Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 1, pp 1–13 | Cite as

Anti-EGFR MoAb treatment in colorectal cancer: limitations, controversies, and contradictories

  • Lei Cheng
  • Wei Ren
  • Li Xie
  • Ming Li
  • Jiang Liu
  • Jing Hu
  • Bao-Rui Liu
  • Xiao-Ping Qian
Review Article


Anti-epidermal growth-factor receptor (EGFR) monoclonal antibody (MoAb) treatment for chemotherapy refractory or metastatic colorectal cancer has obtained great achievement. However, not every colorectal patient responds to such molecular-targeted agent well. Biomarkers associated with anti-EGFR resistance are not limited to KRAS mutation up to now. It was recently reported that cross-talking molecular effectors interacted with EGFR-related pathway were also negative predictor for anti-EGFR treatment. However, the limited data, controversial results, and contradictories between in vitro and clinical studies restrict the clinical application of these new biomarkers. Although the current theory of tumor microenvironment supported the application of multi-target treatment, the results from the clinical studies were less than expected. Moreover, WHO or RECIST guideline for response assessment in anti-EGFR MoAb treatment was also queried by recent AIO KRK-0306 trial. This review focuses on these controversies, contradictories, and limitations, in order to uncover the unmet needs in current status of anti-EGFR MoAb treatment in colorectal cancer.


Colorectal cancer EGFR BRAF RAS Cetuximab Panitumumab 



This work was supported by the Grant 81172094 and 8110186 from the National Science Foundation of China, Grant 2011-WS-005 from the Six Talents Peak Foundation of Jiangsu Province.

Conflict of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi: 10.3322/caac.20107 PubMedCrossRefGoogle Scholar
  2. 2.
    Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol Off J Am Soc Clin Oncol 29(15):2011–2019. doi: 10.1200/jco.2010.33.5091 CrossRefGoogle Scholar
  3. 3.
    Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Eng J Med 360(14):1408–1417. doi: 10.1056/NEJMoa0805019 CrossRefGoogle Scholar
  4. 4.
    Patel GS, Karapetis CS (2013) Personalized treatment for advanced colorectal cancer: KRAS and beyond. Cancer Manag Res 5:387–400. doi: 10.2147/cmar.s35025 PubMedCentralPubMedGoogle Scholar
  5. 5.
    Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, De Bacco F, Menietti E, Han M, Rideout WM 3rd, Perera T, Bertotti A, Trusolino L, Comoglio PM, Boccaccio C (2014) MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. doi: 10.1158/0008-5472.can-13-2340-t PubMedGoogle Scholar
  6. 6.
    Yang L, Li J, Ran L, Pan F, Zhao X, Ding Z, Chen Y, Peng Q, Liang H (2011) Phosphorylated insulin-like growth factor 1 receptor is implicated in resistance to the cytostatic effect of gefitinib in colorectal cancer cells. J Gastrointest Surg Off J Soc Surg Aliment Tract 15(6):942–957. doi: 10.1007/s11605-011-1504-z CrossRefGoogle Scholar
  7. 7.
    Chang EH, Furth ME, Scolnick EM, Lowy DR (1982) Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature 297(5866):479–483PubMedCrossRefGoogle Scholar
  8. 8.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) 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 Off J Am Soc Clin Oncol 28(31):4697–4705. doi: 10.1200/jco.2009.27.4860 CrossRefGoogle Scholar
  9. 9.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasilska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R (2014) Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol/ESMO. doi: 10.1093/annonc/mdu141 Google Scholar
  10. 10.
    Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP (2011) 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 377(9783):2103–2114. doi: 10.1016/s0140-6736(11)60613-2 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T (2012) 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 Off J Am Soc Clin Oncol 30(15):1755–1762. doi: 10.1200/jco.2011.38.0915 CrossRefGoogle Scholar
  12. 12.
    Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O’Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P (2013) Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 14(8):749–759. doi: 10.1016/s1470-2045(13)70163-3 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Eng J Med 366(10):883–892. doi: 10.1056/NEJMoa1113205 CrossRefGoogle Scholar
  14. 14.
