胃癌的靶向治疗
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摘要
目前,胃癌治疗取得了很大进展,但进展期胃癌的化疗方案都较为单一,总生存时间仍较差,同时,几乎没有分子靶向治疗方案用于治疗胃癌。对于肿瘤分子特征研究包括HER2、EGFR、FGFR2、MET、PI3K和其他癌基因及候选生物标志物和肿瘤驱动因子位点等,本文对其关键突变位点、蛋白表达、治疗影响以及可能影响蛋白表达的途径进行介绍。
At present,great progress has been made in the treatment of gastric cancer,but the chemotherapy regimen for advanced gastric cancer is relatively simple,and the overall survival time is still poor. At the same time,there is almost no molecular targeted therapy for gastric cancer. Tumor molecular characterization studies include HER2,EGFR,FGFR2,M ET,PI3 K and other oncogenes,candidate biomarkers and tumor driver factor sites. The article review s the key mutation sites,protein expression,therapeutic effects and pathw ays that may affect protein expression.
At present,great progress has been made in the treatment of gastric cancer,but the chemotherapy regimen for advanced gastric cancer is relatively simple,and the overall survival time is still poor. At the same time,there is almost no molecular targeted therapy for gastric cancer. Tumor molecular characterization studies include HER2,EGFR,FGFR2,M ET,PI3 K and other oncogenes,candidate biomarkers and tumor driver factor sites. The article review s the key mutation sites,protein expression,therapeutic effects and pathw ays that may affect protein expression.
引文
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[3]Koizumi W,Narahara H,Hara T,et al.S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer(SPIRITS trial):a phase III trial[J].Lancet Oncol,2008,9(3):215-221.
[4]Ali SM,Sanford EM,Klempner SJ,et al.Prospective comprehensive genomic profiling of advanced gastric carcinoma cases reveals frequent clinically relevant genomic alterations and new routes for targeted therapies[J].Oncologist,2015,20(5):499-507.
[5]Deng N,Goh LK,Wang H,et al.A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets[J].Gut,2012,61(5):673-684.
[6]Zang ZJ,Ong CK,Cutcutache I,et al.Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing[J].Cancer Res,2011,71(1):29-39.
[7]Stachler MD,Taylor-Weiner A,Peng S,et al.Paired exome analysis of Barrett's esophagus and adenocarcinoma[J].Nat Genet,2015,47(9):1047-1055.
[8]Bang YJ,Van Cutsem E,Feyereislova A,et al.Trastuzumab in combination w ith chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer(To GA):a phase 3,open-label,randomised controlled trial[J].Lancet,2010,376(9742):687-697.
[9]Catenacci DV,Liao WL,Zhao L,et al.Mass-spectrometrybased quantitation of Her2 in gastroesophageal tumor tissue:comparison to IHC and FISH[J].Gastric Cancer,2016,19(4):1066-1079.
[10]Sellappan S,Blackler A,Liao WL,et al.Therapeutically induced changes in HER2,HER3,and EGFR protein expression for treatment guidance[J].J Natl Compr Canc Netw,2016,14(5):503-507.
[11]Shoda K,Masuda K,Ichikawa D,et al.HER2 amplification detected in the circulating DNA of patients w ith gastric cancer:a retrospective pilot study[J].Gastric Cancer,2015,18(4):698-710.
[12]Janjigian YY,Riches JC,Ku GY,et al.Loss of human epidermal grow th factor receptor 2(HER2)expression in HER2-overexpressing esophagogastric(EG)tumors treated w ith trastuzumab[J].J Clin Oncol,2015,33(3_suppl):63.
[13]Catenacci DV.Next-generation clinical trials:novel strategies to address the challenge of tumor molecular heterogeneity[J].M ol Oncol,2015,9(5):967-996.
[14]Denlinger CS,Alsina Maqueda M,Watkins DJ,et al.Randomized phase 2 study of paclitaxel(PTX),trastuzumab(T)w ith or w ithout M M-111 in HER2 expressing gastroesophageal cancers(GEC)[EB/OL].[2018-8-6].http://meeting.ascopubs.org/cgi/content/abstract/34/15_suppl/4043.
[15]Hecht JR,Bang YJ,Qin SK,et al.Lapatinib in combination w ith capecitabine plus oxaliplatin in human epidermal grow th factor receptor 2-positive advanced or metastatic gastric,esophageal,or gastroesophageal adenocarcinoma:TRIO-013/LOG-i C-a randomized phaseⅢtrial[J].J Clin Oncol,2016,34(5):443-451.
[16]Gomez-Martin C,Plaza JC,Pazo-Cid R,et al.Level of HER2gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated w ith trastuzumab[J].J Clin Oncol,2013,31(35):4445-4452.
[17]Ock CY,Lee KW,Kim JW,et al.Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer[J].Clin Cancer Res,2015,21(11):2520-2529.
[18]An E,Ock CY,Kim TY,et al.Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment[J].Ann Oncol,2017,28(1):110-115.
[19]Satoh T,Xu RH,Chung HC,et al.Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations:Ty TAN--a randomized,phase III study[J].J Clin Oncol,2014,32(19):2039-2049.
[20]Oh SY,Kwon HC,Kim SH,et al.Clinicopathologic significance of HIF-1alpha,p53,and VEGF expression and preoperative serum VEGF level in gastric cancer[J].BM C Cancer,2008,8:123.
[21]Fuchs CS,Tomasek J,Yong CJ,et al.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(REGARD):an international,randomised,multicentre,placebo-controlled,phase 3 trial[J].Lancet,2014,383(9911):31-39.
