. and Canada with estrogen receptor– and/or progesterone receptor–positive, human epidermal growth factor receptor 2/neu-negative breast cancer that has not yet spread to the lymph nodes. The European Organi- zation for Research and Treatment of Cancer has designed a trial (Microarray In Node negative Disease May Avoid ChemoTherapy, MINDACT) to study the 70-gene signa- ture in 6,000 node-negative breast cancer patients recruited across Europe. The design of similar trials will be the gold standard for the investigation of the prognostic and predic- tive value of genomic profiles in adjuvant colon cancer. Biomarkers in Colon Cancer Adjuvant Treatment CONCLUSIONS Despite significant methodological progress, CRC re- search has not yet provided biomarkers for clinical use in guiding adjuvant colon cancer treatment, although MSI is promising. Preliminary biomarker data from the PETACC-3 and CALGB 89803 trials suggest that it is possible to perform translational studies on FFPE mate- rial derived from large multicenter clinical trials carried out in the adjuvant setting. Furthermore, the approaches used provide a model for use in the laboratory of material collected during the course of other randomized adjuvant studies. Although the development of platforms for genomewide analysis of molecular alterations in tumors will facilitate biomarker discovery, it is important that our studies are not driven primarily by the availability of superior technology. The selection of hypotheses for testing must be guided in the first instance by putative clinical relevance, irrespective of whether the questions are focused on increasing our understanding of tumor bi- ology or are part of patient reclassification/treatment se- lection procedures. Ultimately, the end product of a translational study must be a clinically relevant biomar- ker that can be easily assayed in the clinical setting, pro- ducing a direct benefit for the individual patient. AUTHOR CONTRIBUTIONS Conception/Design: Sabine Tejpar, Fred Bosman, Levi Garraway, D. Paul Harkin, Ian Tomlinson Provision of study materials or patients: Sabine Tejpar, Heinz-Joseph Lenz, Frederic Waldman, Robert Warren, Charles Swanton, Hans Morreau, Eric Van Cutsem Collection/assembly of data: Sabine Tejpar, Fred Bosman, Heinz-Joseph Lenz, Hejin Hahn Data analysis and interpretation: Sabine Tejpar, Monica Bertagnolli, Heinz- Joseph Lenz, Robert Warren, Andrea Bild, Denise Collins-Brennan, Charles Swanton, Richard Kennedy, Mohammad Ilyas, Roberto Fiocca Manuscript writing: Sabine Tejpar, Monica Bertagnolli, Heinz-Joseph Lenz, Robert Warren, Denise Collins-Brennan, Vitali Proutski, Ian Tomlinson, Mauro Delorenzi, Eric Van Cutsem, Arnaud Roth Final approval of manuscript: Sabine Tejpar, Monica Bertagnolli, Fred Bosman, Heinz-Joseph Lenz, Levi Garraway, Frederic Waldman, Robert Warren, Andrea Bild, Denise Collins-Brennan, Hejin Hahn, D. Paul Harkin, Richard Kennedy, Mohammad Ilyas, Hans Morreau, Vitali Proutski, Charles Swanton, Ian Tomlinson, Mauro Delorenzi, Roberto Fiocca, Eric Van Cutsem, Arnaud Roth The authors take full responsibility for the content of the paper but thank Paul Hoban, Ph.D., from Cancer Communications and Consultancy Ltd., funded by Pfizer, who summarized the discussion of the authors, prepared the initial draft of the manuscript based on the 2008 investigator meeting, and revised accord- ing to the authors’ comments. REFERENCES 1 2 3 Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Can- cer J Clin 2005;55:74 –108. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420 –1425. Gill S, Loprinzi CL, Sargent DJ et al. Pooled analysis of fluorouracil- 4 5 based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? 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