    Lee AJ, Swanton C (2012) Tumour heterogeneity and drug resistance: personalising cancer medicine through functional genomics. Biochem Pharmacol 83(8):1013–1020. doi: 10.1016/j.bcp.2011.12.008 PubMedCrossRefGoogle Scholar
  15. 15.
    Kosmidou V, Oikonomou E, Vlassi M, Avlonitis S, Katseli A, Tsipras I, Mourtzoukou D, Kontogeorgos G, Zografos G, Pintzas A (2014) Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Hum Mutat 35(3):329–340. doi: 10.1002/humu.22496 PubMedCrossRefGoogle Scholar
  16. 16.
    Mao C, Huang YF, Yang ZY, Zheng DY, Chen JZ, Tang JL (2013) KRAS p. G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: a systematic review and meta-analysis. Cancer 119(4):714–721. doi: 10.1002/cncr.27804 PubMedCrossRefGoogle Scholar
  17. 17.
    De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O’Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, Tejpar S (2010) Association of KRAS p. G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA J Am Med Assoc 304(16):1812–1820. doi: 10.1001/jama.2010.1535 CrossRefGoogle Scholar
  18. 18.
    Kumar SS, Price TJ, Mohyieldin O, Borg M, Townsend A, Hardingham JE (2014) KRAS G13D mutation and sensitivity to cetuximab or panitumumab in a colorectal cancer cell line model. Gastrointest Cancer Res : GCR 7(1):23–26PubMedCentralPubMedGoogle Scholar
  19. 19.
    Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E (2012) Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 30(29):3570–3577. doi: 10.1200/jco.2012.42.2592 CrossRefGoogle Scholar
  20. 20.
    Hartman DJ, Chiosea SI (2013) Colorectal carcinomas, KRAS p. G13D mutant allele-specific imbalance, and anti-epidermal growth factor receptor therapy. Cancer 119(24):4366. doi: 10.1002/cncr.28371 PubMedCrossRefGoogle Scholar
  21. 21.
    Hartman DJ, Davison JM, Foxwell TJ, Nikiforova MN, Chiosea SI (2012) Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall survival. Int J Cancer 131(8):1810–1817. doi: 10.1002/ijc.27461 PubMedCrossRefGoogle Scholar
  22. 22.
    Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9(7):517–531. doi: 10.1038/nrm2438 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Janakiraman M, Vakiani E, Zeng Z, Pratilas CA, Taylor BS, Chitale D, Halilovic E, Wilson M, Huberman K, Ricarte Filho JC, Persaud Y, Levine DA, Fagin JA, Jhanwar SC, Mariadason JM, Lash A, Ladanyi M, Saltz LB, Heguy A, Paty PB, Solit DB (2010) Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res 70(14):5901–5911. doi: 10.1158/0008-5472.can-10-0192 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023–1034. doi: 10.1056/NEJMoa1305275 PubMedCrossRefGoogle Scholar
  25. 25.
    Smith CG, Fisher D, Claes B, Maughan TS, Idziaszczyk S, Peuteman G, Harris R, James MD, Meade A, Jasani B, Adams RA, Kenny S, Kaplan R, Lambrechts D, Cheadle JP (2013) Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy ± cetuximab. Clin Cancer Res Off J Am Assoc Cancer Res 19(15):4104–4113. doi: 10.1158/1078-0432.ccr-12-2581 CrossRefGoogle Scholar
  26. 26.
    Jiang L, Huang J, Morehouse C, Zhu W, Korolevich S, Sui D, Ge X, Lehmann K, Liu Z, Kiefer C, Czapiga M, Su X, Brohawn P, Gu Y, Higgs BW, Yao Y (2013) Low frequency KRAS mutations in colorectal cancer patients and the presence of multiple mutations in oncogenic drivers in non-small cell lung cancer patients. Cancer genetics 206(9–10):330–339. doi: 10.1016/j.cancergen.2013.09.004 PubMedCrossRefGoogle Scholar
  27. 27.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, 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 AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762. doi: 10.1016/s1470-2045(10)70130-3 PubMedCrossRefGoogle Scholar
  28. 28.
