The evolving role of microsatellite instability in colorectal cancer: A review

Cancer Treatment Reviews

Volumn 51, Issue , 2016, Pages 19-26

  Gelsomino, Fabio ^a   Barbolini, Monica ^a   Spallanzani, Andrea ^a   Pugliese, Giuseppe ^a   Cascinu, Stefano ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

Author keywords

Colorectal cancer; Immunotherapy; Lynch syndrome; Microsatellite instability; Predictive

Indexed keywords

B RAF KINASE; IPILIMUMAB; MISMATCH REPAIR PROTEIN PMS2; NIVOLUMAB; PEMBROLIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN MLH1; PROTEIN MSH2; PROTEIN MSH6;

BRAF GENE; CANCER IMMUNOTHERAPY; CANCER LOCALIZATION; CANCER PROGNOSIS; CANCER STAGING; CLINICAL FEATURE; COLORECTAL CANCER; GERMLINE MUTATION; HEREDITARY NONPOLYPOSIS COLORECTAL CANCER; HISTOPATHOLOGY; HUMAN; IMMUNE RESPONSE; METASTASIS; MICROSATELLITE INSTABILITY; MISMATCH REPAIR; MLH1 GENE; MSH2 GENE; MSH6 GENE; MUTATIONAL ANALYSIS; PMS2 GENE; PROTEIN EXPRESSION; REVIEW; COLORECTAL TUMOR; GENETICS; PATHOLOGY; PROGNOSIS;

COLORECTAL NEOPLASMS; COLORECTAL NEOPLASMS, HEREDITARY NONPOLYPOSIS; HUMANS; MICROSATELLITE INSTABILITY; PROGNOSIS;

EID: 84994881895     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2016.10.005     Document Type: Review

References (93)

