KRAS mutation testing of colorectal cancer for anti-EGFR therapy: Dogmas versus evidence

Current Cancer Drug Targets

Volumn 10, Issue 8, 2010, Pages 813-823

  Timar J ^a   Hegedus B ^a   Raso E ^a  

^a SEMMELWEIS UNIVERSITY   (Hungary)

Author keywords

Anti EGFR therapy; Colorectal cancer; KRAS; Mutation analysis

Indexed keywords

AMPHIREGULIN; B RAF KINASE; CETUXIMAB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY; EPIREGULIN; FLUOROURACIL; IRINOTECAN; K RAS PROTEIN; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE 3 KINASE; ANTINEOPLASTIC AGENT; KRAS PROTEIN, HUMAN; ONCOPROTEIN; RAS PROTEIN; TUMOR MARKER;

ALGORITHM; ALLELE; ARTICLE; CARCINOGENESIS; CLINICAL TRIAL (TOPIC); CODON; COLORECTAL CARCINOMA; COPY NUMBER VARIATION; DIAGNOSTIC ACCURACY; DIAGNOSTIC TEST ACCURACY STUDY; DRUG EFFICACY; GENE MUTATION; HUMAN; META ANALYSIS (TOPIC); METASTASIS; MICROSATELLITE INSTABILITY; MOLECULAR DIAGNOSTICS; MONOTHERAPY; MUTATION TEST; ONCOGENE K RAS; ONCOGENE N RAS; OVERALL SURVIVAL; PANCREAS CANCER; PRACTICE GUIDELINE; PREDICTIVE VALUE; PRIMARY TUMOR; PROGRESSION FREE SURVIVAL; SENSITIVITY AND SPECIFICITY; SIGNAL TRANSDUCTION; TREATMENT RESPONSE; TUMOR GROWTH; COLORECTAL TUMOR; DRUG ANTAGONISM; GENETICS; MUTATION; PROGNOSIS; REVIEW;

ANTINEOPLASTIC AGENTS; COLORECTAL NEOPLASMS; HUMANS; MUTATION; PROGNOSIS; PROTO-ONCOGENE PROTEINS; RAS PROTEINS; RECEPTOR, EPIDERMAL GROWTH FACTOR; TUMOR MARKERS, BIOLOGICAL;

EID: 79958287180     PISSN: 15680096     EISSN: 18735576     Source Type: Journal    
DOI: 10.2174/156800910793357989     Document Type: Article

References (153)

1. Gold, J. S.; Dematteo, R. P. Combined surgical and molecular therapy: the gastrointestinal stromal tumor model. Ann. Surg. 2006, 244(2), 176-184.
2. Brown, P.; Hunger, S. P.; Smith, F. O.; Carroll, W. L.; Reaman, G. H. Novel targeted drug therapies for the treatment of childhood acute leukemia. Expert Rev. Hematol. 2009, 2(9), 145-158.
3. Riely, G. J.; Politi, K. A.; Miller, V. A.; Pao, W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin. Cancer Res. 2006, 12(24), 7232-7241.
4. Gilbert, J. A.; Goetz, M. P.; Reynolds, C. A.; Ingle, J. N.; Giordano, K. F.; Suman, V. J.; Blair, H. E.; Jenkins, R. B.; Lingle, W. L.; Reinholz, M. M.; Adjei, A. A.; Ames, M. M. Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy. Mol. Cancer Ther. 2008, 7(4), 944-951.
5. Spano, J. P.; Lagorce, C.; Atlan, D.; Milano, G.; Domont, J.; Benamouzig, R.; Attar, A.; Benichou, J.; Martin, A.; Morere, J. F.; Raphael, M.; Penault- Llorca, F.; Breau, J. L.; Fagard, R.; Khayat, D.; Wind, P. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann. Oncol. 2005, 16(1), 102-108.
6. van Krieken, J. H.; Jung, A.; Kirchner, T.; Carneiro, F.; Seruca, R.; Bosman, F. T.; Quirke, P.; Flejou, J. F.; Hansen, T. P.; de Hertogh, G.; Jares, P.; Langner, C.; Hoefler, G.; Ligtenberg, M.; Tiniakos, D.; Tejpar, S.; Bevilacqua, G.; Ensari, A. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch. 2009, 454(2), 233-235.
7. Gupta, R.; Dastane, A. M.; McKenna, R., Jr.; Marchevsky, A. M. The predictive value of epidermal growth factor receptor tests in patients with pulmonary adenocarcinoma: review of current "best evidence" with metaanalysis. Hum. Pathol. 2009, 40(3), 356-365.
8. Mayer, A.; Takimoto, M.; Fritz, E.; Schellander, G.; Kofler, K.; Ludwig, H. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 1993, 71(8), 2454-2460.
9. McKay, J. A.; Murray, L. J.; Curran, S.; Ross, V. G.; Clark, C.; Murray, G. I.; Cassidy, J.; McLeod, H. L. Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and lymph node metastases. Eur. J. Cancer 2002, 38(17), 2258-2264.
10. Hama, T.; Yuza, Y.; Saito, Y.; O-Uchi, J.; Kondo, S.; Okabe, M.; Yamada, H.; Kato, T.; Moriyama, H.; Kurihara, S.; Urashima, M. Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma. Oncologist 2009, 14(9), 900-908.
11. Barber, T. D.; Vogelstein, B.; Kinzler, K. W.; Velculescu, V. E. Somatic mutations of EGFR in colorectal cancers and glioblastomas. N. Engl. J. Med. 2004, 351(27), 2883.
12. Spindler, K. L.; Lindebjerg, J.; Nielsen, J. N.; Olsen, D. A.; Bisgard, C.; Brandslund, I.; Jakobsen, A. Epidermal growth factor receptor analyses in colorectal cancer: a comparison of methods. Int. J. Oncol. 2006, 29(5), 1159-1165.
13. Sauer, T.; Guren, M. G.; Noren, T.; Dueland, S. Demonstration of EGFR gene copy loss in colorectal carcinomas by fluorescence in situ hybridization (FISH): a surrogate marker for sensitivity to specific anti-EGFR therapy? Histopathology 2005, 47(6), 560-564.
