Current Colorectal Cancer Reports

, Volume 8, Issue 1, pp 36–41

Optimal Treatment Strategies for Localized and Advanced Microsatellite Instability–High Colorectal Cancer

Personalized Medicine in Colorectal Cancer (WA Messersmith, Section Editor)


The defective mismatch repair phenotype (MMR-D) has been recognized as a distinct form of colorectal cancers with specific clinical and biologic features. It is caused by a lack of expression of mismatch repair enzymes in tumor cells either on the basis of hereditary or sporadic mutation of gene(s) encoding the enzymes such as in the Lynch syndrome, or by silencing of gene transcription due to promoter methylation. Colorectal cancers of the MMR-D phenotype have consistently shown to be associated with good prognosis and are likely, at least in early-stage disease, resistant to fluoropyrimidine monotherapy. These characteristics have significant implications for clinical practice and treatment strategies, particularly in the adjuvant setting.


Microsatellite instability Colon cancer Mismatch repair enzymes Fluoropyrimidine Irinotecan 


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

  1. 1.
    Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Bozic I, Antal T, Ohtsuki H, et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A. 2010;107:18545–50.PubMedCrossRefGoogle Scholar
  3. 3.
    de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010;28:3380–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–9.PubMedCrossRefGoogle Scholar
  5. 5.
    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;26:1626–34.PubMedCrossRefGoogle Scholar
  6. 6.
    Blanke CD, Goldberg RM, Grothey A, et al. KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice. Oncologist. 2011;16:1061–8.PubMedCrossRefGoogle Scholar
  7. 7.
    De Jong AE, Morreau H, Van Puijenbroek M, et al. The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology. 2004;126:42–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.PubMedCrossRefGoogle Scholar
  11. 11.
    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;58:5248–57.PubMedGoogle Scholar
  12. 12.
    Goel A, Arnold CN, Niedzwiecki D, et al. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res. 2003;63:1608–14.PubMedGoogle Scholar
  13. 13.
    Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20:1043–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713–8.PubMedGoogle Scholar
  15. 15.
    •• Vilar E, Gruber SB: Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7:153-62, 2010 Excellent review of clinical relevance of MSI in colorectal cancer. PubMedCrossRefGoogle Scholar
  16. 16.
    Ogino S, Nosho K, Irahara N, et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009;15:6412–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.PubMedCrossRefGoogle Scholar
  18. 18.
    •• 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 28:3219-26, 2010 The key paper which identifies the lack of benefit of adjuvant 5-fluorouracil in MSI-H/MMR-D colon cancer. PubMedCrossRefGoogle Scholar
  19. 19.
    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;349:247–57.PubMedCrossRefGoogle Scholar
  20. 20.
    Meyers M, Hwang A, Wagner MW, et al. A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage. Oncogene. 2003;22:7376–88.PubMedCrossRefGoogle Scholar
  21. 21.
    Carethers JM, Chauhan DP, Fink D, et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology. 1999;117:123–31.PubMedCrossRefGoogle Scholar
  22. 22.
    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;25:767–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Hemminki A, Mecklin JP, Jarvinen H, et al. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology. 2000;119:921–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Liang JT, Huang KC, Lai HS, et al. High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer. 2002;101:519–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Elsaleh H, Joseph D, Grieu F, et al. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. 2000;355:1745–50.PubMedCrossRefGoogle Scholar
  26. 26.
    Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390–404.PubMedCrossRefGoogle Scholar
  27. 27.
    Hong SP, Min BS, Kim TI, et al: The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer. Eur J Cancer, 2011Google Scholar
  28. 28.
    Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.PubMedCrossRefGoogle Scholar
  29. 29.
    Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–206.PubMedCrossRefGoogle Scholar
  30. 30.
    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.PubMedCrossRefGoogle Scholar
  31. 31.
