Prognostic and Predictive Markers in Colorectal Cancer

Translational Colorectal Oncology (Yixing Jiang, Section Editor)


Prognostic and predictive biomarkers have revolutionized medicine by allowing individualized treatment decisions. Most notably in oncology, where treatment can be associated with significant toxicities and often unpredictable outcomes, there is a need to isolate patients that are likely to benefit from an intervention. In colorectal cancer, there are many markers being investigated but only a few that have sufficient evidence to warrant use in clinical practice. This paper will review these prominent biomarkers in both adjuvant and metastatic colorectal cancer and summarize the data regarding their utility. The markers reviewed include microsatellite instability, 18qLOH, gene profile assays such as ColoPrint and Oncotype DX, Kras, Braf, thymidylate synthase, and circulating tumor cells. The paper will also discuss optimal clinical trial design, with a focus on different validation strategies for emerging biomarkers. By highlighting the pertinent literature, the hope is to facilitate a personalized approach to colorectal cancer care.


Prognostic Predictive Biomarkers Colorectal Colon Kras Braf Circulating tumor cells Microsatellite instability MSI-H dMMR Deficient mismatch repair 18qLOH Thymidylate synthase Coloprint Oncotype dx Gene profiling Clinical trial design 



S. Reddy: none; M. Vergo: none; A. B. Benson: consultant to Amgen and Genomic Health.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Benson AB, Schrag D, Somerfield MR, et al. American society of clinical oncology recommendations on adjuvant therapy for stage II colon cancer. J Clin Oncol. 2004;22:3408–19.PubMedCrossRefGoogle Scholar
  2. 2.
    QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet. 2007;370:2020–9.CrossRefGoogle Scholar
  3. 3.
    •• Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–16. The MOSAIC study shows benefit from addition of oxaliplatin to 5-FU chemotherapy in stage III patients and a trend toward benefit in high-risk stage II patients.PubMedCrossRefGoogle Scholar
  4. 4.
    Colon and rectum. In AJCC cancer staging manual, 7th ed. New York: Springer; 2010, 143–159.Google Scholar
  5. 5.
    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.PubMedCrossRefGoogle Scholar
  6. 6.
    •• 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;28:3219–26. This large, retrospective study shows that stage II patients with dMMR tumors should not receive chemotherapy.PubMedCrossRefGoogle Scholar
  7. 7.
    De Gramont A, Van Cutsem E, Tabernero J, et al. AVANT: results from a randomized, three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer. ASCO Gastrointestinal Cancer Symposium. J Clin Oncol 2011, 29 (suppl; abstr 362).Google Scholar
  8. 8.
    •• Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stage II and III carcinoma of the colon: results of the NSABP protocol C-08. J Clin Oncol. 2001;29:11–6. This study shows no benefit from addition of bevacizumab to FOLFOX for stage II and III patients.CrossRefGoogle Scholar
  9. 9.
    Popat S, Houlston RS. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer. 2005;41:2060–70.PubMedCrossRefGoogle Scholar
  10. 10.
    Ogino S, Nosho K, Irahara N, et al. Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers. J Clin Oncol. 2009;27:4591–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Roth AD, Tejpar S, Yan P, et al. Stage-specific prognostic value of molecular markers in colon cancer: results of the translational study on the PETACC 3-EORTC 40993-SAKK 60–00 trial. ASCO Annual Meeting. J Clin Oncol. 2009;27:15s. suppl; abstr 4002.CrossRefGoogle Scholar
  12. 12.
    Watanabe T, Wu T, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–206.PubMedCrossRefGoogle Scholar
  13. 13.
    Barratt PL, Seymour MT, Stenning SP, et al. DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet. 2002;360:1381–91.PubMedCrossRefGoogle Scholar
  14. 14.
    • 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. ASCO Annual Meeting. J Clin Oncol 2009, 27: 15 s (suppl; abstr 4000). This abstract summarizes how Oncotype DX was developed and validated. Google Scholar
  15. 15.
    O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Rasul KI, Kerr DJ. QUASAR results: the prognostic validity of a colon cancer recurrence score and the role of multigene profiles in determining risk. Curr Colorectal Cancer Rep. 2010;6:144–7.CrossRefGoogle Scholar
  17. 17.
    O’Connell MJ, Lavery C, Gray RG, et al. Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score. ASCO Gastrointestinal Cancer Symposium 2010 (abstr 280).Google Scholar
  18. 18.
    • 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. This article discusses how ColoPrint was developed and validated.PubMedCrossRefGoogle Scholar
  19. 19.
    •• Alberts SR, Sargent DJ, Smyrk TC, et al. Adjuvant mFOLFOX6 with or without cetuximab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): results from NCCTG intergroup phase III trial N0147. ASCO Annual Meeting. J Clin Oncol 2010, 28: 18 s (suppl; abstr CRA3507). This study shows no benefit of treating Kras WT patients with anti-EGFR therapy in the adjuvant setting. Google Scholar