14. Al-Kuraya, K.; Novotny, H.; Bavi, P.; Siraj, A. K.; Uddin, S.; Ezzat, A.; Sanea, N. A.; Al-Dayel, F.; Al-Mana, H.; Sheikh, S. S.; Mirlacher, M.; Tapia, C.; Simon, R.; Sauter, G.; Terracciano, L.; Tornillo, L. HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer. J. Clin. Pathol. 2007, 60(7), 768-772.
15. Moroni, M.; Veronese, S.; Benvenuti, S.; Marrapese, G.; Sartore-Bianchi, A.; Di Nicolantonio, F.; Gambacorta, M.; Siena, S.; Bardelli, A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005, 6(5), 279-286.
16. Nagahara, H.; Mimori, K.; Ohta, M.; Utsunomiya, T.; Inoue, H.; Barnard, G. F.; Ohira, M.; Hirakawa, K.; Mori, M. Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin. Cancer Res. 2005, 11(4), 1368-1371.
17. Ogino, S.; Meyerhardt, J. A.; Cantor, M.; Brahmandam, M.; Clark, J. W.; Namgyal, C.; Kawasaki, T.; Kinsella, K.; Michelini, A. L.; Enzinger, P. C.; Kulke, M. H.; Ryan, D. P.; Loda, M.; Fuchs, C. S. Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer. Clin. Cancer Res. 2005, 11(18), 6650-6656.
18. Azuma, M.; Danenberg, K. D.; Iqbal, S.; El-Khoueiry, A.; Zhang, W.; Yang, D.; Koizumi, W.; Saigenji, K.; Danenberg, P. V.; Lenz, H. J. Epidermal growth factor receptor and epidermal growth factor receptor variant III gene expression in metastatic colorectal cancer. Clin. Colorectal Cancer 2006, 6(3), 214-218.
19. Press, O. A.; Zhang, W.; Gordon, M. A.; Yang, D.; Lurje, G.; Iqbal, S.; El- Khoueiry, A.; Lenz, H. J. Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer. Cancer Res. 2008, 68(8), 3037-3042.
20. Spindler, K. L.; Nielsen, J. N.; Lindebjerg, J.; Brandslund, I.; Jakobsen, A. Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region. Int. J. Radiat. Oncol. Biol. Phys. 2006, 66(2), 500-504.
21. Davies, H.; Bignell, G. R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M. J.; Bottomley, W.; Davis, N.; Dicks, E.; Ewing, R.; Floyd, Y.; Gray, K.; Hall, S.; Hawes, R.; Hughes, J.; Kosmidou, V.; Menzies, A.; Mould, C.; Parker, A.; Stevens, C.; Watt, S.; Hooper, S.; Wilson, R.; Jayatilake, H.; Gusterson, B. A.; Cooper, C.; Shipley, J.; Hargrave, D.; Pritchard-Jones, K.; Maitland, N.; Chenevix- Trench, G.; Riggins, G. J.; Bigner, D. D.; Palmieri, G.; Cossu, A.; Flanagan, A.; Nicholson, A.; Ho, J. W.; Leung, S. Y.; Yuen, S. T.; Weber, B. L.; Seigler, H. F.; Darrow, T. L.; Paterson, H.; Marais, R.; Marshall, C. J.; Wooster, R.; Stratton, M. R.; Futreal, P. A. Mutations of the BRAF gene in human cancer. Nature 2002, 417(6892), 949-954.
22. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.; Willson, J. K.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004, 304(5670), 554.
23. Sartore-Bianchi, A.; Martini, M.; Molinari, F.; Veronese, S.; Nichelatti, M.; Artale, S.; Di Nicolantonio, F.; Saletti, P.; De Dosso, S.; Mazzucchelli, L.; Frattini, M.; Siena, S.; Bardelli, A. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009, 69(5), 1851-1857.
24. Sjoblom, T.; Jones, S.; Wood, L. D.; Parsons, D. W.; Lin, J.; Barber, T. D.; Mandelker, D.; Leary, R. J.; Ptak, J.; Silliman, N.; Szabo, S.; Buckhaults, P.; Farrell, C.; Meeh, P.; Markowitz, S. D.; Willis, J.; Dawson, D.; Willson, J. K.; Gazdar, A. F.; Hartigan, J.; Wu, L.; Liu, C.; Parmigiani, G.; Park, B. H.; Bachman, K. E.; Papadopoulos, N.; Vogelstein, B.; Kinzler, K. W.; Velculescu, V. E. The consensus coding sequences of human breast and colorectal cancers. Science 2006, 314(5797), 268-274.
25. Calistri, D.; Rengucci, C.; Seymour, I.; Lattuneddu, A.; Polifemo, A. M.; Monti, F.; Saragoni, L.; Amadori, D. Mutation analysis of p53, K-ras, and BRAF genes in colorectal cancer progression. J. Cell. Physiol. 2005, 204(2), 484-488.
26. Yang, S.; Farraye, F. A.; Mack, C.; Posnik, O.; O'Brien, M. J. BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am. J. Surg. Pathol. 2004, 28(11), 1452-1459.
27. Velho, S.; Moutinho, C.; Cirnes, L.; Albuquerque, C.; Hamelin, R.; Schmitt, F.; Carneiro, F.; Oliveira, C.; Seruca, R. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis? BMC Cancer 2008, 8, 255.
28. Nosho, K.; Kawasaki, T.; Ohnishi, M.; Suemoto, Y.; Kirkner, G. J.; Zepf, D.; Yan, L.; Longtine, J. A.; Fuchs, C. S.; Ogino, S. PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia 2008, 10(6), 534-541.
29. Perrone, F.; Lampis, A.; Orsenigo, M.; Di Bartolomeo, M.; Gevorgyan, A.; Losa, M.; Frattini, M.; Riva, C.; Andreola, S.; Bajetta, E.; Bertario, L.; Leo, E.; Pierotti, M. A.; Pilotti, S. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann. Oncol. 2009, 20(1), 84-90.
30. Prenen, H.; De Schutter, J.; Jacobs, B.; De Roock, W.; Biesmans, B.; Claes, B.; Lambrechts, D.; Van Cutsem, E.; Tejpar, S. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Cancer Res. 2009, 15(9), 3184-3188.