    Pentheroudakis G, Kotoula V, De Roock W, Kouvatseas G, Papakostas P, Makatsoris T, Papamichael D, Xanthakis I, Sgouros J, Televantou D, Kafiri G, Tsamandas AC, Razis E, Galani E, Bafaloukos D, Efstratiou I, Bompolaki I, Pectasides D, Pavlidis N, Tejpar S, Fountzilas G (2013) Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer 13:49. doi: 10.1186/1471-2407-13-49 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Peeters M, Oliner KS, Parker A, Siena S, Van Cutsem E, Huang J, Humblet Y, Van Laethem JL, Andre T, Wiezorek J, Reese D, Patterson SD (2013) Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res 19(7):1902–1912. doi: 10.1158/1078-0432.ccr-12-1913 CrossRefGoogle Scholar
  30. 30.
    Zucali PA, Ruiz MG, Giovannetti E, Destro A, Varella-Garcia M, Floor K, Ceresoli GL, Rodriguez JA, Garassino I, Comoglio P, Roncalli M, Santoro A, Giaccone G (2008) Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. Ann Oncol Off J Eur Soc Med Oncol/ESMO 19(9):1605–1612. doi: 10.1093/annonc/mdn240 CrossRefGoogle Scholar
  31. 31.
    Troiani T, Martinelli E, Napolitano S, Vitagliano D, Ciuffreda LP, Costantino S, Morgillo F, Capasso A, Sforza V, Nappi A, De Palma R, D’Aiuto E, Berrino L, Bianco R, Ciardiello F (2013) Increased TGF-alpha as a mechanism of acquired resistance to the anti-EGFR inhibitor cetuximab through EGFR-MET interaction and activation of MET signaling in colon cancer cells. Clin Cancer Res Off J Am Assoc Cancer Res 19(24):6751–6765. doi: 10.1158/1078-0432.ccr-13-0423 CrossRefGoogle Scholar
  32. 32.
    Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA Jr, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S (2013) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3(6):658–673. doi: 10.1158/ PubMedCrossRefGoogle Scholar
  33. 33.
    Krumbach R, Schuler J, Hofmann M, Giesemann T, Fiebig HH, Beckers T (2011) Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. Eur J Cancer (Oxford, England 1990) 47 (8):1231–1243. doi: 10.1016/j.ejca.2010.12.019
  34. 34.
    Gao W, Bing X, Li M, Yang Z, Li Y, Chen H (2013) Study of critical role of c-Met and its inhibitor SU11274 in colorectal carcinoma. Med Oncol (Northwood, London, England) 30(2):546. doi: 10.1007/s12032-013-0546-3
  35. 35.
    Inno A, Di Salvatore M, Cenci T, Martini M, Orlandi A, Strippoli A, Ferrara AM, Bagala C, Cassano A, Larocca LM, Barone C (2011) Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer? Clin Colorectal Cancer 10(4):325–332. doi: 10.1016/j.clcc.2011.03.028 PubMedCrossRefGoogle Scholar
  36. 36.
    Kishiki T, Ohnishi H, Masaki T, Ohtsuka K, Ohkura Y, Furuse J, Watanabe T, Sugiyama M (2014) Overexpression of MET is a new predictive marker for anti-EGFR therapy in metastatic colorectal cancer with wild-type KRAS. Cancer Chemother Pharmacol. doi: 10.1007/s00280-014-2401-4 PubMedCentralPubMedGoogle Scholar
  37. 37.
    Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol Off J Am Soc Clin Oncol 22(14):2954–2963. doi: 10.1200/jco.2004.02.141 CrossRefGoogle Scholar
  38. 38.
    Molinari F, Frattini M (2013) Functions and Regulation of the PTEN Gene in Colorectal Cancer. Front Oncol 3:326. doi: 10.3389/fonc.2013.00326 PubMedCentralPubMedGoogle Scholar
  39. 39.
    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 (2009) 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 Off J Am Soc Clin Oncol 27(16):2622–2629. doi: 10.1200/jco.2008.20.2796 CrossRefGoogle Scholar
  40. 40.
    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 (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69(5):1851–1857. doi: 10.1158/0008-5472.can-08-2466 PubMedCrossRefGoogle Scholar
  41. 41.
    Wang ZH, Gao QY, Fang JY (2012) Loss of PTEN expression as a predictor of resistance to anti-EGFR monoclonal therapy in metastatic colorectal cancer: evidence from retrospective studies. Cancer Chemother Pharmacol 69(6):1647–1655. doi: 10.1007/s00280-012-1886-y PubMedCrossRefGoogle Scholar
  42. 42.
