晚期结直肠癌K-ras基因状态的检测及西妥昔单抗联合化疗治疗晚期结直肠癌的病例总结
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摘要
背景与目的
K-ras基因突变在结直肠癌的发生发展过程中起着重要的作用,检测K-ras基因状态及其表达产物对判断结直肠癌预后有重要意义,尤其在预测表皮生长因子受体抑制剂西妥昔单抗治疗晚期结直肠癌患者的疗效时更为重要。本研究总结了结直肠癌患者手术标本K-ras基因突变情况与临床、病理特征、术后复发率的关系,并且观察西妥昔单抗联合化疗在术后复发转移的结直肠癌二线及二线以后治疗中的疗效,及其与K-ras基因状态的关系。
研究方法
本文回顾性分析了邵逸夫医院27例晚期结直肠癌患者的病理标本,采用焦磷酸测序技术检测其K-ras基因突变情况,并且总结K-ras基因状态与临床、病理特征、术后复发率的关系;其中10例患者曾应用西妥昔单抗联合化疗进行复发转移后二线及二线以后治疗,观察治疗效果、不良反应及其与K-ras基因状态的关系。
结果
在27例行K-ras基因检测的患者中,野生型17例,突变型10例,突变率为37.0%,其中12密码子突变5例,13密码子突变5例,K-ras基因突变情况与其临床、病理特征、术后复发率没有明显相关性。其中10例术后复发转移性晚期结直肠癌患者应用西妥昔单抗联合化疗行二线及二线以上化疗,无1例患者达到CR,PR2例,SD5例,PD3例,在6例K-ras基因野生型患者中,PR2例,SD3例,PD1例,在4例K-ras基因突变型患者中,PRO例,SD2例,PD2例。
结论
本研究中晚期结直肠癌患者的K-ras基因突变率和相关报道一致,K-ras基因状态是预测西妥昔单抗联合治疗晚期结直肠癌有效性的重要指标。
Background and purpose:
K-ras gene plays an important role in the progress of colorectal cancer.K-ras detection can be used for determining prognosis of colorectal cancer,especially for predicting the efficacy of Cetuximab treatment in advanced colorectal cancer.This study summarized the association among K-ras mutation,tumor characteristics and relapse rate after surgery,and also explored the efficacy of Cetuximab in the second/third-line treatment.
Methods:
Tissue samples of 27 colorectal cancer patients from Sir Run Run Shaw Hospital were analyzed to detect K-ras gene mutation by using Pyrosequencing method.10 of these patients were treated with Cetuximab combined with second/third-line chemotherapy,and were analyzed the relationship of K-ras gene and efficacy of Cetuximab plus chemotherapy.
Results:
There ware 17 wild-type and 10 mutated-type K-ras gene in all 27 cases with mutation rate of 37%.5 mutations occurred in codon12,and 5 in codon13.Mutations were not associated with clinical and pathologic characters,postoperation recurrent rate. Of the 10 cases who treated with Cetuximab,there were no complete response(CR),2 partial response(PR),5 stable disease(SD) and 3 progressive disease(PD).Of the 6 wild-type K-ras cases,there were no complete response(CR),2 partial response(PR),3 stable disease(SD) and 1 progressive disease(PD).Of the 4 mutated-type K-ras cases, there were no complete response(CR),no partial response(PR),2 stable disease(SD) and 2 progressive disease(PD).
Conclusion:
The mutation rate of the K-ras gene was similar with other reports.K-ras gene is an important biomarker for determining prognosis of colorectal cancer.