31. Frattini, M.; Saletti, P.; Romagnani, E.; Martin, V.; Molinari, F.; Ghisletta, M.; Camponovo, A.; Etienne, L. L.; Cavalli, F.; Mazzucchelli, L. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br. J. Cancer 2007, 97(8), 1139-1145.
32. Laurent-Puig, P.; Cayre, A.; Manceau, G.; Buc, E.; Bachet, J. B.; Lecomte, T.; Rougier, P.; Lievre, A.; Landi, B.; Boige, V.; Ducreux, M.; Ychou, M.; Bibeau, F.; Bouche, O.; Reid, J.; Stone, S.; Penault-Llorca, F. 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(35), 5924-5930.
33. Loupakis, F.; Pollina, L.; Stasi, I.; Ruzzo, A.; Scartozzi, M.; Santini, D.; Masi, G.; Graziano, F.; Cremolini, C.; Rulli, E.; Canestrari, E.; Funel, N.; Schiavon, G.; Petrini, I.; Magnani, M.; Tonini, G.; Campani, D.; Floriani, I.; Cascinu, S.; Falcone, A. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J. Clin. Oncol. 2009, 27(16), 2622-2629.
34. Negri, F. V.; Bozzetti, C.; Lagrasta, C. A.; Crafa, P.; Bonasoni, M. P.; Camisa, R.; Pedrazzi, G.; Ardizzoni, A. PTEN status in advanced colorectal cancer treated with cetuximab. Br. J. Cancer 2010, 102(1), 162-164.
35. Estep, A. L.; Palmer, C.; McCormick, F.; Rauen, K. A. Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PLoS ONE 2007, 2(12), e1279.
36. Zhang, X.; Gureasko, J.; Shen, K.; Cole, P. A.; Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006, 125(6), 1137-1149.
37. Batzer, A. G.; Rotin, D.; Urena, J. M.; Skolnik, E. Y.; Schlessinger, J. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol. Cell Biol. 1994, 14(8), 5192-5201.
38. Lowenstein, E. J.; Daly, R. J.; Batzer, A. G.; Li, W.; Margolis, B.; Lammers, R.; Ullrich, A.; Skolnik, E. Y.; Bar-Sagi, D.; Schlessinger, J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1992, 70(3), 431-442.
39. Vetter, I. R.; Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 2001, 294(5545), 1299-1304.
40. Schmitz, K. J.; Wohlschlaeger, J.; Alakus, H.; Bohr, J.; Stauder, M. A.; Worm, K.; Winde, G.; Schmid, K. W.; Baba, H. A. Activation of extracellular regulated kinases (ERK1/2) but not AKT predicts poor prognosis in colorectal carcinoma and is associated with k-ras mutations. Virchows Arch. 2007, 450(2), 151-159.
41. Lievre, A.; Blons, H.; Laurent-Puig, P. Oncogenic mutations as predictive factors in colorectal cancer. Oncogene 2010, 29(21), 3033-3043.
42. Prenen, H.; Tejpar, S.; Van Cutsem, E. New strategies for treatment of KRAS mutant metastatic colorectal cancer. Clin. Cancer Res. 2010, 16(11), 2921-2926.
43. Kodaki, T.; Woscholski, R.; Hallberg, B.; Rodriguez-Viciana, P.; Downward, J.; Parker, P. J. The activation of phosphatidylinositol 3-kinase by Ras. Curr. Biol. 1994, 4(9), 798-806.
44. Kelley, G. G.; Reks, S. E.; Ondrako, J. M.; Smrcka, A. V. Phospholipase C(epsilon): a novel Ras effector. EMBO J. 2001, 20(4), 743-754.
45. Gonzalez-Garcia, A.; Pritchard, C. A.; Paterson, H. F.; Mavria, G.; Stamp, G.; Marshall, C. J. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 2005, 7(3), 219-226.
46. Bai, Y.; Edamatsu, H.; Maeda, S.; Saito, H.; Suzuki, N.; Satoh, T.; Kataoka, T. Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res. 2004, 64(24), 8808-8810.
47. Gupta, S.; Ramjaun, A. R.; Haiko, P.; Wang, Y.; Warne, P. H.; Nicke, B.; Nye, E.; Stamp, G.; Alitalo, K.; Downward, J. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 2007, 129(5), 957-968.
48. Schubbert, S.; Shannon, K.; Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 2007, 7(4), 295-308.
49. Weinberg, R. A. The Biology of Cancer. Garland Science, Taylor and Francis Group: New York, 2007, p 408.
50. Edkins, S.; O'Meara, S.; Parker, A.; Stevens, C.; Reis, M.; Jones, S.; Greenman, C.; Davies, H.; Dalgliesh, G.; Forbes, S.; Hunter, C.; Smith, R.; Stephens, P.; Goldstraw, P.; Nicholson, A.; Chan, T. L.; Velculescu, V. E.; Yuen, S. T.; Leung, S. Y.; Stratton, M. R.; Futreal, P. A. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol. Ther. 2006, 5(8), 928-932.
51. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Aceto, N.; Remy, V.; Pinson, S.; Houdayer, C.; Arnoulet, C.; Sainty, D.; Bentires-Alj, M.; Olschwang, S.; Vey, N.; Mozziconacci, M. J.; Birnbaum, D.; Chaffanet, M. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer 2008, 8, 299.
52. Gripp, K. W.; Innes, A. M.; Axelrad, M. E.; Gillan, T. L.; Parboosingh, J. S.; Davies, C.; Leonard, N. J.; Lapointe, M.; Doyle, D.; Catalano, S.; Nicholson, L.; Stabley, D. L.; Sol-Church, K. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am. J. Med. Genet. A 2008, 146A(6), 683-690.
53. Yen, L. C.; Uen, Y. H.; Wu, D. C.; Lu, C. Y.; Yu, F. J.; Wu, I. C.; Lin, S. R.; Wang, J. Y. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab. Ann. Surg. 2010, 251(2), 254-260.