1. [1] Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2016. CA Cancer J Clin 66:1 (2016), 7-30.
2. [2] Grady, W.M., Carethers, J.M., Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135:4 (2008), 1079-1099.
3. [3] Nagasaka, T., Rhees, J., Kloor, M., Gebert, J., Naomoto, Y., Boland, C.R., et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch syndrome colorectal cancers. Cancer Res 70:8 (2010), 3098-3108.
4. [4] Cunningham, J.M., Christensen, E.R., Tester, D.J., Kim, C.Y., Roche, P.C., Burgart, L.J., et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:15 (1998), 3455-3460.
5. [5] Ribic, C.M., Sargent, D.J., Moore, M.J., Thibodeau, S.N., French, A.J., Goldberg, R.M., et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:3 (2003), 247-257.
6. [6] Andre, T., de Gramont, A., Vernerey, D., Chibaudel, B., Bonnetain, F., Tijeras-Raballand, A., et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC Study. J Clin Oncol 33:35 (2015), 4176-4187.
7. [7] Koopman, M., Kortman, G.A., Mekenkamp, L., Ligtenberg, M.J., Hoogerbrugge, N., Antonini, N.F., et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 100:2 (2009), 266-273.
8. [8] Vilar, E., Gruber, S.B., Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7:3 (2010), 153-162.
9. [9] Duval, A., Hamelin, R., Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res 62:9 (2002), 2447-2454.
10. [10] Vasen, H.F., Wijnen, J.T., Menko, F.H., Kleibeuker, J.H., Taal, B.G., Griffioen, G., et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110:4 (1996), 1020-1027.
11. [11] Watson, P., Lynch, H.T., Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1 (2001), 57-60.
12. [12] Hampel, H., Stephens, J.A., Pukkala, E., Sankila, R., Aaltonen, L.A., Mecklin, J.P., et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 129:2 (2005), 415-421.
13. [13] Lynch, H.T., Boland, C.R., Rodriguez-Bigas, M.A., Amos, C., Lynch, J.F., Lynch, P.M., Who should be sent for genetic testing in hereditary colorectal cancer syndromes?. J Clin Oncol 25:23 (2007), 3534-3542.
14. [14] Rodriguez-Moranta, F., Castells, A., Andreu, M., Pinol, V., Castellvì-Bel, S., Alenda, C., et al. Clinical performance of original and revised Bethesda guidelines for the identification of MSH2/MLH1 gene carriers in patients with newly diagnosed colorectal cancer: proposal of a new and simpler set of recommendations. Am J Gastroenterol 101:5 (2006), 1104-1111.
15. [15] Umar, A., Boland, C.R., Terdiman, J.P., Syngal, S., de la Chapelle, A., Ruschoff, J., et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:4 (2004), 261-268.
16. [16] Vasen, H.F., Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol 18:21 Suppl (2000), 81S-92S.
17. [17] Balmaña, J., Balaguer, F., Cervantes, A., Arnold, D., ESMO guidelines working group. Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol 24:Suppl 6 (2013), vi73-vi80.
18. [18] Lanza, G., Gafa, R., Santini, A., Maestri, I., Guerzoni, L., Cavazzini, L., Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 24:15 (2006), 2359-2367.
19. [19] Lindor, N.M., Burgart, L.J., Leontovich, O., Goldberg, R.M., Cunningham, J.M., Sargent, D.J., et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:4 (2002), 1043-1048.
20. [20] Boland, C.R., Thibodeau, S.N., Hamilton, S.R., Sidransky, D., Eshleman, J.R., Burt, R.W., 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 58:22 (1998), 5248-5257.
21. [21] Lech, G., Slotwinski, R., Slodkowski, M., Krasnodebski, I.W., Colorectal cancer tumour markers and biomarkers: recent therapeutic advances. World J Gastroenterol 22:5 (2016), 1745-1755.
22. [22] Lynch, H.T., Lynch, P.M., Lanspa, S.J., Snyder, C.L., Lynch, J.F., Boland, C.R., Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 76:1 (2009), 1-18.
23. [23] Raut, C.P., Pawlik, T.M., Rodriguez-Bigas, M.A., Clinicopathologic features in colorectal cancer patients with microsatellite instability. Mutat Res 568:2 (2004 Dec 21), 275-282.
24. [24] Ward, R., Meagher, A., Tomlinson, I., O'Connor, T., Norrie, M., Wu, R., et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:6 (2001), 821-829.
25. [25] Poynter, J.N., Siegmund, K.D., Weisenberger, D.J., Long, T.I., Thibodeau, S.N., Lindor, N., et al. Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev 17:11 (2008), 3208-3215.
26. [26] Thibodeau, S.N., French, A.J., Cunningham, J.M., Tester, D., Burgart, L.J., Roche, P.C., et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58:8 (1998), 1713-1718.
27. [27] Slattery, M.L., Curtin, K., Anderson, K., Ma, K.N., Ballard, L., Edwards, S., et al. Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst 92:22 (2000), 1831-1836.
28. [28] Alexander, J., Watanabe, T., Wu, T.T., Rashid, A., Li, S., Hamilton, S.R., Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:2 (2001), 527-535.
29. [29] Setaffy, L., Langner, C., Microsatellite instability in colorectal cancer: clinicopathological significance. Pol J Pathol 66:3 (2015), 203-218.
30. [30] Kakar, S., Aksoy, S., Burgart, L.J., Smyrk, T.C., Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival. Mod Pathol 17:6 (2004), 696-700.
31. [31] Deschoolmeester, V., Baay, M., Van Marck, E., Weyler, J., Vermeulen, P., Lardon, F., et al. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol, 11, 2010, 19.
