Molecular Genetics and the Role of Molecularly Targeted Agents in Metastatic Colorectal Carcinoma

Abstract

Background

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is the third most common malignancy and fourth leading cancer-related deaths worldwide. In the USA, CRC is the third most commonly diagnosed cancer in both men and women. It is caused by genetic components and potential environmental factors such as consumption of processed meat, red meat, animal fats, low fiber intake, and obesity. Despite the utilization of effective screening modalities and guidelines in the USA, a significant number of patients are diagnosed with advanced, metastatic disease at the time of presentation to the physician. Recent advances in the understanding of molecular medicine with subsequent development and incorporation of newer therapeutic agents into current chemotherapeutic regimens have improved outcomes; however, the management of metastatic CRC remains challenging, particularly for the treating oncologists.

Methods

We conducted a literature search on CRC mainly related to molecular genetics, targeted biologic agents, and published clinical trials. We also searched and reviewed ongoing clinical trials from Clinicaltrials.gov.

Results and Conclusions

Alterations in several oncogenes are associated with CRC, among those RAS, BRAF, and HER2 are of current clinical importance. Chemotherapy drugs, along with vascular endothelial growth factor or epidermal growth factor receptor monoclonal antibodies, are proven to be efficient with manageable toxicity profiles in metastatic CRC. Additional researches on Her-2-directed therapy, BRAF-targeted agents, immunotherapeutic, and newer molecularly targeted agents are needed for further improvement in outcome.

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References

  1. 1.

    Gandomani HS, Yousefi SM, Aghajani M, Mohammadian-Hafshejani A, Tarazoj AA, Pouyesh V, et al. Colorectal cancer in the world: incidence, mortality and risk factors. Biomed Res Ther. 2017;4:1656.

    Google Scholar 

  2. 2.

    Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, regional, and National Cancer Incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 Cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3:524–48.

    Google Scholar 

  3. 3.

    Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2016;66:7–30.

    Google Scholar 

  4. 4.

    SEER Cancer Stat Facts: Colorectal Cancer. National Cancer Institute Bethesda No Title.

  5. 5.

    Ali S (2010) Colorectal cancer incidence , mortality, stage at diagnosis, and treatment patterns among Whites and African Americans in North Carolina.

  6. 6.

    Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67:177–93.

    Google Scholar 

  7. 7.

    Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Sameer AS. Colorectal cancer: molecular mutations and polymorphisms. Front Oncol. 2013;3:114.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Stigliano V, Sanchez-Mete L, Martayan A, Anti M. Early-onset colorectal cancer: a sporadic or inherited disease? World J Gastroenterol. 2014;20:12420–30.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Campos FGCM, Figueiredo MN, Monteiro M, Nahas SC, Cecconello I. Incidence of colorectal cancer in young patients. Rev Col Bras Cir. 2017;44:208–15.

    PubMed  Google Scholar 

  11. 11.

    Norat T, Lukanova A, Ferrari P, Riboli E. Meat consumption and colorectal cancer risk: dose-response meta-analysis of epidemiological studies. Int J Cancer. 2002;98:241–56.

    CAS  PubMed  Google Scholar 

  12. 12.

    Jahani-Sherafat S, Alebouyeh M, Moghim S, Ahmadi Amoli H, Ghasemian-Safaei H. Role of gut microbiota in the pathogenesis of colorectal cancer; a review article. Gastroenterol Hepatol Bed Bench. 2018;11:101–9.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Mazmanian SK. Capsular polysaccharides of symbiotic bacteria modulate immune responses during experimental colitis. J Pediatr Gastroenterol Nutr. 2008;46(Suppl 1):E11–2.

    PubMed  Google Scholar 

  14. 14.

    Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013;14:207–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27:1423–31.

    CAS  PubMed  Google Scholar 

  16. 16.

    Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.

    CAS  PubMed  Google Scholar 

  18. 18.

    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.

    CAS  PubMed  Google Scholar 

  19. 19.

    Weinstein IB. CANCER: enhanced: addiction to oncogenes--the Achilles heal of Cancer. Science. 2002;297:63–4.