54. De Roock, W.; Claes, B.; Bernasconi, D.; De Schutter, J.; Biesmans, B.; Fountzilas, G.; Kalogeras, K. T.; Kotoula, V.; Papamichael, D.; Laurent-Puig, P.; Penault-Llorca, F.; Rougier, P.; Vincenzi, B.; Santini, D.; Tonini, G.; Cappuzzo, F.; Frattini, M.; Molinari, F.; Saletti, P.; De Dosso, S.; Martini, M.; Bardelli, A.; Siena, S.; Sartore-Bianchi, A.; Tabernero, J.; Macarulla, T.; Di Fiore, F.; Gangloff, A. O.; Ciardiello, F.; Pfeiffer, P.; Qvortrup, C.; Hansen, T. P.; Van Cutsem, E.; Piessevaux, H.; Lambrechts, D.; Delorenzi, M.; Tejpar, S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapyrefractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010, 11(8), 753-762.
55. Loupakis, F.; Ruzzo, A.; Cremolini, C.; Vincenzi, B.; Salvatore, L.; Santini, D.; Masi, G.; Stasi, I.; Canestrari, E.; Rulli, E.; Floriani, I.; Bencardino, K.; Galluccio, N.; Catalano, V.; Tonini, G.; Magnani, M.; Fontanini, G.; Basolo, F.; Falcone, A.; Graziano, F. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br. J. Cancer 2009, 101(4), 715-721.
56. Wan, J.; Li, H.; Li, Y.; Zhu, M. L.; Zhao, P. Loss of heterozygosity of Kras2 gene on 12p12-13 in Chinese colon carcinoma patients. World J. Gastroenterol. 2006, 12(7), 1033-1037.
57. Jonsson, M.; Ekstrand, A.; Edekling, T.; Eberhard, J.; Grabau, D.; Borg, D.; Nilbert, M. Experiences from treatment-predictive KRAS testing; high mutation frequency in rectal cancers from females and concurrent mutations in the same tumor. BMC Clin. Pathol. 2009, 9, 8.
58. Kalady, M. F.; Sanchez, J. A.; Manilich, E.; Hammel, J.; Casey, G.; Church, J. M. Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas. Dis. Colon Rectum 2009, 52(6), 1039-1045.
59. Deng, G.; Kakar, S.; Tanaka, H.; Matsuzaki, K.; Miura, S.; Sleisenger, M. H.; Kim, Y. S. Proximal and distal colorectal cancers show distinct genespecific methylation profiles and clinical and molecular characteristics. Eur. J. Cancer 2008, 44(9), 1290-1301.
60. Ogino, S.; Meyerhardt, J. A.; Irahara, N.; Niedzwiecki, D.; Hollis, D.; Saltz, L. B.; Mayer, R. J.; Schaefer, P.; Whittom, R.; Hantel, A.; Benson, A. B., 3rd; Goldberg, R. M.; Bertagnolli, M. M.; Fuchs, C. S. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin. Cancer Res. 2009, 15(23), 7322-7329.
61. Ogino, S.; Goel, A. Molecular classification and correlates in colorectal cancer. J. Mol. Diagn. 2008, 10(1), 13-27.
62. Sanchez, J. A.; Krumroy, L.; Plummer, S.; Aung, P.; Merkulova, A.; Skacel, M.; DeJulius, K. L.; Manilich, E.; Church, J. M.; Casey, G.; Kalady, M. F. Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer. Br. J. Surg. 2009, 96(10), 1196-1204.
63. Nash, G. M.; Gimbel, M.; Cohen, A. M.; Zeng, Z. S.; Ndubuisi, M. I.; Nathanson, D. R.; Ott, J.; Barany, F.; Paty, P. B. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann. Surg. Oncol. 2010, 17(2), 416-424.
64. Zlobec, I.; Bihl, M. P.; Schwarb, H.; Terracciano, L.; Lugli, A. Clinicopathological and protein characterization of BRAF-and K-RASmutated colorectal cancer and implications for prognosis. Int. J. Cancer 2009, 127(2), 367-380.
65. Brim, H.; Mokarram, P.; Naghibalhossaini, F.; Saberi-Firoozi, M.; Al-Mandhari, M.; Al-Mawaly, K.; Al-Mjeni, R.; Al-Sayegh, A.; Raeburn, S.; Lee, E.; Giardiello, F.; Smoot, D. T.; Vilkin, A.; Boland, C. R.; Goel, A.; Hafezi, M.; Nouraie, M.; Ashktorab, H. Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study. Mol. Cancer 2008, 7, 68.
66. Pathologists, C. o. A. KRAS mutation testing for colorectal cancer. http://www.cap.org/POET (accessed August 15, 2010).
67. Allegra, C. J.; Jessup, J. M.; Somerfield, M. R.; Hamilton, S. R.; Hammond, E. H.; Hayes, D. F.; McAllister, P. K.; Morton, R. F.; Schilsky, R. L. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 2009, 27(12), 2091-2096.
68. Srinivasan, M.; Sedmak, D.; Jewell, S. Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Am. J. Pathol. 2002, 161(6), 1961-1971.
69. Williams, C.; Ponten, F.; Moberg, C.; Soderkvist, P.; Uhlen, M.; Ponten, J.; Sitbon, G.; Lundeberg, J. A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am. J. Pathol. 1999, 155(5), 1467-1471.
70. Simkens, L.; Tol, J.; Koopman, M.; Mol, L.; Antonini, N.; van Krieken, H.; Punt, C. Current questions in the treatment of advanced colorectal cancer: the CAIRO studies of the Dutch Colorectal Cancer Group. Clin. Colorectal Cancer 2008, 7(2), 105-109.
71. Windsor, A. C.; Cohen, R.; Jiao, L. R.; Stebbing, J. Cetuximab in the firstline therapy of metastatic colorectal carcinoma: not so CRYSTAL clear. Future Oncol. 2008, 4(6), 741-744.
72. Lee, J. C.; Wang, S. T.; Lai, M. D.; Lin, Y. J.; Yang, H. B. K-ras gene mutation is a useful predictor of the survival of early stage colorectal cancers. Anticancer Res. 1996, 16(6B), 3839-3844.
73. Benhattar, J.; Losi, L.; Chaubert, P.; Givel, J. C.; Costa, J. Prognostic significance of K-ras mutations in colorectal carcinoma. Gastroenterology 1993, 104(4), 1044-1048.