[22]Wilke H,Muro K,Van Cutsem E,et al.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients w ith previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(RAINBOW):a double-blind,randomised phase 3 trial[J].Lancet Oncol,2014,15(11):1224-1235.
[23]Li J,Qin S,Xu J,et al.Randomized,double-blind,placebocontrolled phase III trial of apatinib in patients w ith chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction[J].J Clin Oncol,2016,34(13):1448-1454.
[24]Ohtsu A,Shah MA,Van Cutsem E,et al.Bevacizumab in combination w ith chemotherapy as first-line therapy in advanced gastric cancer:a randomized,double-blind,placebocontrolled phase III study[J].J Clin Oncol,2011,29(30):3968-3976.
[25]Enzinger PC,Mccleary NJ,Zheng H,et al.Multicenter doubleblind randomized phase II:FOLFOX+ziv-aflibercept/placebo for patients(pts)w ith chemo-naive metastatic esophagogastric adenocarcinoma(M EGA)[J].J Clin Oncol,2016,34(suppl 4):4.
[26]Nagatsuma AK,Aizawa M,Kuwata T,et al.Expression profiles of HER2,EGFR,M ET and FGFR2 in a large cohort of patients w ith gastric adenocarcinoma[J].Gastric Cancer,2015,18(2):227-238.
[27]Terashima M,Kitada K,Ochiai A,et al.Impact of expression of human epidermal grow th factor receptors EGFR and ERBB2on survival in stage II/III gastric cancer[J].Clin Cancer Res,2012,18(21):5992-6000.
[28]Cancer Genome Atlas Research Network.Comprehensive molecular characterization of gastric adenocarcinoma[J].Nature,2014,513(7517):202-209.
[29]Dulak AM,Stojanov P,Peng S,et al.Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity[J].Nat Genet,2013,45(5):478-486.
[30]Kimura H,Sakai K,Arao T,et al.Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells w ith w ild-type or mutant epidermal grow th factor receptor[J].Cancer Sci,2007,98(8):1275-1280.
[31]Enzinger PC,Burtness BA,Niedzwiecki D,et al.CALGB80403(Alliance)/E1206:a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers[J].J Clin Oncol,2016,34(23):2736-2742.
[32]Tebbutt NC,Price TJ,Ferraro DA,et al.Panitumumab added to docetaxel,cisplatin and fluoropyrimidine in oesophagogastric cancer:ATTAX3 phase II trial[J].Br J Cancer,2016,114(5):505-509.
[33]Dragovich T,Mc Coy S,Fenoglio-Preiser CM,et al.Phase IItrial of erlotinib in gastroesophageal junction and gastric adenocarcinomas:SWOG 0127[J].J Clin Oncol,2006,24(30):4922-4927.
[34]Lordick F,Kang YK,Chung HC,et al.Capecitabine and cisplatin w ith or w ithout cetuximab for patients w ith previously untreated advanced gastric cancer(EXPAND):a randomised,open-label phase 3 trial[J].Lancet Oncol,2013,14(6):490-499.
[35]Dutton SJ,Ferry DR,Blazeby JM,et al.Gefitinib for oesophageal cancer progressing after chemotherapy(COG):a phase3,multicentre,double-blind,placebo-controlled randomised trial[J].Lancet Oncol,2014,15(8):894-904.
[36]Zhang L,Yang J,Cai J,et al.A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy[J].Sci Rep,2013,3:2992.
[37]Luber B,Deplazes J,Keller G,et al.Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in firstline metastatic gastric and oesophago-gastric junction cancer:results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie(AIO)[J].BM C Cancer,2011,11:509.
[38]Lordick F,Kang YK,Salman P,et al.Clinical outcome according to tumor HER2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study[J].JClin Oncol,2013,31(Suppl):55-56
[39]Catenacci DVT,Polite BN,Henderson L,et al.Toward personalized treatment for gastroesophageal adenocarcinoma(GEC):Strategies to address tumor heterogeneity-PANGEA[J].JClin Oncol,2014,32(suppl 3):66.
[40]Yu S,Yu Y,Zhao N,et al.C-Met as a prognostic marker in gastric cancer:a systematic review and meta-analysis[J].PLo S One,2013,8(11):e79137.
[41]Hack SP,Bruey JM,Koeppen H.HGF/MET-directed therapeutics in gastroesophageal cancer:a review of clinical and biomarker development[J].Oncotarget,2014,5(10):2866-2880.
[42]Metzger ML,Behrens HM,B9ger C,et al.MET in gastric cancer-discarding a 10%cutoff rule[J].Histopathology,2016,68(2):241-253.
[43]Iveson T,Donehower RC,Davidenko I,et al.Rilotumumab in combination w ith epirubicin,cisplatin,and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma:an open-label,dose de-escalation phase 1b study and a double-blind,randomised phase 2 study[J].Lancet Oncol,2014,15(9):1007-1018.
[44]Yamaguchi H,Chang SS,Hsu JL,et al.Signaling cross-talk in the resistance to HER family receptor targeted therapy[J].Oncogene,2014,33(9):1073-1081.
[45]Catenacci DV,Liao WL,Thyparambil S,et al.Absolute quantitation of M et using mass spectrometry for clinical application:assay precision,stability,and correlation w ith M ET gene amplification in FFPE tumor tissue[J].PLo S One,2014,9(7):e100586.
[46]Jardim DL,Tang C,Gagliato Dde M,et al.Analysis of 1,115patients tested for M ET amplification and therapy response in the M D Anderson Phase I Clinic[J].Clin Cancer Res,2014,20(24):6336-6345.
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