Table 1.

Study	N	Stage	KRAS Mutation Rate	BRAF Mutation Rate
European consortium dataset²⁰	773^*	IV	40%	4.7%
COIN⁴⁸	1316^†	IV	43%	8%
CAIRO2¹⁸	559	IV	39.4%	8.7%
PETACC-3³⁶	1564	II and III	37%	7.9%

KRAS and BRAF Mutation Incidence in Selected Randomized Studies

^*649 samples were eligible for outcome analyses.
^† Evaluable for mutation analyses.

Table 2.

Biomarker Name	Type of Specimen Required	Type of Test	Stage of Disease	Intended Use	Current Validation Status	Commercial Availability
ColoPrint	Fresh, unfixed tumor tissue	Gene expression profile by oligonucleotide array	II	Prognostic marker for recurrence risk in stage II colon cancer	Two nonrandomized validation studies;^65,66 PARSC trial underway⁶⁷	Anticipated (Agendia)
CTC	Peripheral blood collected in preservative tube	Immunomagnetic separation of epithelial cells from whole blood	IV	Prognostic marker for survival in patients with metastatic colorectal cancer	Multiple studies, including meta- analysis data and randomized subset from CAIRO2 study^68–70	Multiple, including CellSearch System (Veridex, LLC)
Oncotype DX colon cancer test	FFPE tumor tissue	Gene expression profile by RT-PCR	II	Prognostic marker for recurrence risk in stage II colon cancer	Independent validation in randomized subset from QUASAR study;⁷¹ second independent validation set presented at 2011 ASCO Annual Meeting⁷²	Yes (Genomic Health, Inc.)

Colorectal Cancer Biomarker Tests in Development

Abbreviations: CTC, circulating tumor cells; FFPE, formalin-fixed, paraffin-embedded; PARSC, Prospective Analysis of Risk Stratification by ColoPrint; RT-PCR, reverse transcriptase-polymerase chain reaction.