74. Thebo, J. S.; Senagore, A. J.; Reinhold, D. S.; Stapleton, S. R. Molecular staging of colorectal cancer: K-ras mutation analysis of lymph nodes upstages Dukes B patients. Dis. Colon Rectum 2000, 43(2), 155-9; discussion 159-162.
75. Finkelstein, S. D.; Sayegh, R.; Bakker, A.; Swalsky, P. Determination of tumor aggressiveness in colorectal cancer by K-ras-2 analysis. Arch. Surg. 1993, 128(5), 526-531; discussion 531-532.
76. Moerkerk, P.; Arends, J. W.; van Driel, M.; de Bruine, A.; de Goeij, A.; ten Kate, J. Type and number of Ki-ras point mutations relate to stage of human colorectal cancer. Cancer Res. 1994, 54(13), 3376-3378.
77. Pajkos, G.; Kiss, I.; Sandor, J.; Ember, I.; Kishazi, P. The prognostic value of the presence of mutations at the codons 12, 13, 61 of K-ras oncogene in colorectal cancer. Anticancer Res. 2000, 20(3A), 1695-1701.
78. Suchy, B.; Zietz, C.; Rabes, H. M. K-ras point mutations in human colorectal carcinomas: relation to aneuploidy and metastasis. Int. J. Cancer 1992, 52(1), 30-3.
79. Halter, S. A.; Webb, L.; Rose, J. Lack of ras mutations and prediction of long-term survival in carcinoma of the colon. Mod. Pathol. 1992, 5(2), 131-134.
80. Oudejans, J. J.; Slebos, R. J.; Zoetmulder, F. A.; Mooi, W. J.; Rodenhuis, S. Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int. J. Cancer 1991, 49(6), 875-879.
81. Tanaka, M.; Omura, K.; Watanabe, Y.; Oda, Y.; Nakanishi, I. Prognostic factors of colorectal cancer: K-ras mutation, overexpression of the p53 protein, and cell proliferative activity. J. Surg. Oncol. 1994, 57(1), 57-64.
82. Belly, R. T.; Rosenblatt, J. D.; Steinmann, M.; Toner, J.; Sun, J.; Shehadi, J.; Peacock, J. L.; Raubertas, R. F.; Jani, N.; Ryan, C. K. Detection of mutated K12-ras in histologically negative lymph nodes as an indicator of poor prognosis in stage II colorectal cancer. Clin. Colorectal Cancer 2001, 1(2), 110-116.
83. Bazan, V.; Migliavacca, M.; Zanna, I.; Tubiolo, C.; Grassi, N.; Latteri, M. A.; La Farina, M.; Albanese, I.; Dardanoni, G.; Salerno, S.; Tomasino, R. M.; Labianca, R.; Gebbia, N.; Russo, A. Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann. Oncol. 2002, 13(9), 1438-1446.
84. Span, M.; Moerkerk, P. T.; De Goeij, A. F.; Arends, J. W. A detailed analysis of K-ras point mutations in relation to tumor progression and survival in colorectal cancer patients. Int. J. Cancer 1996, 69(3), 241-245.
85. Esteller, M.; Gonzalez, S.; Risques, R. A.; Marcuello, E.; Mangues, R.; Germa, J. R.; Herman, J. G.; Capella, G.; Peinado, M. A. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J. Clin. Oncol. 2001, 19(2), 299-304.
86. Cerottini, J. P.; Caplin, S.; Saraga, E.; Givel, J. C.; Benhattar, J. The type of K-ras mutation determines prognosis in colorectal cancer. Am. J. Surg. 1998, 175(3), 198-202.
87. Ahnen, D. J.; Feigl, P.; Quan, G.; Fenoglio-Preiser, C.; Lovato, L. C.; Bunn, P. A., Jr.; Stemmerman, G.; Wells, J. D.; Macdonald, J. S.; Meyskens, F. L., Jr. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res. 1998, 58(6), 1149-1158.
88. Bazan, V.; Agnese, V.; Corsale, S.; Calo, V.; Valerio, M. R.; Latteri, M. A.; Vieni, S.; Grassi, N.; Cicero, G.; Dardanoni, G.; Tomasino, R. M.; Colucci, G.; Gebbia, N.; Russo, A. Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study. Ann. Oncol. 2005, 16 Suppl 4, iv50-55.
89. Russo, A.; Bazan, V.; Agnese, V.; Rodolico, V.; Gebbia, N. Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. Ann. Oncol. 2005, 16 Suppl 4, iv44-49.
90. Conlin, A.; Smith, G.; Carey, F. A.; Wolf, C. R.; Steele, R. J. The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma. Gut 2005, 54(9), 1283-1286.
91. Poehlmann, A.; Kuester, D.; Meyer, F.; Lippert, H.; Roessner, A.; Schneider-Stock, R. K-ras mutation detection in colorectal cancer using the Pyrosequencing technique. Pathol. Res. Pract. 2007, 203(7), 489-497.
92. Andreyev, H. J.; Norman, A. R.; Cunningham, D.; Oates, J. R.; Clarke, P. A. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J. Natl. Cancer Inst. 1998, 90(9), 675-684.