K-ras基因突变在结直肠癌的发生发展过程中起着重要的作用,检测K-ras基因状态及其表达产物对判断结直肠癌预后有重要意义,尤其在预测表皮生长因子受体抑制剂西妥昔单抗治疗晚期结直肠癌患者的疗效时更为重要。本研究总结了结直肠癌患者手术标本K-ras基因突变情况与临床、病理特征、术后复发率的关系,并且观察西妥昔单抗联合化疗在术后复发转移的结直肠癌二线及二线以后治疗中的疗效,及其与K-ras基因状态的关系。
研究方法
本文回顾性分析了邵逸夫医院27例晚期结直肠癌患者的病理标本,采用焦磷酸测序技术检测其K-ras基因突变情况,并且总结K-ras基因状态与临床、病理特征、术后复发率的关系;其中10例患者曾应用西妥昔单抗联合化疗进行复发转移后二线及二线以后治疗,观察治疗效果、不良反应及其与K-ras基因状态的关系。
结果
在27例行K-ras基因检测的患者中,野生型17例,突变型10例,突变率为37.0%,其中12密码子突变5例,13密码子突变5例,K-ras基因突变情况与其临床、病理特征、术后复发率没有明显相关性。其中10例术后复发转移性晚期结直肠癌患者应用西妥昔单抗联合化疗行二线及二线以上化疗,无1例患者达到CR,PR2例,SD5例,PD3例,在6例K-ras基因野生型患者中,PR2例,SD3例,PD1例,在4例K-ras基因突变型患者中,PRO例,SD2例,PD2例。
结论
本研究中晚期结直肠癌患者的K-ras基因突变率和相关报道一致,K-ras基因状态是预测西妥昔单抗联合治疗晚期结直肠癌有效性的重要指标。
Background and purpose:
K-ras gene plays an important role in the progress of colorectal cancer.K-ras detection can be used for determining prognosis of colorectal cancer,especially for predicting the efficacy of Cetuximab treatment in advanced colorectal cancer.This study summarized the association among K-ras mutation,tumor characteristics and relapse rate after surgery,and also explored the efficacy of Cetuximab in the second/third-line treatment.
Methods:
Tissue samples of 27 colorectal cancer patients from Sir Run Run Shaw Hospital were analyzed to detect K-ras gene mutation by using Pyrosequencing method.10 of these patients were treated with Cetuximab combined with second/third-line chemotherapy,and were analyzed the relationship of K-ras gene and efficacy of Cetuximab plus chemotherapy.
Results:
There ware 17 wild-type and 10 mutated-type K-ras gene in all 27 cases with mutation rate of 37%.5 mutations occurred in codon12,and 5 in codon13.Mutations were not associated with clinical and pathologic characters,postoperation recurrent rate. Of the 10 cases who treated with Cetuximab,there were no complete response(CR),2 partial response(PR),5 stable disease(SD) and 3 progressive disease(PD).Of the 6 wild-type K-ras cases,there were no complete response(CR),2 partial response(PR),3 stable disease(SD) and 1 progressive disease(PD).Of the 4 mutated-type K-ras cases, there were no complete response(CR),no partial response(PR),2 stable disease(SD) and 2 progressive disease(PD).
Conclusion:
The mutation rate of the K-ras gene was similar with other reports.K-ras gene is an important biomarker for determining prognosis of colorectal cancer.
引文
[1]Carlo M.Croce.Oncogenes and Cancer.N Engl J Med 2008;358:502-511.
[2]Pawson T,Warner N.Oncogenic rewiring of cellular signaling pathways.Oncogene 2007;26:1268-1275.
[3]Caroline McNeil.K-Ras Mutations Are Changing Practice in Advanced Colorectal Cancer.JNCI News 2008;1667-1669.
[4]Ryan BM,Lefort F,McManus R et al.A prospective study of circulating mutant K-RAS2 in the serum of patients with colorectal neoplasia:strong prognostic indicator in postoperative follow up.Cancer 2003;52:101-108.
[5]Carsten Bokemeyer,Igor Bondarenko,et al.Fluorouracil,Leucovorin,and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer.J Clin Oncol 2008,27.
[6]Van Cutsem E,Bodoky G,Kyung Roh J,et al.CRYSTAL,a randomized phase Ⅲ trial of Cetuximab plus FOLFIRI vs FOLFIRI in first-line metastatic colorectal cancer (mCRC).Presented at 14th European Cancer Conference2007,September 23-27,Barcelona,Spain (abstr 3.001).
[7]Mostafa Ronaghi,Elahe Elahi.Pyrosequencing for microbial typing.J Chromatogr B Analyt Technol Biomed Life Sci,2002;782 (1-2):67-72.