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
Ogino S, Chan AT, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut 2011;60:397–411.
Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626–1634.
Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–4705.
Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765.
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–1417.
McShane LM, Altman DG, Sauerbrei W, et al. Reporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer 2005;41:1690–1696.
Simon R. Clinical trial designs for evaluating the medical utility of prognostic and predictive biomarkers in oncology. Per Med 2010;7:33–47.
Benson AB III, Arnoletti JP, Bekaii-Saab T, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 1, 2012. Available at: www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed September 20, 2011.
Benson AB III, Arnoletti JP, Bekaii-Saab T, et al. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 1, 2012. Available at: www.nccn.org/professionals/physician_gls/PDF/rectal.pdf. Accessed September 20, 2011.
Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011;29:1261–1270.
Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247–257.
Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010;28:3219–3226.
Bertagnolli MM, Redston M, Compton CC, et al. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer—a study of CALGB 9581 and 89803. J Clin Oncol 2011;29:3153–3162.
Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:1196–1206.
Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 2001;10:917–923.
Tol J, Dijkstra JR, Klomp M, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer 2010;46:1997–2009.
Bokemeyer C, Kohne C, Rougier P, et al. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status [abstract]. J Clin Oncol 2010;28(Suppl 1):Abstract 3506.
De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010;11:753–762.
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705–5712.
Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009;27:5924–5930.
Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009;361:98–99.
Benson AB III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22:3408–3419.
Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248–5257.
Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–5788.
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–618.
Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–268.
Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998;58:3455–3460.
Cunningham JM, Kim CY, Christensen ER, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 2001;69:780–790.
Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919–932.
Kakar S, Aksoy S, Burgart LJ, Smyrk TC. Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival. Mod Pathol 2004;17:696–700.
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816–819.
Lanza G, Ferracin M, Gafa R, et al. mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. Mol Cancer 2007;6:54.
Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002;20:1043–1048.
Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 2010;28:466–474.
Kim GP, Colangelo LH, Wieand HS, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study. J Clin Oncol 2007;25:767–772.
Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer 2009;45:1890–1896.
Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 2010;46:2788–2798.
Julie C, Tresallet C, Brouquet A, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 2008;103:2825–2835.
Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 2009;58:90–96.
Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer, in press.
De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010;304:1812–1820.
U.S. Food and Drug Administration. Erbitux (cetuximab) medication guide. Available at: www.accessdata.fda.gov/drugsatfda_docs//label/2004/125084lbl.pdf. Accessed 17 October 2011.
U.S. Food and Drug Administration. Highlights of prescribing information: Vectibix (panitumumab). Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2009/125147s067lbl.pdf. Accessed 17 October 2011.
Tanaka N, Huttenhower C, Nosho K, et al. Novel application of structural equation modeling to correlation structure analysis of CpG island methylation in colorectal cancer. Am J Pathol 2010;177:2731–2740.
Quasar Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007;370:2020–2029.
Maughan TS, Adams R, Smith CG, et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first line advanced colorectal cancer (aCRC): mature results of the MRC COIN trial [abstract]. J Clin Oncol 2010;28(Suppl 1):Abstract 3502.
Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 2007;67:2643–2648.
Van Cutsem E, Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial [abstract]. Presented at the ASCO Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, Florida. Abstract 281.
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.
Hecht JR, Mitchell E, Neubauer MA, et al. Lack of correlation between epidermal growth factor receptor status and response to panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res 2010;16:2205–2213.
Yin M, Yan J, Martinez-Balibrea E, et al. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res 2011;17:1632–1640.
Braun MS, Richman SD, Quirke P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008;26:2690–2698.
Braun MS, Richman SD, Thompson L, et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 2009;27:5519–5528.
Koopman M, Venderbosch S, van Tinteren H, et al. Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study. Eur J Cancer 2009;45:1999–2006.
Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004;22:529–536.
Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000;6:1322–1327.
Asghar U, Hawkes E, Cunningham D. Predictive and prognostic biomarkers for targeted therapy in metastatic colorectal cancer. Clin Colorectal Cancer 2010;9:274–281.
Zhang W, Azuma M, Lurje G, et al. Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study). Anticancer Res 2010;30:4209–4217.
Gutman S, Kessler LG. The US Food and Drug Administration perspective on cancer biomarker development. Nat Rev Cancer 2006;6:565–571.
Phillips KA, Van Bebber SL. Regulatory perspectives on pharmacogenomics: a review of the literature on key issues faced by the United States Food and Drug Administration. Med Care Res Rev 2006;63:301–326.
Feldman MD, Petersen AJ, Karliner LS, Tice JA. Who is responsible for evaluating the safety and effectiveness of medical devices? The role of independent technology assessment. J Gen Intern Med 2008;23(Suppl 1):57–63.
Ahn JB, Chung WB, Maeda O, et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 2011;117:1847–1854.
Rosenberg R, Maak M, Simon I, et al. Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients [abstract]. J Clin Oncol 2011;29(Suppl 1):Abstract 358.
Salazar R, Roepman P, Capella G, et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 2011;29:17–24.
Salazar R, Marshall J, Stork-Sloots L, et al. The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint [abstract]. J Clin Oncol 2010;28(Suppl 1):Abstract TPS199.
Cohen SJ, Punt CJ, Iannotti N, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 2009;20:1223–1229.
Rahbari NN, Aigner M, Thorlund K, et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology 2010;138:1714–1726.
Tol J, Koopman M, Miller MC, et al. Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Ann Oncol 2010;21:1006–1012.
Kerr D, Gray R, Quirke P, et al. A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4000.
Venook AP, Niedzwiecki D, Lopatin M, et al. Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581 [abstract]. J Clin Oncol 2011;29(Suppl 1):Abstract 3518.

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Author(s)

Robin K. Kelley, MD

University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, California

Disclosures

Disclosure: Robin K. Kelley, MD, has disclosed the following relevant financial relationships:
Supported by the Maisin Foundation
Received an unrestricted educational grant from Genomic Health, Inc. for a pilot research study of the clinical utility of new molecular tests in colorectal cancer management, and an honorarium for participating in a speaker training program

Grace Wang, PhD

Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) at UCSF, San Francisco, California

Disclosures

Disclosure: Grace Wang, PhD, has disclosed no relevant financial relationships.

Alan P. Venook, MD

University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, California

Disclosures

Disclosure: Alan P. Venook, MD, has disclosed the following relevant financial relationships:
Held an uncompensated advisory role to and collaborated on research projects with Genomic Health, Inc.
This manuscript was supported in part by a grant from the National Cancer Institute (P01CA130818) through the Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) at the University of California, San Francisco.

Editor(s)

Kerrin M. Green, MA

Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosures

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

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Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

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Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

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Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

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Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC

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Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

CME

Biomarker Use in Colorectal Cancer Therapy

Authors: Robin K. Kelley, MD; Grace Wang, PhD; Alan P. Venook, MD
CME Released: 11/7/2011
THIS ACTIVITY HAS EXPIRED FOR CREDIT
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Target Audience and Goal Statement

This activity is intended for primary care clinicians, internists, gastroenterologists, oncologists, and other clinicians caring for patients with colorectal cancer.

The goal of this activity is to describe the role of genetic biomarkers in management of patients with colorectal cancer.