    Tural D, Batur S, Erdamar S, Akar E, Kepil N, Mandel NM, Serdengecti S (2014) Analysis of PTEN, BRAF and PI3 K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS. Tumour Biol J Int Soc Oncodev Biol Med 35(2):1041–1049. doi: 10.1007/s13277-013-1138-8 CrossRefGoogle Scholar
  43. 43.
    Sood A, McClain D, Maitra R, Basu-Mallick A, Seetharam R, Kaubisch A, Rajdev L, Mariadason JM, Tanaka K, Goel S (2012) PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer 11(2):143–150. doi: 10.1016/j.clcc.2011.12.001 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, 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 (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol Off J Am Soc Clin Oncol 27(35):5924–5930. doi: 10.1200/jco.2008.21.6796 CrossRefGoogle Scholar
  45. 45.
    Liao X, Morikawa T, Lochhead P, Imamura Y, Kuchiba A, Yamauchi M, Nosho K, Qian ZR, Nishihara R, Meyerhardt JA, Fuchs CS, Ogino S (2012) Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res Off J Am Assoc Cancer Res 18(8):2257–2268. doi: 10.1158/1078-0432.ccr-11-2410 CrossRefGoogle Scholar
  46. 46.
    Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68(6):1953–1961. doi: 10.1158/0008-5472.can-07-5659 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Ganesan P, Janku F, Naing A, Hong DS, Tsimberidou AM, Falchook GS, Wheler JJ, Piha-Paul SA, Fu S, Stepanek VM, Lee JJ, Luthra R, Overman MJ, Kopetz ES, Wolff RA, Kurzrock R (2013) Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations. Mol Cancer Ther 12(12):2857–2863. doi: 10.1158/1535-7163.mct-13-0319-t PubMedCrossRefGoogle Scholar
  48. 48.
    Shen Y, Wang J, Han X, Yang H, Wang S, Lin D, Shi Y (2013) Effectors of epidermal growth factor receptor pathway: the genetic profiling of KRAS, BRAF, PIK3CA, NRAS Mutations in Colorectal Cancer Characteristics and Personalized Medicine. PLoS ONE 8(12):e81628. doi: 10.1371/journal.pone.0081628 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Razis E, Pentheroudakis G, Rigakos G, Bobos M, Kouvatseas G, Tzaida O, Makatsoris T, Papakostas P, Bai M, Goussia A, Samantas E, Papamichael D, Romanidou O, Efstratiou I, Tsolaki E, Psyrri A, De Roock W, Bafaloukos D, Klouvas G, Tejpar S, Kalogeras KT, Pectasides D, Fountzilas G (2014) EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab. J Cancer Res Clin Oncol 140(5):737–748. doi: 10.1007/s00432-014-1626-2 PubMedCrossRefGoogle Scholar
  50. 50.
    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 (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 26(35):5705–5712. doi: 10.1200/jco.2008.18.0786 CrossRefGoogle Scholar
  51. 51.
    Modest DP, Jung A, Moosmann N, Laubender RP, Giessen C, Schulz C, Haas M, Neumann J, Boeck S, Kirchner T, Heinemann V, Stintzing S (2012) The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int J Cancer 131(4):980–986. doi: 10.1002/ijc.26467 PubMedCrossRefGoogle Scholar
  52. 52.
    Tol J, Dijkstra JR, Klomp M, Teerenstra S, Dommerholt M, Vink-Borger ME, van Cleef PH, van Krieken JH, Punt CJ, Nagtegaal ID (2010) Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer (Oxford, England 1990) 46 (11):1997–2009. doi: 10.1016/j.ejca.2010.03.036
  53. 53.
    O’Byrne KJ, Gatzemeier U, Bondarenko I, Barrios C, Eschbach C, Martens UM, Hotko Y, Kortsik C, Paz-Ares L, Pereira JR, von Pawel J, Ramlau R, Roh JK, Yu CT, Stroh C, Celik I, Schueler A, Pirker R (2011) Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 12(8):795–805. doi: 10.1016/s1470-2045(11)70189-9 PubMedCrossRefGoogle Scholar
  54. 54.