[8]WeissB,Bollag G,Shannon K.Hyperactive Ras as a therapeutictarget in neurofibromatosis type 1 [J].Am J Med Genet,1999,89(1):14-22.
[9]H.Jervoise N.Andreyev,Andrew R.Journal of the National Cancer Institute,Vol.90,No.9,May 6,1998;675-684.
[10]Pajkos G,Kiss I,Sander J,et al.The prognostic value of the presence of mutation at the codons 12,13,61 of k-ras oncogene in colorectal cancer.Anticancer Res,2000,20(3A):1695-1701.
[11]V.Bazan,V.Agnese,S.Corsale,et al.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.Annals of Oncology 16 (Supplement 4),2005;50-55.
[12]Liang JT,Cheng YM,Cheng KT,et al.Rappraisal of k-ras and p53 gene mutation in the recurrence of Ducks'B2 rectal cancer after curative resection.Hepatogastroenterology,1999,46(26):830-837.
[13]Sweetser.DA,Chen CS,Blomberg.AA,et al.Loss of heterozygosity in childhood de novo acute myelogenous leukemia.Blood,2001,98 4:1188-1194.
[14]Fearon E.A genetic model for colorectal tumorigenesis.Cell,2002,61:159-161.
[15]Adenis A,Aranda Aguilar E,Robin YM,et al.Expression of the epidermal growth factor receptor (EGFR or HER1)and human epidermal growth factor receptor 2 (HER2)in a large scale metastatic colorectal cancer (mCRC)trial.J Clin Oncol 2005,23:278s,(suppl;abstr 3630).
[16]Cunningham D,Humblet Y,Siena S,et al.Cetuximab monotherapy and Cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.N Engl J Med 2004,351:337-345.
[17]Folprecht G,Lutz MP,Schoffski P,et al.Cetuximab and irinotecan /5-fluorouracil /folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.Ann Oncol 2006,17:450-456.
[18]Kawaguchi Y,Kono K,Mimura K,et al.Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma.Int J Cancer2006,120:781-787.
[19]Mendelshon J,Baselga J:Epidermal growth factor targeting in cancer.Semin Oncol 2006,33:369-385.
[20]Rocha-Lima CM,Soares HP,Raez LE,et al.EGFR targeting of solid tumors.Cancer Control 2007,14:295-304.
[21]Rivera F,Vega-Villegas ME,Lopez-Brea MF,et al.Current situation of panitumumab,matuzumab,nimotuzumab and zalutuzumab.Acta Oncologica 2008,47:9-19.
[22]Omerovic J,Hammond DE,Clague MJ et al.Ras isoform abundance and signalling in human cancer cell lines.Oncogene 2008,27:2754-2762.
[23]Christos SK,Shirin KF,et al.K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer.N Engl J Med 2008,359:17.
[24]Jhawer M,Goel S,Wilson AJ,et al.PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor Cetuximab.Cancer Res 2008,68:1953-1961.
[25]F.Perronel,A.Lampisl,M.Orsenigo et al.PI3KCA/PTEN deregulation contributes to impaired responses to Cetuximab in metastatic colorectal cancer patients.Annals of Oncology 2009,20:84-90.
[1]Adenis A,Aranda Aguilar E,Robin YM,et al.Expression of the epidermal growth factor receptor(EGFR or HER1) and human epidermal growth factor receptor 2(HER2) in a large scale metastatic colorectal cancer(mCRC) trial.J Clin Oncol 2005,23:278s,(suppl;abstr 3630).
[2]Cunningham D,Humblet Y,Siena S,et al.Cetuximab monotherapy and Cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.N Engl J Med 2004,351:337-345.
[3]Folprecht G,Lutz MP,Schoffski P,et al.Cetuximab and irinotecan/5-fluorouracil /folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.Ann Oncol 2006,17:450-456.
[4]Kawaguchi Y,Kono K,Mimura K,et al.Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma.Int J Cancer2006,120:781-787.
[5]Mendelshon J,Baselga J:Epidermal growth factor targeting in cancer.Semin Oncol 2006,33:369-385.
[6]Rocha-Lima CM,Soares HP,Raez LE,et al.EGFR targeting of solid tumors.Cancer Control 2007,14:295-304.