  20. 20.
    Goldberg RM, Sargent DJ, Thibodeau SN, et al. Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG intergroup phase III trial N0147. ASCO Annual Meeting. J Clin Oncol. 2010;28:15 s. suppl; abstr 3508.Google Scholar
  21. 21.
    Peach G, Kim C, Zacharakis E, et al. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Brit J Cancer. 2010;102:1327–34.PubMedCrossRefGoogle Scholar
  22. 22.
    Koch M, Kienle P, Kastrati D, et al. Prognostic impact of hematogenous tumor cell dissemination in patients with stage II colorectal cancer. Int J Cancer. 2006;118:3072–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Uen Y, Lin S, Wu D, et al. Prognostic significance of multiple molecular markers for patients with stage II colorectal cancer undergoing curative resection. Ann Surg. 2007;246:1040–6.PubMedCrossRefGoogle Scholar
  24. 24.
    •• Van Cutsem E, Kohne C, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17. The CRYSTAL study shows that Kras WT mCRC patients and not Kras-mutant patients benefit from addition of cetuximab to first-line treatment with FOLFIRI.PubMedCrossRefGoogle Scholar
  25. 25.
    Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.PubMedCrossRefGoogle Scholar
  26. 26.
    • Douillard J, 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;28:4697–705. This study shows a benefit in adding panitumumab to first-line treatment of mCRC with FOLFOX.PubMedCrossRefGoogle Scholar
  27. 27.
    • Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13. This study shows a benefit in adding panitumumab to second-line treatment of mCRC with FOLFIRI.PubMedCrossRefGoogle Scholar
  28. 28.
    Maughan TS, Adams R, Smith CG, et al. Oxaliplatin and fluoropyrimidine chemotherapy plus or minus cetuximab: the effect of infusional 5-FU or capecitabine on the outcomes of the MRC COIN trial in advanced colorectal cancer (ACRC). ASCO Gastrointestinal Cancers Symposium 2010 (abstr 402).Google Scholar
  29. 29.
    Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–372.PubMedCrossRefGoogle Scholar
  30. 30.
    DeRoock 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. 2010;11:753–62.CrossRefGoogle Scholar
  31. 31.
    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;26:5705–12.PubMedCrossRefGoogle Scholar
  32. 32.
    Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcomes in colon cancer. Gut. 2009;58:90–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Tol J, Nagtegaal ID, Punt CJA. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361:98–9.PubMedCrossRefGoogle Scholar
  34. 34.
    • 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. ASCO Annual Meeting. J Clin Oncol 2010, 28:15 s (suppl; abstr 3506). This abstract argues that Braf has prognostic but not predictive value based on analysis of the CRYSTAL and OPUS studies. Google Scholar
  35. 35.
    Cohen SJ, Punt CJA, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:3213–21.PubMedCrossRefGoogle Scholar
  36. 36.
    • Cohen SJ, Punt CJA, Iannotti N, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20:1223–9. This is the first large prospective randomized controlled trial to show that circulating tumor cells have prognostic and predictive value.PubMedCrossRefGoogle Scholar
  37. 37.
    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;21:1006–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Negin BP, Cohen SJ. Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Option On. 2010;11:1–13.CrossRefGoogle Scholar
  39. 39.
    Qiu L, Tang Q, Bai J, et al. Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: evidence from 24 studies. Int J Cancer. 2008;123:2384–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2004;22:529–36.PubMedCrossRefGoogle Scholar
  41. 41.
    Lurje G, Manegold PC, Ning Y, et al. Thymidylate synthase gene variations: predictive and prognostic markers. Mol Cancer Ther. 2009;8:1000–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Marcuello E, Altes A, Del Rio E, et al. Single nucleotide polymorphism in the 5’ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer. 2004;112:733–7.PubMedCrossRefGoogle Scholar
  43. 43.
    • Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol. 2009;27:4027–34. This article reviews various clinical trial designs for adequate predictive biomarker validation.PubMedCrossRefGoogle Scholar
  44. 44.
    Sargent DJ, Taylor JMG. Current issues in oncology drug development, with a focus on phase II trials. J Biopharm Stat. 2009;19:556–62.PubMedCrossRefGoogle Scholar
  45. 45.
    Mandrekar SJ, Sargent DJ. Randomized phase II trials: time for a new era in clinical trial design. J Thorac Oncol. 2010;5:932–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Sangeetha Reddy
    • 1
  • Maxwell Vergo
    • 2
  • Al B. BensonIII
    • 2
  1. 1.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicagoUSA

Personalised recommendations