93. Andreyev, H. J.; Norman, A. R.; Cunningham, D.; Oates, J.; Dix, B. R.; Iacopetta, B. J.; Young, J.; Walsh, T.; Ward, R.; Hawkins, N.; Beranek, M.; Jandik, P.; Benamouzig, R.; Jullian, E.; Laurent-Puig, P.; Olschwang, S.; Muller, O.; Hoffmann, I.; Rabes, H. M.; Zietz, C.; Troungos, C.; Valavanis, C.; Yuen, S. T.; Ho, J. W.; Croke, C. T.; O'Donoghue, D. P.; Giaretti, W.; Rapallo, A.; Russo, A.; Bazan, V.; Tanaka, M.; Omura, K.; Azuma, T.; Ohkusa, T.; Fujimori, T.; Ono, Y.; Pauly, M.; Faber, C.; Glaesener, R.; de Goeij, A. F.; Arends, J. W.; Andersen, S. N.; Lovig, T.; Breivik, J.; Gaudernack, G.; Clausen, O. P.; De Angelis, P. D.; Meling, G. I.; Rognum, T. O.; Smith, R.; Goh, H. S.; Font, A.; Rosell, R.; Sun, X. F.; Zhang, H.; Benhattar, J.; Losi, L.; Lee, J. Q.; Wang, S. T.; Clarke, P. A.; Bell, S.; Quirke, P.; Bubb, V. J.; Piris, J.; Cruickshank, N. R.; Morton, D.; Fox, J. C.; Al-Mulla, F.; Lees, N.; Hall, C. N.; Snary, D.; Wilkinson, K.; Dillon, D.; Costa, J.; Pricolo, V. E.; Finkelstein, S. D.; Thebo, J. S.; Senagore, A. J.; Halter, S. A.; Wadler, S.; Malik, S.; Krtolica, K.; Urosevic, N. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br. J. Cancer 2001, 85(5), 692-696.
94. Bell, S. M.; Scott, N.; Cross, D.; Sagar, P.; Lewis, F. A.; Blair, G. E.; Taylor, G. R.; Dixon, M. F.; Quirke, P. Prognostic value of p53 overexpression and c-Ki-ras gene mutations in colorectal cancer. Gastroenterology 1993, 104(1), 57-64.
95. Markowitz, S.; Hines, J. D.; Lutterbaugh, J.; Myeroff, L.; Mackay, W.; Gordon, N.; Rustum, Y.; Luna, E.; Kleinerman, J. Mutant K-ras oncogenes in colon cancers Do not predict Patient's chemotherapy response or survival. Clin. Cancer Res. 1995, 1(4), 441-445.
96. Andreyev, H. J.; Tilsed, J. V.; Cunningham, D.; Sampson, S. A.; Norman, A. R.; Schneider, H. J.; Clarke, P. A. K-ras mutations in patients with early colorectal cancers. Gut 1997, 41(3), 323-329.
97. Clarke, G. A.; Ryan, E.; Crowe, J. P.; O'Keane, J. C.; MacMathuna, P. Tumour-derived mutated K-ras codon 12 expression in regional lymph nodes of stage II colorectal cancer patients is not associated with increased risk of cancer-related death. Int. J. Colorectal Dis. 2001, 16(2), 108-111.
98. Kastrinakis, W. V.; Ramchurren, N.; Maggard, M.; Steele, G., Jr.; Summerhayes, I. C. K-ras status does not predict successful hepatic resection of colorectal cancer metastasis. Arch. Surg. 1995, 130(1), 9-14.
99. Laurent-Puig, P.; Olschwang, S.; Delattre, O.; Remvikos, Y.; Asselain, B.; Melot, T.; Validire, P.; Muleris, M.; Girodet, J.; Salmon, R. J.; et al. Survival and acquired genetic alterations in colorectal cancer. Gastroenterology 1992, 102(4 Pt 1), 1136-1141.
100. Dix, B. R.; Robbins, P.; Soong, R.; Jenner, D.; House, A. K.; Iacopetta, B. J. The common molecular genetic alterations in Dukes' B and C colorectal carcinomas are not short-term prognostic indicators of survival. Int. J. Cancer 1994, 59(6), 747-751.
101. Bouzourene, H.; Gervaz, P.; Cerottini, J. P.; Benhattar, J.; Chaubert, P.; Saraga, E.; Pampallona, S.; Bosman, F. T.; Givel, J. C. p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer. Eur. J. Cancer 2000, 36(8), 1008-1015.
102. Bleeker, W. A.; Hayes, V. M.; Karrenbeld, A.; Hofstra, R. M.; Hermans, J.; Buys, C. C.; Plukker, J. T. Impact of KRAS and TP53 mutations on survival in patients with left-and right-sided Dukes' C colon cancer. Am. J. Gastroenterol. 2000, 95(10), 2953-2957.
103. Morrin, M.; Kelly, M.; Barrett, N.; Delaney, P. Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. Gut 1994, 35(11), 1627-1631.
104. Andersen, S. N.; Lovig, T.; Breivik, J.; Lund, E.; Gaudernack, G.; Meling, G. I.; Rognum, T. O. K-ras mutations and prognosis in large-bowel carcinomas. Scand. J. Gastroenterol. 1997, 32(1), 62-69.
105. Hirvikoski, P.; Auvinen, A.; Servomaa, K.; Kiuru, A.; Rytomaa, T.; Makkonen, K.; Kosma, V. M. K-ras and p53 mutations and overexpressions as prognostic factors in female rectal carcinoma. Anticancer Res. 1999, 19(1B), 685-691.
106. Pricolo, V. E.; Finkelstein, S. D.; Wu, T. T.; Keller, G.; Bakker, A.; Swalsky, P. A.; Bland, K. I. Prognostic value of TP53 and K-ras-2 mutational analysis in stage III carcinoma of the colon. Am. J. Surg. 1996, 171(1), 41-46.
107. Kern, S. E.; Fearon, E. R.; Tersmette, K. W.; Enterline, J. P.; Leppert, M.; Nakamura, Y.; White, R.; Vogelstein, B.; Hamilton, S. R. Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected]. JAMA 1989, 261(21), 3099-3103.
108. Barault, L.; Veyrie, N.; Jooste, V.; Lecorre, D.; Chapusot, C.; Ferraz, J. M.; Lievre, A.; Cortet, M.; Bouvier, A. M.; Rat, P.; Roignot, P.; Faivre, J.; Laurent-Puig, P.; Piard, F. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int. J. Cancer 2008, 122(10), 2255-2259.
109. Roth, A. D.; Tejpar, S.; Delorenzi, M.; Yan, P.; Fiocca, R.; Klingbiel, D.; Dietrich, D.; Biesmans, B.; Bodoky, G.; Barone, C.; Aranda, E.; Nordlinger, B.; Cisar, L.; Labianca, R.; Cunningham, D.; Van Cutsem, E.; Bosman, F. 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(3), 466-474.
110. Richman, S. D.; Seymour, M. T.; Chambers, P.; Elliott, F.; Daly, C. L.; Meade, A. M.; Taylor, G.; Barrett, J. H.; Quirke, P. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J. Clin. Oncol. 2009, 27(35), 5931-5937.