[7]C.Dreyer,E.Raymond,S.Faivre.Targeted therapies and their indications in solid neoplasias,Rev Med Interne2009,Mar 17.
[8]Khambata-Ford S,Garret CR,Meropol NJ,et al.Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with Cetuximab.J Clin Oncol 2007,25:3230-3237.
[9]Castillo L,Etienne-Grimaldi MC,Fischel JL,et al.Pharmacological background of EGFR targeting.AnnOncol 2004,15:1007-1012.
[10]Karnoub AE,Weinberg.RA Ras oncogenes:split personalities.Nat Rev Mol Cell Biol 2008,9:517-531.
[11]Jasminka Omerovic,Ian A.Prior.Compartmentalized signalling:Ras proteins and signalling nanoclusters.FEBS Journal 2009,276:1817-1825.
[12]Omerovic J,Hammond DE,Clague MJ et al.Ras isoform abundance and signalling in human cancer cell lines.Oncogene 2008,27:2754-2762.
[13]Rivera F,Vega-Villegas ME,Lopez-Brea MF,et al.Current situation of panitumumab,matuzumab,nimotuzumab and zalutuzumab.Acta Oncologica 2008,47:9-19.
[14]VincenziB,SantiniD,Russo et al.Angiogenesis modifications related with Cetuximab plus irinotecan as anticancer treatment in advanced colorectal cancer patients.Ann Oncol 2006,17(5):835-841.
[15]Bonner J,Giralt J,Harari P,et al.High dose radiation with or without erbitux in the treatment of local recoregionally advanced SCCHN(phase III)[J].Proc Am Soc Clin Oncol 2004,23(19):5507.
[16]Christos SK,Shirin KF,et al.K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer.N Engl J Med 2008,359:17.
[17]David Cunningham,Yves Humblet,et al.Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer.N Engl J Med 2004,351:337-345.
[18]Alberto F.Sobrero,Joan Maurel,et al.EPIC:Phase Ⅲ Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer.J Clin Oncol 2008,26:2311-2319.
[19]Carsten Bokemeyer,Igor Bondarenko,et al.Fluorouracil,Leucovorin,and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer.J Clin Oncol 2008,27.
[20]Van Cutsem E,Bodoky G,Kyung Roh J,et al.CRYSTAL,a randomized phase III trial of Cetuximab plus FOLFIRI vs FOLFIRI in first-line metastatic colorectal cancer (mCRC).Presented at 14th European Cancer Conference2007,September 23-27,Barcelona,Spain (abstr 3.001).
[21]Moroni M,Veronese S,Benvenuti S,et al.Gene copy number for epidermal growth factor receptor (EGFR)and clinical response to antiEGFR treatment in colorectal cancer:A cohort study.Lancet Oncol 2005,6:279-286.
[22]Lenz HJ,Van Cutsem E,Khambata-Ford S,et al.Multicenter phase Ⅱ and translational study of Cetuximab in metastatic colorectal carcinoma refractory to irinotecan,oxaliplatin,and fluoropyrimidines.J Clin Oncol 2006,24:4914-4921.
[23]Astrid Lie vre,Jean-Baptiste Bachet,et al.K-RAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab.J Clin Oncol 2008,26:374-379.
[24]Carlo M.Croce,M.D.Oncogenes and Cancer.N Engl J Med 2008,358:502-11.
[25]Carmen J.Allegra,J.Milburn Jessup,et al.American Society of Clinical Oncology Provisional Clinical Opinion:Testing for K-RAS 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.
[26]F.Perronel,A.Lampisl,M.Orsenigo et al.PDKCA/PTEN deregulation contributes to impaired responses to Cetuximab in metastatic colorectal cancer patients.Annals of Oncology 2009,20:84-90.
[27]Jhawer M,Goel S,Wilson AJ,et al.PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor Cetuximab.Cancer Res 2008,68:1953-1961.
[2]Pawson T,Warner N.Oncogenic rewiring of cellular signaling pathways.Oncogene 2007;26:1268-1275.
[3]Caroline McNeil.K-Ras Mutations Are Changing Practice in Advanced Colorectal Cancer.JNCI News 2008;1667-1669.
