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A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies

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Abstract

Purpose

Although KRAS mutation has been identified as a negative predictive biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR antibodies work by blocking ligand binding, but the significance of EGFR ligands in mCRC has not been completely described. This study was conducted to identify the correlation between all seven EGFR ligands and clinical outcomes in mCRC treated with anti-EGFR antibodies. Furthermore, we determined an appropriate predictive strategy for anti-EGFR antibodies using these EGFR ligands.

Methods

Among 36 mCRC patients who had been treated with cetuximab or panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated properly as the second and further lines and analyzed the relationship between immunoreactivity to seven EGFR ligands and clinical outcomes.

Results

Good clinical outcomes were associated with immunoreactivity against amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when compared with patients with immunoreactivity against zero or one ligand.

Conclusions

Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, TGF-α, and EREG) might be a novel predictive biomarker and may help optimize patient selection for cetuximab and panitumumab therapy in patients with mCRC.

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References

  • Asbert M, Montaner B, Perez-Tomas R (2001) Transforming growth factor-alpha precursors in human colon carcinoma cells. Dig Dis Sci 46(6):1157–1162

    Article  PubMed  CAS  Google Scholar 

  • Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S, Rowinsky EK, Xu LA, Harbison CT, Clark EA, Mauro DJ, Khambata-Ford S (2011) Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer 104(3):488–495. doi:10.1038/sj.bjc.6606054

    Article  PubMed  CAS  Google Scholar 

  • Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A (2007) 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 67(6):2643–2648. doi:10.1158/0008-5472.can-06-4158

    Article  PubMed  CAS  Google Scholar 

  • Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26(12):2006–2012. doi:10.1200/jco.2007.14.9898

    Article  PubMed  CAS  Google Scholar 

  • 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 (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345. doi:10.1056/NEJMoa033025

    Article  PubMed  CAS  Google Scholar 

  • Dahlhoff M, Horst D, Gerhard M, Kolligs FT, Wolf E, Schneider MR (2008) Betacellulin stimulates growth of the mouse intestinal epithelium and increases adenoma multiplicity in Apc+/Min mice. FEBS Lett 582(19):2911–2915. doi:10.1016/j.febslet.2008.07.026

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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 26(35):5705–5712. doi:10.1200/jco.2008.18.0786

    Article  PubMed  Google Scholar 

  • Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047

    Article  PubMed  CAS  Google Scholar 

  • 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 28(31):4697–4705. doi:10.1200/jco.2009.27.4860

    Article  PubMed  CAS  Google Scholar 

  • Dunbar AJ, Goddard C (2000) Structure-function and biological role of betacellulin. Int J Biochem Cell Biol 32(8):805–815

    Article  PubMed  CAS  Google Scholar 

  • Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. doi:10.1016/j.ejca.2008.10.026

    Article  PubMed  CAS  Google Scholar 

  • Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F, Mazzucchelli L (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97(8):1139–1145. doi:10.1038/sj.bjc.6604009

    Article  PubMed  CAS  Google Scholar 

  • Fuchs CS, Marshall J, Barrueco J (2008) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol 26(4):689–690. doi:10.1200/jco.2007.15.5390

    Article  PubMed  Google Scholar 

  • Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (2007) 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 25(12):1539–1544. doi:10.1200/jco.2006.09.6305

    Article  PubMed  CAS  Google Scholar 

  • Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1):23–30. doi:10.1200/jco.2004.09.046

    Article  PubMed  CAS  Google Scholar 

  • Harris RC, Chung E, Coffey RJ (2003) EGF receptor ligands. Exp Cell Res 284(1):2–13

    Article  PubMed  CAS  Google Scholar 

  • Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N (2008) Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci 99(2):214–220. doi:10.1111/j.1349-7006.2007.00676.x

    Article  PubMed  CAS  Google Scholar 

  • Ito Y, Higashiyama S, Takeda T, Okada M, Matsuura N (2001) Bimodal expression of heparin-binding EGF-like growth factor in colonic neoplasms. Anticancer Res 21(2B):1391–1394

    Google Scholar 

  • Itoh Y, Joh T, Tanida S, Sasaki M, Kataoka H, Itoh K, Oshima T, Ogasawara N, Togawa S, Wada T, Kubota H, Mori Y, Ohara H, Nomura T, Higashiyama S, Itoh M (2005) IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells. Cytokine 29(6):275–282. doi:10.1016/j.cyto.2004.11.005

    PubMed  CAS  Google Scholar 

  • Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Penault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074. doi:10.1200/jco.2008.21.3744

    Article  PubMed  CAS  Google Scholar 

  • Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20):2040–2048. doi:10.1056/NEJMoa071834

    Article  PubMed  CAS  Google Scholar 

  • Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765. doi:10.1056/NEJMoa0804385

    Article  PubMed  CAS  Google Scholar 

  • 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 25(22):3230–3237. doi:10.1200/jco.2006.10.5437

    Article  PubMed  CAS  Google Scholar 

  • Kochupurakkal BS, Harari D, Di-Segni A, Maik-Rachline G, Lyass L, Gur G, Kerber G, Citri A, Lavi S, Eilam R, Chalifa-Caspi V, Eshhar Z, Pikarsky E, Pinkas-Kramarski R, Bacus SS, Yarden Y (2005) Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem 280(9):8503–8512. doi:10.1074/jbc.M413919200

    Article  PubMed  CAS  Google Scholar 

  • 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 27(35):5924–5930. doi:10.1200/jco.2008.21.6796