    CAS  PubMed  Google Scholar 

  20. 20.

    Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in Cancer. Cancer Res. 2012;72:2457–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Takayama T, Ohi M, Hayashi T, Miyanishi K, Nobuoka A, Nakajima T, et al. Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis. Gastroenterology. 2001;121:599–611.

    CAS  PubMed  Google Scholar 

  22. 22.

    Clarke CN, Kopetz ES. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointest Oncol. 2015;6:660–7.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal Cancer: practical application of patient selection. J Clin Oncol. 2009;27:1130–6.

    CAS  PubMed  Google Scholar 

  24. 24.

    Network NCC National Comprehensive Cancer Network. Colon Cancer (Version 2.2019).

  25. 25.

    Network NCC National Comprehensive Cancer Network. Rectal Cancer (Version 2.2019).

  26. 26.

    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    CAS  PubMed  Google Scholar 

  27. 27.

    Issa J-P. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4:988–93.

    CAS  PubMed  Google Scholar 

  28. 28.

    Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–93.

    CAS  PubMed  Google Scholar 

  29. 29.

    Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science. 1986;232:1644–6.

    CAS  PubMed  Google Scholar 

  30. 30.

    Jorissen RN, Walker F, Pouliot N, Garrett TPJ, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31–53.

    CAS  PubMed  Google Scholar 

  31. 31.

    Li C, Liu D, Ye L, Huang L, Jaiswal S, Li X, et al. HER-2 overexpression and survival in colorectal cancer: a meta-analysis. J Zhejiang Univ Sci B. 2014;15:582–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Seo AN, Kwak Y, Kim D-W, Kang S-B, Choe G, Kim WH, et al. HER2 status in colorectal Cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS One. 2014;9:e98528.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4:22.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Naccarati A, Polakova V, Pardini B, Vodickova L, Hemminki K, Kumar R, et al. Mutations and polymorphisms in TP53 gene—an overview on the role in colorectal cancer. Mutagenesis. 2012;27:211–8.

    CAS  PubMed  Google Scholar 

  35. 35.

    Børresen-Dale AL, Lothe RA, Meling GI, Hainaut P, Rognum TO, Skovlund E. TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival. Clin Cancer Res. 1998;4:203–10.

    PubMed  Google Scholar 

  36. 36.

    Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N, et al. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol. 2005;23:7518–28.

    CAS  PubMed  Google Scholar 

  37. 37.

    Watanabe T, Sullenger BA. Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts. Proc Natl Acad Sci U S A. 2000;97:8490–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Warren RS, Kirn DH. Liver-directed viral therapy for cancer p53-targeted adenoviruses and beyond. Surg Oncol Clin N Am. 2002;11(571–88):vi.

    Google Scholar 

  39. 39.

    Raj K, Ogston P, Beard P. Virus-mediated killing of cells that lack p53 activity. Nature. 2001;412:914–7.

    CAS  PubMed  Google Scholar 

  40. 40.

    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.

    CAS  PubMed  Google Scholar 

  41. 41.

    Hedrick L, Cho KR, Fearon ER, Wu TC, Kinzler KW, Vogelstein B. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 1994;8:1174–83.

    CAS  PubMed  Google Scholar 

  42. 42.

    Sun XF, Rütten S, Zhang H, Nordenskjöld B. Expression of the deleted in colorectal cancer gene is related to prognosis in DNA diploid and low proliferative colorectal adenocarcinoma. J Clin Oncol. 1999;17:1745–50.

    CAS  PubMed  Google Scholar 

  43. 43.

    Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res. 2002;8:1838–42.

    CAS  PubMed  Google Scholar 

  44. 44.

    Miyaki M, Iijima T, Konishi M, Sakai K, Ishii A, Yasuno M, et al. Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene. 1999;18:3098–103.

    CAS  PubMed  Google Scholar 

  45. 45.

    Howe JR. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Parsons R, Myeroff LL, Liu B, Willson JK, Markowitz SD, Kinzler KW, et al. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 1995;55:5548–50.