    Licitra L, Storkel S, Kerr KM, Van Cutsem E, Pirker R, Hirsch FR, Vermorken JB, von Heydebreck A, Esser R, Celik I, Ciardiello F (2013) Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. European J Cancer (Oxford, England 1990) 49 (6):1161–1168. doi: 10.1016/j.ejca.2012.11.018
  55. 55.
    Kang MJ, Hong YS, Kim KP, Kim SY, Baek JY, Ryu MH, Lee JL, Chang HM, Kim MJ, Chang HJ, Kang YK, Kim TW (2012) Biweekly cetuximab plus irinotecan as second-line chemotherapy for patients with irinotecan-refractory and KRAS wild-type metastatic colorectal cancer according to epidermal growth factor receptor expression status. Invest New Drugs 30(4):1607–1613. doi: 10.1007/s10637-011-9703-8 PubMedCrossRefGoogle Scholar
  56. 56.
    Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6(5):279–286. doi: 10.1016/s1470-2045(05)70102-9 PubMedCrossRefGoogle Scholar
  57. 57.
    Cappuzzo F, Finocchiaro G, Rossi E, Janne PA, Carnaghi C, Calandri C, Bencardino K, Ligorio C, Ciardiello F, Pressiani T, Destro A, Roncalli M, Crino L, Franklin WA, Santoro A, Varella-Garcia M (2008) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol Off J Eur Soc Med Oncol/ESMO 19(4):717–723. doi: 10.1093/annonc/mdm492 CrossRefGoogle Scholar
  58. 58.
    Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, De Roock W, Capoen A, Debiec-Rychter M, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res Off J Am Assoc Cancer Res 14(18):5869–5876. doi: 10.1158/1078-0432.ccr-08-0449 CrossRefGoogle Scholar
  59. 59.
    Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA 3rd, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 25(22):3230–3237. doi: 10.1200/jco.2006.10.5437 CrossRefGoogle Scholar
  60. 60.
    Saridaki Z, Tzardi M, Papadaki C, Sfakianaki M, Pega F, Kalikaki A, Tsakalaki E, Trypaki M, Messaritakis I, Stathopoulos E, Mavroudis D, Georgoulias V, Souglakos J (2011) Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in >/= 2 line cetuximab-based therapy of colorectal cancer patients. PLoS ONE 6(1):e15980. doi: 10.1371/journal.pone.0015980 PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Zhang R, Xu GL, Li Y, He LJ, Chen LM, Wang GB, Lin SY, Luo GY, Gao XY, Shan HB (2013) The role of insulin-like growth factor 1 and its receptor in the formation and development of colorectal carcinoma. J Int Med Res 41(4):1228–1235. doi: 10.1177/0300060513487631 PubMedCrossRefGoogle Scholar
  62. 62.
    Allison AS, McIntyre MA, McArdle C, Habib FK (2007) The insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion. Hum Pathol 38(11):1590–1602. doi: 10.1016/j.humpath.2007.03.013 PubMedCrossRefGoogle Scholar
  63. 63.
    Tao Y, Pinzi V, Bourhis J, Deutsch E (2007) Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway–therapeutic perspectives in cancer. Nat Clin Pract Oncol 4(10):591–602. doi: 10.1038/ncponc0934 PubMedCrossRefGoogle Scholar
  64. 64.
    Pollak M (2012) The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer 12(3):159–169. doi: 10.1038/nrc3215 PubMedGoogle Scholar
  65. 65.
    Scartozzi M, Mandolesi A, Giampieri R, Pierantoni C, Loupakis F, Zaniboni A, Galizia E, Giustini L, Silva RR, Bisonni R, Berardi R, Biagetti S, Menzo S, Falcone A, Bearzi I, Cascinu S (2010) Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan. Int J Cancer 127(8):1941–1947. doi: 10.1002/ijc.25193 PubMedCrossRefGoogle Scholar
  66. 66.
    Winder T, Zhang W, Yang D, Ning Y, Bohanes P, Gerger A, Wilson PM, Pohl A, Mauro DJ, Langer C, Rowinsky EK, Lenz HJ (2010) Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients. Clin Cancer Res Off J Am Assoc Cancer Res 16(22):5591–5602. doi: 10.1158/1078-0432.ccr-10-2092 CrossRefGoogle Scholar
  67. 67.