    Article  PubMed  CAS  Google Scholar 

  • Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24(30):4914–4921. doi:10.1200/JCO.2006.06.7595

    Article  PubMed  CAS  Google Scholar 

  • Lievre A, Laurent-Puig P (2008) Predictive factors of response to anti-EGFR treatments in colorectal cancer. Bull Cancer 95(1):133–140. doi:10.1684/bdc.2008.0551

    PubMed  CAS  Google Scholar 

  • Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995. doi:10.1158/0008-5472.can-06-0191

    Article  PubMed  CAS  Google Scholar 

  • 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 (2009a) 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 27(16):2622–2629. doi:10.1200/jco.2008.20.2796

    Article  PubMed  CAS  Google Scholar 

  • 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 (2009b) 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 101(4):715–721. doi:10.1038/sj.bjc.6605177

    Article  PubMed  CAS  Google Scholar 

  • Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352(5):476–487. doi:10.1056/NEJMra040958

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J (2010) 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 28(31):4706–4713. doi:10.1200/jco.2009.27.6055

    Article  PubMed  CAS  Google Scholar 

  • 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 MA, Pilotti S (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol Off J Eur Soc Med Oncol/ESMO 20(1):84–90. doi:10.1093/annonc/mdn541

    Article  CAS  Google Scholar 

  • 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 14(18):5869–5876. doi:10.1158/1078-0432.ccr-08-0449

    Article  PubMed  CAS  Google Scholar 

  • Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S (2009) PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 15(9):3184–3188. doi:10.1158/1078-0432.ccr-08-2961

    Article  PubMed  CAS  Google Scholar 

  • Razis E, Briasoulis E, Vrettou E, Skarlos DV, Papamichael D, Kostopoulos I, Samantas E, Xanthakis I, Bobos M, Galanidi E, Bai M, Gikonti I, Koukouma A, Kafiri G, Papakostas P, Kalogeras KT, Kosmidis P, Fountzilas G (2008) Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer 8:234. doi:10.1186/1471-2407-8-234

    Article  PubMed  Google Scholar 

  • Sahin U, Blobel CP (2007) Ectodomain shedding of the EGF-receptor ligand epigen is mediated by ADAM17. FEBS Lett 581(1):41–44. doi:10.1016/j.febslet.2006.11.074

    Article  PubMed  CAS  Google Scholar 

  • Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019. doi:10.1200/jco.2007.14.9930

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Sasaki T, Nakamura T, Rebhun RB, Cheng H, Hale KS, Tsan RZ, Fidler IJ, Langley RR (2008) Modification of the primary tumor microenvironment by transforming growth factor alpha-epidermal growth factor receptor signaling promotes metastasis in an orthotopic colon cancer model. Am J Pathol 173(1):205–216. doi:10.2353/ajpath.2008.071147

    Article  PubMed  CAS  Google Scholar 

  • Sawhney RS, Cookson MM, Sharma B, Hauser J, Brattain MG (2004) Autocrine transforming growth factor alpha regulates cell adhesion by multiple signaling via specific phosphorylation sites of p70S6 kinase in colon cancer cells. J Biol Chem 279(45):47379–47390. doi:10.1074/jbc.M402031200

    Article  PubMed  CAS  Google Scholar 

  • Scartozzi M, Bearzi I, Mandolesi A, Pierantoni C, Loupakis F, Zaniboni A, Negri F, Quadri A, Zorzi F, Galizia E, Berardi R, Biscotti T, Labianca R, Masi G, Falcone A, Cascinu S (2009) Epidermal Growth Factor Receptor (EGFR) gene copy number (GCN) correlates with clinical activity of irinotecan-cetuximab in K-RAS wild-type colorectal cancer: a fluorescence in situ (FISH) and chromogenic in situ hybridization (CISH) analysis. BMC Cancer 9:303. doi:10.1186/1471-2407-9-303

    Article  PubMed  Google Scholar 

  • Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kroning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26(14):2311–2319. doi:10.1200/jco.2007.13.1193

    Article  PubMed  CAS  Google Scholar 

  • 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 46(11):1997–2009. doi:10.1016/j.ejca.2010.03.036

    Article  PubMed  CAS  Google Scholar 

  • Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG (2007) 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 25(13):1658–1664. doi:10.1200/jco.2006.08.1620

    Article  PubMed  Google Scholar 

  • 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 Engl J Med 360(14):1408–1417. doi:10.1056/NEJMoa0805019

    Article  PubMed  Google Scholar 

  • 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 29(15):2011–2019. doi:10.1200/jco.2010.33.5091

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Yukimi Hashidume for technical assistance. This study was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 24590923).

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Authors and Affiliations

  1. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

    Michihiro Yoshida, Takaya Shimura, Masahide Ebi, Takahiro Nakazawa & Takashi Joh

  2. Vascular Biology Program and Department of Surgery, Boston Children’s Hospital, Boston, MA, USA

    Takaya Shimura

  3. Department of Surgery, Harvard Medical School, Boston, MA, USA

    Takaya Shimura

  4. Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Mikinori Sato & Hiromitsu Takeyama

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  1. Michihiro Yoshida
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Correspondence to Takaya Shimura.

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Yoshida, M., Shimura, T., Sato, M. et al. A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies. J Cancer Res Clin Oncol 139, 367–378 (2013). https://doi.org/10.1007/s00432-012-1340-x

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