32. [32] Boissiere-Michot, F., Lazennec, G., Frugier, H., Jarlier, M., Roca, L., Duffour, J., et al. Characterization of an adaptive immune response in microsatellite-instable colorectal cancer. Oncoimmunology, 3, 2014, e29256.
33. [33] Takemoto, N., Konishi, F., Yamashita, K., Kojima, M., Furukawa, T., Miyakura, Y., et al. The correlation of microsatellite instability and tumor-infiltrating lymphocytes in hereditary non-polyposis colorectal cancer (HNPCC) and sporadic colorectal cancers: the significance of different types of lymphocyte infiltration. Jpn J Clin Oncol 34:2 (2004), 90-98.
34. [34] Tougeron, D., Fauquembergue, E., Rouquette, A., Le Pessot, F., Sesboue, R., Laurent, M., et al. Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol 22:9 (2009), 1186-1195.
35. [35] Maby, P., Tougeron, D., Hamieh, M., Mlecnik, B., Kora, H., Bindea, G., et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res 75:17 (2015), 3446-3455.
36. [36] Kim, J.H., Kang, G.H., Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J Gastroenterol 20:15 (2014), 4230-4243.
37. [37] Parsons, M.T., Buchanan, D.D., Thompson, B., Young, J.P., Spurdle, A.B., Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet 49:3 (2012), 151-157.
38. [38] Weisenberger, D.J., Siegmund, K.D., Campan, M., Young, J., Long, T.I., Faasse, M.A., et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:7 (2006), 787-793.
39. [39] Senter, L., Clendenning, M., Sotamaa, K., Hampel, H., Green, J., Potter, J.D., et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:2 (2008), 419-428.
40. [40] Stadler, Z.K., Battaglin, F., Middha, S., Hechtman, J.F., Tran, C., Cercek, A., et al. Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J Clin Oncol 34:18 (2016), 2141-2147.
41. [41] Lukish, J.R., Muro, K., DeNobile, J., Katz, R., Williams, J., Cruess, D.F., et al. Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg 227:1 (1998), 51-56.
42. [42] Benatti, P., Gafa, R., Barana, D., Marino, M., Scarselli, A., Pedroni, M., et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 11:23 (2005), 8332-8340.
43. [43] Merok, M.A., Ahlquist, T., Royrvik, E.C., Tufteland, K.F., Hektoen, M., Sjo, O.H., et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 24:5 (2013), 1274-1282.
44. [44] Samowitz, W.S., Curtin, K., Ma, K.N., Schaffer, D., Coleman, L.W., Leppert, M., et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 10:9 (2001), 917-923.
45. [45] Popat, S., Hubner, R., Houlston, R.S., Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:3 (2005), 609-618.
46. [46] 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 46:15 (2010), 2788-2798.
47. [47] Sinicrope, F.A., Foster, N.R., Thibodeau, S.N., Marsoni, S., Monges, G., Labianca, R., et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 103:11 (2011), 863-875.
48. [48] Hutchins, G., Southward, K., Handley, K., Magill, L., Beaumont, C., Stahlschmidt, J., et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 29:10 (2011), 1261-1270.
49. [49] Roth, A.D., Tejpar, S., Delorenzi, M., Yan, P., Fiocca, R., Klingbiel, D., 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 28:3 (2010), 466-474.
50. [50] Tougeron, D., Sickersen, G., Mouillet, G., Zaanan, A., Trouilloud, I., Coriat, R., et al. Predictors of disease-free survival in colorectal cancer with microsatellite instability: an AGEO multicentre study. Eur J Cancer 51:8 (2015), 925-934.
51. [51] Samowitz, W.S., Sweeney, C., Herrick, J., Albertsen, H., Levin, T.R., Murtaugh, M.A., et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65:14 (2005), 6063-6069.
52. [52] Lochhead, P., Kuchiba, A., Imamura, Y., Liao, X., Yamauchi, M., Nishihara, R., et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 105:15 (2013), 1151-1156.
53. [53] Ogino, S., Shima, K., Meyerhardt, J.A., McCleary, N.J., Ng, K., Hollis, D., et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 18:3 (2012), 890-900.
54. [54] French, A.J., Sargent, D.J., Burgart, L.J., Foster, N.R., Kabat, B.F., Goldberg, R., et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 14:11 (2008), 3408-3415.
55. [55] Malesci, A., Laghi, L., Bianchi, P., Delconte, G., Randolph, A., Torri, V., et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 13:13 (2007), 3831-3839.
56. [56] Kim, C.G., Ahn, J.B., Jung, M., Beom, S.H., Kim, C., Kim, J.H., et al. Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers. Br J Canc 115:1 (2016), 25-33.
57. [57] Venderbosch, S., Nagtegaal, I.D., Maughan, T.S., Smith, C.G., Cheadle, J.P., Fisher, D., et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 20:20 (2014), 5322-5330.
58. [58] Goldstein, J., Tran, B., Ensor, J., Gibbs, P., Wong, H.L., Wong, S.F., et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol 25:5 (2014), 1032-1038.
59. [59] Jover, R., Zapater, P., Castells, A., Llor, X., Andreu, M., Cubiella, J., et al. The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur J Cancer 45:3 (2009), 365-373.
60. [60] Kim, G.P., Colangelo, L.H., Wieand, H.S., Paik, S., Kirsch, I.R., Wolmark, N., 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 25:7 (2007), 767-772.
61. [61] Hemminki, A., Mecklin, J.P., Jarvinen, H., Aaltonen, L.A., Joensuu, H., Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 119:4 (2000), 921-928.
62. [62] Elsaleh, H., Joseph, D., Grieu, F., Zeps, N., Spry, N., Iacopetta, B., Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355:9217 (2000), 1745-1750.