[4]Ryan BM,Lefort F,McManus R et al.A prospective study of circulating mutant K-RAS2 in the serum of patients with colorectal neoplasia:strong prognostic indicator in postoperative follow up.Cancer 2003;52:101-108.
[5]Carsten Bokemeyer,Igor Bondarenko,et al.Fluorouracil,Leucovorin,and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer.J Clin Oncol 2008,27.
[6]Van Cutsem E,Bodoky G,Kyung Roh J,et al.CRYSTAL,a randomized phase Ⅲ trial of Cetuximab plus FOLFIRI vs FOLFIRI in first-line metastatic colorectal cancer (mCRC).Presented at 14th European Cancer Conference2007,September 23-27,Barcelona,Spain (abstr 3.001).
[7]Mostafa Ronaghi,Elahe Elahi.Pyrosequencing for microbial typing.J Chromatogr B Analyt Technol Biomed Life Sci,2002;782 (1-2):67-72.
[8]WeissB,Bollag G,Shannon K.Hyperactive Ras as a therapeutictarget in neurofibromatosis type 1 [J].Am J Med Genet,1999,89(1):14-22.
[9]H.Jervoise N.Andreyev,Andrew R.Journal of the National Cancer Institute,Vol.90,No.9,May 6,1998;675-684.
[10]Pajkos G,Kiss I,Sander J,et al.The prognostic value of the presence of mutation at the codons 12,13,61 of k-ras oncogene in colorectal cancer.Anticancer Res,2000,20(3A):1695-1701.
[11]V.Bazan,V.Agnese,S.Corsale,et al.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.Annals of Oncology 16 (Supplement 4),2005;50-55.
[12]Liang JT,Cheng YM,Cheng KT,et al.Rappraisal of k-ras and p53 gene mutation in the recurrence of Ducks'B2 rectal cancer after curative resection.Hepatogastroenterology,1999,46(26):830-837.
[13]Sweetser.DA,Chen CS,Blomberg.AA,et al.Loss of heterozygosity in childhood de novo acute myelogenous leukemia.Blood,2001,98 4:1188-1194.
[14]Fearon E.A genetic model for colorectal tumorigenesis.Cell,2002,61:159-161.
[15]Adenis A,Aranda Aguilar E,Robin YM,et al.Expression of the epidermal growth factor receptor (EGFR or HER1)and human epidermal growth factor receptor 2 (HER2)in a large scale metastatic colorectal cancer (mCRC)trial.J Clin Oncol 2005,23:278s,(suppl;abstr 3630).
[16]Cunningham D,Humblet Y,Siena S,et al.Cetuximab monotherapy and Cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.N Engl J Med 2004,351:337-345.
[17]Folprecht G,Lutz MP,Schoffski P,et al.Cetuximab and irinotecan /5-fluorouracil /folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.Ann Oncol 2006,17:450-456.
[18]Kawaguchi Y,Kono K,Mimura K,et al.Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma.Int J Cancer2006,120:781-787.
[19]Mendelshon J,Baselga J:Epidermal growth factor targeting in cancer.Semin Oncol 2006,33:369-385.
[20]Rocha-Lima CM,Soares HP,Raez LE,et al.EGFR targeting of solid tumors.Cancer Control 2007,14:295-304.
[21]Rivera F,Vega-Villegas ME,Lopez-Brea MF,et al.Current situation of panitumumab,matuzumab,nimotuzumab and zalutuzumab.Acta Oncologica 2008,47:9-19.
[22]Omerovic J,Hammond DE,Clague MJ et al.Ras isoform abundance and signalling in human cancer cell lines.Oncogene 2008,27:2754-2762.
[23]Christos SK,Shirin KF,et al.K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer.N Engl J Med 2008,359:17.
[24]Jhawer M,Goel S,Wilson AJ,et al.PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor Cetuximab.Cancer Res 2008,68:1953-1961.
[25]F.Perronel,A.Lampisl,M.Orsenigo et al.PI3KCA/PTEN deregulation contributes to impaired responses to Cetuximab in metastatic colorectal cancer patients.Annals of Oncology 2009,20:84-90.