Upon completion of this activity, participants will be able to:

Describe the role of MMR protein testing or microsatellite instability (MSI) testing in management of patients with stage II colon cancer
Describe the role of KRAS mutational analysis in management of patients with metastatic colorectal cancers
Describe the role of BRAF mutational analysis in management of patients with metastatic colorectal cancers

Disclosures

Author(s)

Robin K. Kelley, MD

University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, California

Disclosures

Disclosure: Robin K. Kelley, MD, has disclosed the following relevant financial relationships:
Supported by the Maisin Foundation
Received an unrestricted educational grant from Genomic Health, Inc. for a pilot research study of the clinical utility of new molecular tests in colorectal cancer management, and an honorarium for participating in a speaker training program

Grace Wang, PhD

Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) at UCSF, San Francisco, California

Disclosures

Disclosure: Grace Wang, PhD, has disclosed no relevant financial relationships.

Alan P. Venook, MD

University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, California

Disclosures

Disclosure: Alan P. Venook, MD, has disclosed the following relevant financial relationships:
Held an uncompensated advisory role to and collaborated on research projects with Genomic Health, Inc.
This manuscript was supported in part by a grant from the National Cancer Institute (P01CA130818) through the Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) at the University of California, San Francisco.

Editor(s)

Kerrin M. Green, MA

Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosures

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosures

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

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Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC

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Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Abstract and Introduction

Abstract

Biomarkers reflective of the molecular and genetic heterogeneity in colorectal cancers now guide certain aspects of clinical management and offer great potential for enrichment, stratification, and identification of novel therapeutic targets in drug development. Using case-based examples, this article reviews biomarkers that have an established role in the clinical management of colorectal cancer: mismatch repair protein testing and KRAS and BRAF mutational analysis. A selection of biomarkers undergoing validation for future clinical application is presented, and the dynamic and challenging interface between biomarkers in research and clinical practice is discussed. (JNCCN 2011;9:1293–1303)

Introduction

Despite the development of multiple new therapeutics over the past decade, colorectal cancer continues to be the second leading cause of cancer mortality in the United States and worldwide, with a median survival of less than 2 years for patients with advanced disease.^[1,2] The evolving understanding of the genetic heterogeneity of colorectal tumors suggests that a purely anatomic classification may be obsolete.^[3] Recent identification of molecular tumor subtypes with distinctive treatment responsiveness and prognosis in some cancers has led to an emerging paradigm of genetically tailored clinical management, and promises to guide future drug development in oncology. A prominent example in colorectal cancer is the finding that an activating mutation in the KRAS oncogene is a biomarker for tumor resistance to monoclonal antibodies targeting the epidermal growth factor receptor (EGFR); this has led to the widespread adoption of tumor KRAS mutational analysis before treatment with this class of drugs.^[4–7]

Biomarkers are measures, such as the presence of a mutation in the KRAS gene found through polymerase chain reaction (PCR) testing, associated with a clinically distinct prognosis, diagnosis, or response to a specific treatment. Conventional analyses such as tumor immunohistochemistry for cytokeratin profile or serum carcinoembryonic antigen (CEA) measurement are also types of biomarkers according to this broad definition. So-called predictive markers are associated with response (or lack thereof) to a particular therapy, whereas prognostic markers are baseline measurements associated with future disease trajectory.^[8,9] This article focuses on newer, genetically based tests of tumor, host, or both, that are used to evaluate prognosis and/or to predict the likelihood of treatment response.

Using case-based examples, this article reviews biomarkers with an established role in clinical colorectal cancer management, presents a selection of biomarkers undergoing validation for future clinical application, and concludes with a discussion of the dynamic interface between biomarkers in research and clinical practice.

Page 1 of 4

Overview of Established Biomarkers in Colorectal Cancer Clinical Management

CME Information

Abstract and Introduction
Overview of Established Biomarkers in Colorectal Cancer Clinical Management
Selected Colorectal Cancer Biomarkers in Validation Stages of Development
Conclusions

References

References

Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

Published by Harborside Press

Table 1.

Table 2.

References

Faculty and Disclosures

Author(s)

Robin K. Kelley, MD

Grace Wang, PhD

Alan P. Venook, MD

Editor(s)

Kerrin M. Green, MA

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

CME

Biomarker Use in Colorectal Cancer Therapy

Target Audience and Goal Statement

Disclosures

Author(s)

Robin K. Kelley, MD

Grace Wang, PhD

Alan P. Venook, MD

Editor(s)

Kerrin M. Green, MA

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Biomarker Use in Colorectal Cancer Therapy

Abstract and Introduction

Abstract

Introduction

Table of Contents