    CAS  PubMed  Google Scholar 

  47. 47.

    Myeroff LL, Parsons R, Kim SJ, Hedrick L, Cho KR, Orth K, et al. A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res. 1995;55:5545–7.

    CAS  PubMed  Google Scholar 

  48. 48.

    Park K, Kim SJ, Bang YJ, Park JG, Kim NK, Roberts AB, et al. Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci U S A. 1994;91:8772–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Söreide K, Janssen EAM, Söiland H, Körner H, Baak JPA. Microsatellite instability in colorectal cancer. Br J Surg. 2006;93:395–406.

    PubMed  Google Scholar 

  50. 50.

    Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–2087.e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011;135:1269–77.

    CAS  PubMed  Google Scholar 

  52. 52.

    Pawlik TM, Raut CP, Rodriguez-Bigas MA. Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers. 2004;20:199–206.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Koehne C-H, Dubois RN. COX-2 inhibition and colorectal cancer. Semin Oncol. 2004;31:12–21.

    CAS  PubMed  Google Scholar 

  54. 54.

    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, Dubois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183–8.

    CAS  PubMed  Google Scholar 

  55. 55.

    Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1:11–21.

    CAS  PubMed  Google Scholar 

  56. 56.

    Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, et al. Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci U S A. 2002;99:303–8.

    CAS  PubMed  Google Scholar 

  57. 57.

    Gupta RA, Tan J, Krause WF, Geraci MW, Willson TM, Dey SK, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci U S A. 2000;97:13275–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. Cancer susceptibility gene mutations in individuals with colorectal Cancer. J Clin Oncol. 2017;35:1086–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 1999;36:801–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Salovaara R, Loukola A, Kristo P, Kääriäinen H, Ahtola H, Eskelinen M, et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2000;18:2193–200.

    CAS  PubMed  Google Scholar 

  61. 61.

    Lynch HT, Smyrk T, Lynch JF. Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation. Oncology. 55:103–8.

  62. 62.

    Boland CR, Koi M, Chang DK, Carethers JM. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Familial Cancer. 2008;7:41–52.

    CAS  PubMed  Google Scholar 

  63. 63.

    Kolodner RD, Tytell JD, Schmeits JL, et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999;59:5068–74.

    CAS  PubMed  Google Scholar 

  64. 64.

    Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with somatic G:C→T:a mutations in colorectal tumors. Nat Genet. 2002;30:227–32.

    CAS  PubMed  Google Scholar 

  65. 65.

    Frucht H, Lucas AL. Molecular genetics of colorectal cancer. Savarese DMF, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed March 01 2019.

  66. 66.

    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85.

    CAS  PubMed  Google Scholar 

  67. 67.

    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and Leucovorin for metastatic colorectal Cancer. N Engl J Med. 2004;350:2335–42.

    CAS  PubMed  Google Scholar 

  68. 68.

    Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9.

    CAS  PubMed  Google Scholar 

  69. 69.

    Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005;333:328–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200. J Clin Oncol. 2007;25:1539–44.

    CAS  PubMed  Google Scholar 

  71. 71.

    Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.

    CAS  PubMed  Google Scholar 

  72. 72.

    Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29–37.

    CAS  PubMed  Google Scholar 

  73. 73.

    Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol Off J Eur Soc Med Oncol. 2015;26:724–30.

    CAS  Google Scholar 

  74. 74.

    Cartwright TH, Yim YM, Yu E, Chung H, Halm M, Forsyth M. Survival outcomes of bevacizumab beyond progression in metastatic colorectal cancer patients treated in US community oncology. Clin Colorectal Cancer. 2012;11:238–46.

    CAS  PubMed  Google Scholar 

  75. 75.

    Simkens LHJ, van Tinteren H, May A, ten Tije AJ, Creemers GJM, Loosveld OJL, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch colorectal Cancer group. Lancet. 2015;385:1843–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015;16:1355–69.

    CAS  PubMed  Google Scholar 

  77. 77.

    Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blin. Lancet Oncol. 2015;16:499–508.

    CAS  PubMed  Google Scholar 

  78. 78.

    Shord SS, Bressler LR, Tierney LA, Cuellar S, George A. Understanding and managing the possible adverse effects associated with bevacizumab. Am J Heal Pharm. 2009;66:999–1013.

    CAS  Google Scholar 

  79. 79.

    Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–506.

    PubMed  Google Scholar 

  80. 80.

    Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6:465–77.

    CAS  PubMed  Google Scholar 

  81. 81.

    Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26:13–21.

    CAS  PubMed  Google Scholar 

  82. 82.

    Molinari F, Felicioni L, Buscarino M, de Dosso S, Buttitta F, Malatesta S, et al. Increased detection sensitivity for KRAS mutations enhances the prediction of Anti-EGFR monoclonal antibody resistance in metastatic colorectal Cancer. Clin Cancer Res. 2011;17:4901–14.

    CAS  PubMed  Google Scholar 

  83. 83.

    Saltz LB, Meropol NJ, Loehrer PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.

    CAS  PubMed  Google Scholar 

  84. 84.

    Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and Cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal Cancer. N Engl J Med. 2004;351:337–45.

    CAS  PubMed  Google Scholar 

  85. 85.

    Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal Cancer. N Engl J Med. 2007;357:2040–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–64.

    PubMed  Google Scholar 

  87. 87.

    Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15:569–79.

    CAS  PubMed  Google Scholar 

  88. 88.

    Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal Cancer. N Engl J Med. 2009;360:1408–17.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Van Cutsem E, Lenz H-J, Köhne C-H, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33:692–700.

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, 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.

    CAS  PubMed  Google Scholar 

  91. 91.

    Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol Off J Eur Soc Med Oncol. 2011;22:1535–46.

    CAS  Google Scholar 

  92. 92.

    Qin S, Li J, Wang L, et al (2018) Efficacy and tolerability of first-line Cetuximab plus Leucovorin, fluorouracil, and Oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal Cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol JCO2018783183.

  93. 93.

    Douillard J-Y, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, 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.

    CAS  PubMed  Google Scholar 

  94. 94.

    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol. 2014;25:1346–55.

    CAS  Google Scholar 

  95. 95.

    Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet (London, England). 2011;377:2103–14.

    CAS  Google Scholar 

  96. 96.

    Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755–62.

    CAS  PubMed  Google Scholar 

  97. 97.

    Primrose J, Falk S, Finch-Jones M, Valle J, O'Reilly D, Siriwardena A, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the new EPOC randomised controlled trial. Lancet Oncol. 2014;15:601–11.

    CAS  PubMed  Google Scholar 

  98. 98.

    Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75.

    CAS  PubMed  Google Scholar 

  99. 99.

    Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17:1426–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Mahoney MR, O'Neil BH, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or re. J Clin Oncol. 2014;32:LBA3.

    Google Scholar 

  101. 101.

    Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, et al. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Color Dis. 2017;32:1179–90.

    Google Scholar 

  102. 102.

    Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27:672–80.

    CAS  PubMed  Google Scholar 

  103. 103.

    Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJM, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.

    CAS  PubMed  Google Scholar 

  104. 104.

    Hochster HS, Catalano PJ, O’Dwyer PJ, et al. Randomized trial of irinotecan and cetuximab (IC) versus irinotecan, cetuximab and ramucirumab (ICR) as 2nd line therapy of advanced colorectal cancer (CRC) following oxaliplatin and bevacizumb based therapy: result of E7208. J Clin Oncol. 2018;36:3504.

    Google Scholar 

  105. 105.

    Weiss JM, Pfau PR, O’Connor ES, King J, LoConte N, Kennedy G, et al. Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results--Medicare data. J Clin Oncol. 2011;29:4401–9.

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Bauer KM, Hummon AB, Buechler S. Right-side and left-side colon cancer follow different pathways to relapse. Mol Carcinog. 2012;51:411–21.

    CAS  PubMed  Google Scholar 

  107. 107.

    Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, et al. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018;101:263–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Pietrantonio F, Morano F, Corallo S, Lonardi S, Cremolini C, Rimassa L, et al. First-line FOLFOX plus panitumumab (Pan) followed by 5FU/LV plus Pan or single-agent Pan as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC): the VALENTINO study. J Clin Oncol. 2018;36:3505.

  109. 109.

    Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015;112:1888–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Hong DS, Morris VK, El Osta B, et al. Phase IB study of Vemurafenib in combination with irinotecan and Cetuximab in patients with metastatic colorectal Cancer with BRAFV600E mutation. Cancer Discov. 2016;6:1352–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Van Cutsem E, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer (mCRC): efficacy and tumor markers. J Clin Oncol. 2018;36:627.

    Google Scholar 

  112. 112.

    Bendell JC, Atreya CE, André T, Tabernero J, Gordon MS, Bernards R, et al. Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol. 2014;32:3515.

    Google Scholar 

  113. 113.

    Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16:1306–15.

    CAS  PubMed  Google Scholar 

  114. 114.

    Venderbosch S, Nagtegaal ID, Maughan TS, Smith CG, Cheadle JP, 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. 2014;20:5322–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.

    CAS  PubMed  Google Scholar 

  116. 116.

    Li J, Qin S, Xu R, Yau TCC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–29.

    CAS  PubMed  Google Scholar 

  117. 117.

    Ross JS, Fakih M, Ali SM, Elvin JA, Schrock AB, Suh J, et al. Targeting HER2 in colorectal cancer: the landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer. 2018;124:1358–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Valtorta E, Martino C, Sartore-Bianchi A, Penaullt-Llorca F, Viale G, Risio M, et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol. 2015;28:1481–91.

    CAS  PubMed  Google Scholar 

  119. 119.

    Fakih MG. Trastuzumab plus Pertuzumab resistance does not preclude response to Lapatinib plus Trastuzumab in HER2-amplified colorectal Cancer. Oncologist. 2018;23:474–7.

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Raghav KPS, Overman MJ, Yu R, Meric-Bernstam F, Menter D, Kee BK, et al. HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. J Clin Oncol. 2016;34:3517.

    Google Scholar 

  121. 121.

    Parikh A, Atreya C, Korn WM, Venook AP. Prolonged response to HER2-directed therapy in a patient with HER2-amplified, rapidly progressive metastatic colorectal Cancer. J Natl Compr Cancer Netw. 2017;15:3–8.

    Google Scholar 

  122. 122.

    Siena S, Sartore-Bianchi A, Trusolino L, et al. Abstract CT005: final results of the HERACLES trial in HER2-amplified colorectal cancer. Cancer Res. 2017. https://doi.org/10.1158/1538-7445.AM2017-CT005.

  123. 123.

    Meric-Bernstam F, Hurwitz H, Raghav KPS, McWilliams RR, Fakih M, VanderWalde A, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20:518–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Dougan M, Dranoff G. Immune therapy for Cancer. Annu Rev Immunol. 2009;27:83–117.

    CAS  PubMed  Google Scholar 

  125. 125.

    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with Nivolumab plus Ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal Cancer. J Clin Oncol. 2018;36:773–9.

    CAS  PubMed  Google Scholar 

  130. 130.

    Diaz LA, Le DT, Yoshino T, André T, Bendell JC, Rosales M, et al. KEYNOTE-177: phase 3, open-label, randomized study of first-line pembrolizumab (Pembro) versus investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC). J Clin Oncol. 2018;36:–TPS877.

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Naeem, A., Tun, A.M. & Guevara, E. Molecular Genetics and the Role of Molecularly Targeted Agents in Metastatic Colorectal Carcinoma. J Gastrointest Canc 51, 387–400 (2020). https://doi.org/10.1007/s12029-019-00272-3

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Keywords

  • Metastatic colorectal carcinoma
  • Epidemiology
  • Risk factors
  • Pathogenesis
  • Molecular genetics
  • Molecularly targeted agents