    • 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 28:466-74, 2010 Pivotal analysis of biomarkers in the large adjuvant trial PETACC-3. PubMedCrossRefGoogle Scholar
  32. 32.
    Gray RG, Quirke P, Handley K, et al. Validation Study of a Quantitative Multigene Reverse Transcriptase-Polymerase Chain Reaction Assay for Assessment of Recurrence Risk in Patients With Stage II Colon Cancer. J Clin Oncol. 2011;29:4611–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Tejpar S, Bosman F, Delorenzi M, et al. Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). ASCO Meeting Abstracts. 2009;27:4001.Google Scholar
  34. 34.
    Grothey A. Risk assessment in stage II colon cancer: to treat or not to treat? Oncology (Williston Park). 2010;24:1–2.Google Scholar
  35. 35.
    Jover R, Paya A, Alenda C, et al. Defective mismatch-repair colorectal cancer: clinicopathologic characteristics and usefulness of immunohistochemical analysis for diagnosis. Am J Clin Pathol. 2004;122:389–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Lamberti C, Lundin S, Bogdanow M, et al. Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis. 2007;22:145–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Buyse M, Sargent DJ, Grothey A, et al. Biomarkers and surrogate end points–the challenge of statistical validation. Nat Rev Clin Oncol. 2010;7:309–17.PubMedCrossRefGoogle Scholar
  38. 38.
    Vilar E, Scaltriti M, Balmana J, et al. Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines. Br J Cancer. 2008;99:1607–12.PubMedCrossRefGoogle Scholar
  39. 39.
    Magrini R, Bhonde MR, Hanski ML, et al. Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer. 2002;101:23–31.PubMedCrossRefGoogle Scholar
  40. 40.
    Jacob S, Aguado M, Fallik D, et al. The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res. 2001;61:6555–62.PubMedGoogle Scholar
  41. 41.
    • Bertagnolli MM, Niedzwiecki D, Compton CC, et al: Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol 27:1814-21, 2009 Pivotal paper to support increased activity of irinotecan in MSI-H/MMR-D colorectal cancers. PubMedCrossRefGoogle Scholar
  42. 42.
    Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6:789–802.PubMedCrossRefGoogle Scholar
  43. 43.
    Fallik D, Borrini F, Boige V, et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 2003;63:5738–44.PubMedGoogle Scholar
  44. 44.
    Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100:266–73.PubMedCrossRefGoogle Scholar
  45. 45.
    Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007;25:3456–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Van Cutsem E, Labianca R, Hossfeld DK, et al: Randomized phase III trial comparing infused irinotecan / 5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3). J Clin Oncol 23:abstr. LBA8, 2005Google Scholar
  47. 47.
    Sergent C, Franco N, Chapusot C, et al. Human colon cancer cells surviving high doses of cisplatin or oxaliplatin in vitro are not defective in DNA mismatch repair proteins. Cancer Chemother Pharmacol. 2002;49:445–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Yim KL: Microsatellite instability in metastatic colorectal cancer: a review of pathology, response to chemotherapy and clinical outcome. Med Oncol, 2011Google Scholar
  49. 49.
    Des Guetz G, Mariani P, Cucherousset J, et al. Microsatellite instability and sensitivitiy to FOLFOX treatment in metastatic colorectal cancer. Anticancer Res. 2007;27:2715–9.PubMedGoogle Scholar
  50. 50.
    Kim ST, Lee J, Park SH, et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol. 2010;66:659–67.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim ST, Lee J, Park SH, et al. The effect of DNA mismatch repair (MMR) status on oxaliplatin-based first-line chemotherapy as in recurrent or metastatic colon cancer. Med Oncol. 2010;27:1277–85.PubMedCrossRefGoogle Scholar
  52. 52.
    Zaanan A, Cuilliere-Dartigues P, Guilloux A, et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. Ann Oncol. 2010;21:772–80.PubMedCrossRefGoogle Scholar
  53. 53.
    Muller CI, Schulmann K, Reinacher-Schick A, et al. Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing first-line chemotherapy. A report of the AIO Colorectal Study Group. Int J Colorectal Dis. 2008;23:1033–9.PubMedCrossRefGoogle Scholar
  54. 54.
    •• 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 45:1890-6, 2009 Pivotal meta-analysis of the effect of MSI on chemosensitivity in colorectal cancer. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Medical Oncology, Mayo Clinic RochesterRochesterUSA

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