63. [63] Tejpar, S., Saridaki, Z., Delorenzi, M., Bosman, F., Roth, A.D., Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle. J Natl Cancer Inst 103:11 (2011), 841-844.
64. [64] Liang, J.T., Huang, K.C., Lai, H.S., Lee, P.H., Cheng, Y.M., Hsu, H.C., 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 101:6 (2002), 519-525.
65. [65] Lamberti, C., Lundin, S., Bogdanow, M., Pagenstecher, C., Friedrichs, N., Buttner, R., et al. Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis 22:2 (2007), 145-152.
66. [66] Carethers, J.M., Smith, E.J., Behling, C.A., Nguyen, L., Tajima, A., Doctolero, R.T., et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 126:2 (2004), 394-401.
67. [67] Arnold, C.N., Goel, A., Boland, C.R., Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int J Cancer 106:1 (2003), 66-73.
68. [68] Fischer, F., Baerenfaller, K., Jiricny, J., 5-Fluorouracil is efficiently removed from DNA by the base excision and mismatch repair systems. Gastroenterology 133:6 (2007), 1858-1868.
69. [69] Sargent, D.J., Marsoni, S., Monges, G., Thibodeau, S.N., Labianca, R., Hamilton, S.R., et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:20 (2010), 3219-3226.
70. [70] Quasar Collaborative, G., Gray, R., Barnwell, J., McConkey, C., Hills, R.K., Williams, N.S., et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370:9604 (2007), 2020-2029.
71. [71] Sargent, D.J., Shi, Q., Yothers, G., Tejpar, S., Bertagnolli, M.M., Thibodeau, S.N., Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): a pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J Clin Oncol, 32, 2014, 5s.
72. [72] Andre, T., Boni, C., Mounedji-Boudiaf, L., Navarro, M., Tabernero, J., Hickish, T., et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. New Engl J Med 350:23 (2004), 2343-2351.
73. [73] Kuebler, J.P., Wieand, H.S., O'Connell, M.J., Smith, R.E., Colangelo, L.H., Yothers, G., et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25:16 (2007), 2198-2204.
74. [74] Haller, D.G., Tabernero, J., Maroun, J., de Braud, F., Price, T., Van Cutsem, E., et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 29:11 (2011), 1465-1471.
75. [75] Fink, D., Nebel, S., Aebi, S., Zheng, H., Cenni, B., Nehme, A., et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res 56:21 (1996), 4881-4886.
76. [76] Zaanan, A., Cuilliere-Dartigues, P., Guilloux, A., Parc, Y., Louvet, C., de Gramont, 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 21:4 (2010), 772-780.
77. [77] Des Guetz, G., Lecaille, C., Mariani, P., Bennamoun, M., Uzzan, B., Nicolas, P., et al. Prognostic impact of microsatellite instability in colorectal cancer patients treated with adjuvant FOLFOX. Anticancer Res 30:10 (2010), 4297-4301.
78. [78] Kim, S.T., Lee, J., Park, S.H., Park, J.O., Lim, H.Y., Kang, W.K., et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol 66:4 (2010), 659-667.
79. [79] Gavin, P.G., Colangelo, L.H., Fumagalli, D., Tanaka, N., Remillard, M.Y., Yothers, G., et al. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin Cancer Res 18:23 (2012), 6531-6541.
80. [80] Sinicrope, F.A., Mahoney, M.R., Smyrk, T.C., Thibodeau, S.N., Warren, R.S., Bertagnolli, M.M., et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 31:29 (2013), 3664-3672.
81. [81] Tougeron, D., Mouillet, G., Trouilloud, I., Lecomte, T., Coriat, R., Aparicio, T., et al. Efficacy of adjuvant chemotherapy in colon cancer with microsatellite instability: a large multicenter AGEO Study. J Natl Cancer Inst, 108(7), 2016.
82. [82] Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 374:3 (2016), 211-222.
83. [83] de Rosa, N., Rodriguez-Bigas, M.A., Chang, G.J., Veerapong, J., Borras, E., Krishnan, S., et al. DNA Mismatch repair deficiency in rectal cancer: benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics. J Clin Oncol 34:25 (2016), 3039-3046.
84. [84] Des Guetz, G., Uzzan, B., Nicolas, P., Schischmanoff, O., Perret, G.Y., Morere, J.F., Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. Anticancer Res 29:5 (2009), 1615-1620.
85. [85] Westdorp, H., Fennemann, F.L., Weren, R.D., Bisseling, T.M., Ligtenberg, M.J., Figdor, C.G., et al. Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol Immunother, 2016.
86. [86] Koido, S., Ohkusa, T., Homma, S., Namiki, Y., Takakura, K., Saito, K., et al. Immunotherapy for colorectal cancer. World J Gastroenterol 19:46 (2013), 8531-8542.
87. [87] Llosa, N.J., Cruise, M., Tam, A., Wicks, E.C., Hechenbleikner, E.M., Taube, J.M., et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:1 (2015), 43-51.
88. [88] Kroemer, G., Galluzzi, L., Zitvogel, L., Fridman, W.H., Colorectal cancer: the first neoplasia found to be under immunosurveillance and the last one to respond to immunotherapy?. Oncoimmunology, 4(7), 2015, e1058597.
89. [89] Lipson, E.J., Sharfman, W.H., Drake, C.G., Wollner, I., Taube, J.M., Anders, R.A., et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:2 (2013), 462-468.
90. [90] Le, D.T., Uram, J.N., Wang, H., Bartlett, B.R., Kemberling, H., Eyring, A.D., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:26 (2015), 2509-2520.
91. [91] https://clinicaltrials.gov/ct2/show/NCT02460198?term=KEYNOTE+164&rank=1.
92. [92] https://clinicaltrials.gov/ct2/show/NCT02563002?term=KEYNOTE+177&rank=1.
93. [93] https://clinicaltrials.gov/ct2/show/NCT02060188?term=CHECKMATE+142&rank=1.