    Huang F, Xu LA, Khambata-Ford S (2012) Correlation between gene expression of IGF-1R pathway markers and cetuximab benefit in metastatic colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res 18(4):1156–1166. doi: 10.1158/1078-0432.ccr-11-1135 CrossRefGoogle Scholar
  68. 68.
    Cappuzzo F, Varella-Garcia M, Finocchiaro G, Skokan M, Gajapathy S, Carnaghi C, Rimassa L, Rossi E, Ligorio C, Di Tommaso L, Holmes AJ, Toschi L, Tallini G, Destro A, Roncalli M, Santoro A, Janne PA (2008) Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99(1):83–89. doi: 10.1038/sj.bjc.6604439 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY (2007) Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res Off J Am Assoc Cancer Res 13(9):2795–2803. doi: 10.1158/1078-0432.ccr-06-2077 CrossRefGoogle Scholar
  70. 70.
    Wood SL, Pernemalm M, Crosbie PA, Whetton AD (2013) The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. doi: 10.1016/j.ctrv.2013.10.001 Google Scholar
  71. 71.
    Wood SL, Pernemalm M, Crosbie PA, Whetton AD (2014) The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev 40(4):558–566. doi: 10.1016/j.ctrv.2013.10.001 PubMedCrossRefGoogle Scholar
  72. 72.
    Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504. doi: 10.1038/nature11183 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Harbinski F, Craig VJ, Sanghavi S, Jeffery D, Liu L, Sheppard KA, Wagner S, Stamm C, Buness A, Chatenay-Rivauday C, Yao Y, He F, Lu CX, Guagnano V, Metz T, Finan PM, Hofmann F, Sellers WR, Porter JA, Myer VE, Graus-Porta D, Wilson CJ, Buckler A, Tiedt R (2012) Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discov 2(10):948–959. doi: 10.1158/ PubMedCrossRefGoogle Scholar
  74. 74.
    Lin YC, Mahalingam J, Chiang JM, Su PJ, Chu YY, Lai HY, Fang JH, Huang CT, Chiu CT, Lin CY (2013) Activated but not resting regulatory T cells accumulated in tumor microenvironment and correlated with tumor progression in patients with colorectal cancer. Int J Cancer 132(6):1341–1350. doi: 10.1002/ijc.27784 PubMedCrossRefGoogle Scholar
  75. 75.
    Cui G, Shi Y, Cui J, Tang F, Florholmen J (2012) Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets? Scand J Gastroenterol 47(4):367–377. doi: 10.3109/00365521.2011.648950 PubMedCrossRefGoogle Scholar
  76. 76.
    Volker Heinemann LFvW, Decker T, Kiani A, Vehling-Kaiser U, Salah-Eddin Al-Batran, Heintges T, Lerchenmueller J, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W (2013) Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol Off J Am Soc Clin Oncol 2013 ASCO Annual MeetingGoogle Scholar
  77. 77.
    Stintzing S, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Jager E, Heintges T, Stoll C, Giessen C, Modest DP, Neumann J, Jung A, Kirchner T, Scheithauer W, Heinemann V (2012) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol Off J Eur Soc Med Oncol/ESMO 23(7):1693–1699. doi: 10.1093/annonc/mdr571 CrossRefGoogle Scholar
  78. 78.
    Chun YS, Vauthey JN, Boonsirikamchai P, Maru DM, Kopetz S, Palavecino M, Curley SA, Abdalla EK, Kaur H, Charnsangavej C, Loyer EM (2009) Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA, J Am Med Assoc 302(21):2338–2344. doi: 10.1001/jama.2009.1755 CrossRefGoogle Scholar
  79. 79.
    Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, Tejpar S (2013) Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol Off J Am Soc Clin Oncol 31(30):3764–3775. doi: 10.1200/jco.2012.42.8532 CrossRefGoogle Scholar
  80. 80.
    Piessevaux H, Buyse M, De Roock W, Prenen H, Schlichting M, Van Cutsem E, Tejpar S (2009) Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial). Ann Oncol Off J Eur Soc Med Oncol/ESMO 20(8):1375–1382. doi: 10.1093/annonc/mdp011 CrossRefGoogle Scholar
  81. 81.