[1]Adenis A,Aranda Aguilar E,Robin YM,et al.Expression of the epidermal growth factor receptor(EGFR or HER1) and human epidermal growth factor receptor 2(HER2) in a large scale metastatic colorectal cancer(mCRC) trial.J Clin Oncol 2005,23:278s,(suppl;abstr 3630).
[2]Cunningham D,Humblet Y,Siena S,et al.Cetuximab monotherapy and Cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.N Engl J Med 2004,351:337-345.
[3]Folprecht G,Lutz MP,Schoffski P,et al.Cetuximab and irinotecan/5-fluorouracil /folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.Ann Oncol 2006,17:450-456.
[4]Kawaguchi Y,Kono K,Mimura K,et al.Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma.Int J Cancer2006,120:781-787.
[5]Mendelshon J,Baselga J:Epidermal growth factor targeting in cancer.Semin Oncol 2006,33:369-385.
[6]Rocha-Lima CM,Soares HP,Raez LE,et al.EGFR targeting of solid tumors.Cancer Control 2007,14:295-304.
[7]C.Dreyer,E.Raymond,S.Faivre.Targeted therapies and their indications in solid neoplasias,Rev Med Interne2009,Mar 17.
[8]Khambata-Ford S,Garret CR,Meropol NJ,et al.Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with Cetuximab.J Clin Oncol 2007,25:3230-3237.
[9]Castillo L,Etienne-Grimaldi MC,Fischel JL,et al.Pharmacological background of EGFR targeting.AnnOncol 2004,15:1007-1012.
[10]Karnoub AE,Weinberg.RA Ras oncogenes:split personalities.Nat Rev Mol Cell Biol 2008,9:517-531.
[11]Jasminka Omerovic,Ian A.Prior.Compartmentalized signalling:Ras proteins and signalling nanoclusters.FEBS Journal 2009,276:1817-1825.
[12]Omerovic J,Hammond DE,Clague MJ et al.Ras isoform abundance and signalling in human cancer cell lines.Oncogene 2008,27:2754-2762.
[13]Rivera F,Vega-Villegas ME,Lopez-Brea MF,et al.Current situation of panitumumab,matuzumab,nimotuzumab and zalutuzumab.Acta Oncologica 2008,47:9-19.
[14]VincenziB,SantiniD,Russo et al.Angiogenesis modifications related with Cetuximab plus irinotecan as anticancer treatment in advanced colorectal cancer patients.Ann Oncol 2006,17(5):835-841.
[15]Bonner J,Giralt J,Harari P,et al.High dose radiation with or without erbitux in the treatment of local recoregionally advanced SCCHN(phase III)[J].Proc Am Soc Clin Oncol 2004,23(19):5507.
[16]Christos SK,Shirin KF,et al.K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer.N Engl J Med 2008,359:17.
[17]David Cunningham,Yves Humblet,et al.Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer.N Engl J Med 2004,351:337-345.
[18]Alberto F.Sobrero,Joan Maurel,et al.EPIC:Phase Ⅲ Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer.J Clin Oncol 2008,26:2311-2319.
[19]Carsten Bokemeyer,Igor Bondarenko,et al.Fluorouracil,Leucovorin,and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer.J Clin Oncol 2008,27.
[20]Van Cutsem E,Bodoky G,Kyung Roh J,et al.CRYSTAL,a randomized phase III trial of Cetuximab plus FOLFIRI vs FOLFIRI in first-line metastatic colorectal cancer (mCRC).Presented at 14th European Cancer Conference2007,September 23-27,Barcelona,Spain (abstr 3.001).
[21]Moroni M,Veronese S,Benvenuti S,et al.Gene copy number for epidermal growth factor receptor (EGFR)and clinical response to antiEGFR treatment in colorectal cancer:A cohort study.Lancet Oncol 2005,6:279-286.
[22]Lenz HJ,Van Cutsem E,Khambata-Ford S,et al.Multicenter phase Ⅱ and translational study of Cetuximab in metastatic colorectal carcinoma refractory to irinotecan,oxaliplatin,and fluoropyrimidines.J Clin Oncol 2006,24:4914-4921.
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