111. Etienne-Grimaldi, M. C.; Formento, J. L.; Francoual, M.; Francois, E.; Formento, P.; Renee, N.; Laurent-Puig, P.; Chazal, M.; Benchimol, D.; Delpero, J. R.; Letoublon, C.; Pezet, D.; Seitz, J. F.; Milano, G. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin. Cancer Res. 2008, 14(15), 4830-4835.
112. EMEA European public assessment report for Vectibix. http://www.emea.europa.eu/humandocs/PDFs/EPAR/vectibix/H-741-en1.pdf (accessed August 15, 2010).
113. EMEA Assessment report for Erbitux. http://www.emea.europa.eu/human docs/PDFs/EPAR/erbitux/H-558-II-26-AR.pdf (accessed August 15, 2010).
114. FDA Label Information for Erbitux. http://www.fda.gov/cder/foi/label/2004/125084lbl.pdf (accessed August 15, 2010).
115. FDA Full prescribing information for Vectibix. http://www.fda.gov/cder/foi/label/2006/125147lbl.pdf (accessed August 15, 2010).
116. Cunningham, D.; Humblet, Y.; Siena, S.; Khayat, D.; Bleiberg, H.; Santoro, A.; Bets, D.; Mueser, M.; Harstrick, A.; Verslype, C.; Chau, I.; Van Cutsem, E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N. Engl. J. Med. 2004, 351(4), 337-345.
117. Gibson, T. B.; Ranganathan, A.; Grothey, A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin. Colorectal Cancer 2006, 6(1), 29-31.
118. Van Cutsem, E.; Peeters, M.; Siena, S.; Humblet, Y.; Hendlisz, A.; Neyns, B.; Canon, J. L.; Van Laethem, J. L.; Maurel, J.; Richardson, G.; Wolf, M.; Amado, R. G. 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(13), 1658-1664.
119. Saltz, L. B.; Meropol, N. J.; Loehrer, P. J., Sr.; Needle, M. N.; Kopit, J.; Mayer, R. J. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 2004, 22(7), 1201-1208.
120. Chung, K. Y.; Shia, J.; Kemeny, N. E.; Shah, M.; Schwartz, G. K.; Tse, A.; Hamilton, A.; Pan, D.; Schrag, D.; Schwartz, L.; Klimstra, D. S.; Fridman, D.; Kelsen, D. P.; Saltz, L. B. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J. Clin. Oncol. 2005, 23(9), 1803-1810.
121. Derecskei, K.; Moldvay, J.; Bogos, K.; Timar, J. Protocol modifications influence the result of EGF receptor immunodetection by EGFR pharmDx in paraffin-embedded cancer tissues. Pathol. Oncol. Res. 2006, 12(4), 243-246.
122. Penault-Llorca, F.; Cayre, A.; Arnould, L.; Bibeau, F.; Bralet, M. P.; Rochaix, P.; Savary, J.; Sabourin, J. C. Is there an immunohistochemical technique definitively valid in epidermal growth factor receptor assessment? Oncol. Rep. 2006, 16(6), 1173-1179.
123. Kuwai, T.; Nakamura, T.; Sasaki, T.; Kim, S. J.; Fan, D.; Villares, G. J.; Zigler, M.; Wang, H.; Bar-Eli, M.; Kerbel, R. S.; Fidler, I. J. Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells is a primary target for therapy with tyrosine kinase inhibitors. Neoplasia 2008, 10(5), 489-500.
124. Massarelli, E.; Varella-Garcia, M.; Tang, X.; Xavier, A. C.; Ozburn, N. C.; Liu, D. D.; Bekele, B. N.; Herbst, R. S.; Wistuba, II, KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin. Cancer Res. 2007, 13(10), 2890-2896.
125. Lievre, A.; Bachet, J. B.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J. F.; Cote, J. F.; Tomasic, G.; Penna, C.; Ducreux, M.; Rougier, P.; Penault-Llorca, F.; Laurent-Puig, P. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66(8), 3992-3995.
126. Khambata-Ford, S.; Garrett, C. R.; Meropol, N. J.; Basik, M.; Harbison, C. T.; Wu, S.; Wong, T. W.; Huang, X.; Takimoto, C. H.; Godwin, A. K.; Tan, B. R.; Krishnamurthi, S. S.; Burris, H. A., 3rd; Poplin, E. A.; Hidalgo, M.; Baselga, J.; Clark, E. A.; Mauro, D. J. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 2007, 25(22), 3230-3237.
127. Karapetis, C. S.; Khambata-Ford, S.; Jonker, D. J.; O'Callaghan, C. J.; Tu, D.; Tebbutt, N. C.; Simes, R. J.; Chalchal, H.; Shapiro, J. D.; Robitaille, S.; Price, T. J.; Shepherd, L.; Au, H. J.; Langer, C.; Moore, M. J.; Zalcberg, J. R. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 2008, 359(17), 1757-1765.
128. Bengala, C.; Bettelli, S.; Bertolini, F.; Salvi, S.; Chiara, S.; Sonaglio, C.; Losi, L.; Bigiani, N.; Sartori, G.; Dealis, C.; Malavasi, N.; D'Amico, R.; Luppi, G.; Gatteschi, B.; Maiorana, A.; Conte, P. F. Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer. Ann. Oncol. 2009, 20(3), 469-474.
129. Lievre, A.; Bachet, J. B.; Boige, V.; Cayre, A.; Le Corre, D.; Buc, E.; Ychou, M.; Bouche, O.; Landi, B.; Louvet, C.; Andre, T.; Bibeau, F.; Diebold, M. D.; Rougier, P.; Ducreux, M.; Tomasic, G.; Emile, J. F.; Penault-Llorca, F.; Laurent-Puig, P. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008, 26(3), 374-379.
130. Amado, R. G.; Wolf, M.; Peeters, M.; Van Cutsem, E.; Siena, S.; Freeman, D. J.; Juan, T.; Sikorski, R.; Suggs, S.; Radinsky, R.; Patterson, S. D.; Chang, D. D. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 2008, 26(10), 1626-1634.