    De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol Off J Eur Soc Med Oncol/ESMO 19(3):508–515. doi: 10.1093/annonc/mdm496 CrossRefGoogle Scholar
  82. 82.
    Modest DP, Laubender RP, Stintzing S, Giessen C, Schulz C, Haas M, Mansmann U, Heinemann V (2013) Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: an analysis of the German AIO KRK 0104 trial. Acta Oncol (Stockholm, Sweden) 52(5):956–962. doi: 10.3109/0284186x.2012.752580
  83. 83.
    Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jane-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi P Jr, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483(7391):603–607. doi: 10.1038/nature11003 PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Lee J, Hong YS, Hong JY, Han SW, Kim TW, Kang HJ, Kim TY, Kim KP, Kim SH, Do IG, Kim KM, Sohn I, Park SH, Park JO, Lim HY, Cho YB, Lee WY, Yun SH, Kim HC, Park YS, Kang WK (2014) Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab. Invest New Drugs. doi: 10.1007/s10637-014-0065-x Google Scholar
  85. 85.
    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312. doi: 10.1016/s0140-6736(12)61900-x PubMedCrossRefGoogle Scholar
  86. 86.
    Regorafenib. Metastatic colorectal cancer in treatment failure: may prolong survival by a few weeks (2014). Prescrire international 23 (145):8-11Google Scholar
  87. 87.
    Wang Z, Xu J, Nie W, Huang G, Tang J, Guan X (2014) Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. Eur J Clin Pharmacol 70(2):225–231. doi: 10.1007/s00228-013-1598-1 PubMedCrossRefGoogle Scholar
  88. 88.
    Syed YY, Scott LJ (2013) Lenalidomide: a review of its use in patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndrome associated with 5q chromosome deletion. Drugs 73(11):1183–1196. doi: 10.1007/s40265-013-0071-x PubMedCrossRefGoogle Scholar
  89. 89.
    Gandhi AK, Shi T, Li M, Jungnelius U, Romano A, Tabernero J, Siena S, Schafer PH, Chopra R (2013) Immunomodulatory effects in a phase II study of lenalidomide combined with cetuximab in refractory KRAS-mutant metastatic colorectal cancer patients. PLoS ONE 8(11):e80437. doi: 10.1371/journal.pone.0080437 PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Siena S, Van Cutsem E, Li M, Jungnelius U, Romano A, Beck R, Bencardino K, Elez ME, Prenen H, Sanchis M, Sartore-Bianchi A, Tejpar S, Gandhi A, Shi T, Tabernero J (2013) Phase II open-label study to assess efficacy and safety of lenalidomide in combination with cetuximab in KRAS-mutant metastatic colorectal cancer. PLoS ONE 8(11):e62264. doi: 10.1371/journal.pone.0062264 PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Reidy DL, Vakiani E, Fakih MG, Saif MW, Hecht JR, Goodman-Davis N, Hollywood E, Shia J, Schwartz J, Chandrawansa K, Dontabhaktuni A, Youssoufian H, Solit DB, Saltz LB (2010) Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 28(27):4240–4246. doi: 10.1200/jco.2010.30.4154 CrossRefGoogle Scholar
  92. 92.
    Cunningham MP, Thomas H, Marks C, Green M, Fan Z, Modjtahedi H (2008) Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells. Int J Oncol 33(5):1107–1113PubMedGoogle Scholar
  93. 93.
    Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O’Callaghan CJ (2013) Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol Off J Am Soc Clin Oncol 31(19):2477–2484. doi: 10.1200/jco.2012.46.0543 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lei Cheng
    • 1
  • Wei Ren
    • 1
  • Li Xie
    • 1
  • Ming Li
    • 2
  • Jiang Liu
    • 1
  • Jing Hu
    • 1
  • Bao-Rui Liu
    • 1
  • Xiao-Ping Qian
    • 1
  1. 1.Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing UniversityClinical Cancer Institute of Nanjing UniversityNanjingChina
  2. 2.Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life SciencesNanjing UniversityNanjingChina

Personalised recommendations