131. Benvenuti, S.; Sartore-Bianchi, A.; Di Nicolantonio, F.; Zanon, C.; Moroni, M.; Veronese, S.; Siena, S.; Bardelli, A. 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(6), 2643-2648.
132. Freeman, D. J.; Juan, T.; Reiner, M.; Hecht, J. R.; Meropol, N. J.; Berlin, J.; Mitchell, E.; Sarosi, I.; Radinsky, R.; Amado, R. G. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin. Colorectal Cancer 2008, 7(3), 184-190.
133. Linardou, H.; Dahabreh, I. J.; Kanaloupiti, D.; Siannis, F.; Bafaloukos, D.; Kosmidis, P.; Papadimitriou, C. A.; Murray, S. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced nonsmall-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008, 9(10), 962-972.
134. Di Nicolantonio, F.; Martini, M.; Molinari, F.; Sartore-Bianchi, A.; Arena, S.; Saletti, P.; De Dosso, S.; Mazzucchelli, L.; Frattini, M.; Siena, S.; Bardelli, A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol. 2008, 26(35), 5705-5712.
135. Gorden, A.; Osman, I.; Gai, W.; He, D.; Huang, W.; Davidson, A.; Houghton, A. N.; Busam, K.; Polsky, D. Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res. 2003, 63(14), 3955-3957.
136. Razis, E.; Briasoulis, E.; Vrettou, E.; Skarlos, D. V.; Papamichael, D.; Kostopoulos, I.; Samantas, E.; Xanthakis, I.; Bobos, M.; Galanidi, E.; Bai, M.; Gikonti, I.; Koukouma, A.; Kafiri, G.; Papakostas, P.; Kalogeras, K. T.; Kosmidis, P.; Fountzilas, G. Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer 2008, 8, 234.
137. Ogino, S.; Nosho, K.; Kirkner, G. J.; Shima, K.; Irahara, N.; Kure, S.; Chan, A. T.; Engelman, J. A.; Kraft, P.; Cantley, L. C.; Giovannucci, E. L.; Fuchs, C. S. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J. Clin. Oncol. 2009, 27(9), 1477-1484.
138. Jacobs, B.; De Roock, W.; Piessevaux, H.; Van Oirbeek, R.; Biesmans, B.; De Schutter, J.; Fieuws, S.; Vandesompele, J.; Peeters, M.; Van Laethem, J. L.; Humblet, Y.; Penault-Llorca, F.; De Hertogh, G.; Laurent-Puig, P.; Van Cutsem, E.; Tejpar, S. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J. Clin. Oncol. 2009, 27(30), 5068-5074.
139. Bernards, R.; Weinberg, R. A. A progression puzzle. Nature 2002, 418(6900), 823.
140. Fearon, E. R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61(5), 759-767.
141. Gray, J. W. Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors. Cancer Cell 2003, 4(1), 4-6.
142. Frost, P.; Fidler, I. J. Biology of metastasis. Cancer 1986, 58(2 Suppl), 550-553.
143. Molinari, F.; Martin, V.; Saletti, P.; De Dosso, S.; Spitale, A.; Camponovo, A.; Bordoni, A.; Crippa, S.; Mazzucchelli, L.; Frattini, M. Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br. J. Cancer 2009, 100(7), 1087-1094.
144. Tortola, S.; Steinert, R.; Hantschick, M.; Peinado, M. A.; Gastinger, I.; Stosiek, P.; Lippert, H.; Schlegel, W.; Reymond, M. A. Discordance between K-ras mutations in bone marrow micrometastases and the primary tumor in colorectal cancer. J. Clin. Oncol. 2001, 19(11), 2837-2843.
145. Baldus, S. E.; Schaefer, K. L.; Engers, R.; Hartleb, D.; Stoecklein, N. H.; Gabbert, H. E. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin. Cancer Res. 2010, 16(3), 790-799.
146. Italiano, A.; Hostein, I.; Soubeyran, I.; Fabas, T.; Benchimol, D.; Evrard, S.; Gugenheim, J.; Becouarn, Y.; Brunet, R.; Fonck, M.; Francois, E.; Saint-Paul, M. C.; Pedeutour, F. KRAS and BRAF Mutational Status in Primary Colorectal Tumors and Related Metastatic Sites: Biological and Clinical Implications. Ann. Surg. Oncol. 2010, 17(5), 1429-1434.
147. Al-Mulla, F.; Going, J. J.; Sowden, E. T.; Winter, A.; Pickford, I. R.; Birnie, G. D. Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. J. Pathol. 1998, 185(2), 130-138.
148. Artale, S.; Sartore-Bianchi, A.; Veronese, S. M.; Gambi, V.; Sarnataro, C. S.; Gambacorta, M.; Lauricella, C.; Siena, S. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J. Clin. Oncol. 2008, 26(25), 4217-4219.
149. Losi, L.; Baisse, B.; Bouzourene, H.; Benhattar, J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005, 26(5), 916-922.
150. Goasguen, N.; de Chaisemartin, C.; Brouquet, A.; Julie, C.; Prevost, G. P.; Laurent-Puig, P.; Penna, C. Evidence of heterogeneity within colorectal liver metastases for allelic losses, mRNA level expression and in vitro response to chemotherapeutic agents. Int. J. Cancer 2010, 127(5), 1028-1037.
151. Losi, L.; Luppi, G.; Benhattar, J. Assessment of K-ras, Smad4 and p53 gene alterations in colorectal metastases and their role in the metastatic process. Oncol. Rep. 2004, 12(6), 1221-1225.
152. Badalian, G.; Barbai, T.; Raso, E.; Derecskei, K.; Szendroi, M.; Timar, J. Phenotype of bone metastases of non-small cell lung cancer: epidermal growth factor receptor expression and K-RAS mutational status. Pathol. Oncol. Res. 2007, 13(2), 99-104.
153. Kalikaki, A.; Koutsopoulos, A.; Trypaki, M.; Souglakos, J.; Stathopoulos, E.; Georgoulias, V.; Mavroudis, D.; Voutsina, A. Comparison of EGFR and KRAS gene status between primary tumours and corresponding metastases in NSCLC. Br. J. Cancer 2008, 99(6), 923-929.