Current and emerging therapies in unresectable and recurrent gastric cancer
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摘要
Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confersonly a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.
Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confersonly a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.
Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confersonly a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.
引文
1 Siegel R,Ma J,Zou Z,Jemal A.Cancer statistics,2014.CACancer J Clin 2014;64:9-29[PMID:24399786 DOI:10.3322/caac.21208]
2 Jemal A,Bray F,Center MM,Ferlay J,Ward E,Forman D.Global cancer statistics.CA Cancer J Clin 2011;61:69-90[PMID:21296855 DOI:10.3322/caac.20107]
3 Ferlay J,Shin HR,Bray F,Forman D,Mathers C,Parkin DM.Estimates of worldwide burden of cancer in 2008:GLOBOCAN2008.Int J Cancer 2010;127:2893-2917[PMID:21351269 DOI:10.1002/ijc.25516]
4 Cunningham D,O kines A F,Ashley S.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl JMed 2010;362:858-859[PMID:20200397 DOI:10.1056/NEJMc0911925]
5 Kamangar F,Dores GM,Anderson WF.Patterns of cancer incidence,mortality,and prevalence across five continents:defining priorities to reduce cancer disparities in different geographic regions of the world.J Clin Oncol 2006;24:2137-2150[PMID:16682732 DOI:10.1200/JCO.2005.05.2308]
6 Wagner AD,Grothe W,Haerting J,Kleber G,Grothey A,Fleig WE.Chemotherapy in advanced gastric cancer:a systematic review and meta-analysis based on aggregate data.J Clin Oncol 2006;24:2903-2909[PMID:16782930 DOI:10.1200/JCO.2005.05.0245]
7 Van Cutsem E,Moiseyenko VM,Tjulandin S,Majlis A,Constenla M,Boni C,Rodrigues A,Fodor M,Chao Y,Voznyi E,Risse ML,Ajani JA.Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer:a report of the V325 Study Group.J Clin Oncol 2006;24:4991-4997[PMID:17075117 DOI:10.1200/JCO.2006.06.8429]
8 Al-Batran SE,Hartmann JT,Probst S,Schmalenberg H,Hollerbach S,Hofheinz R,Rethwisch V,Seipelt G,Homann N,Wilhelm G,Schuch G,Stoehlmacher J,Derigs HG,HegewischBecker S,Grossmann J,Pauligk C,Atmaca A,Bokemeyer C,Knuth A,J?ger E.Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil,leucovorin plus either oxaliplatin or cisplatin:a study of the Arbeitsgemeinschaft Internistische Onkologie.J Clin Oncol 2008;26:1435-1442[PMID:18349393 DOI:10.1200/JCO.2007.13.9378]
9 Cunningham D,Starling N,Rao S,Iveson T,Nicolson M,Coxon F,Middleton G,Daniel F,Oates J,Norman AR.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med 2008;358:36-46[PMID:18172173 DOI:10.1056/NEJMoa073149]
10 Kang YK,Kang WK,Shin DB,Chen J,Xiong J,Wang J,Lichinitser M,Guan Z,Khasanov R,Zheng L,Philco-Salas M,Suarez T,Santamaria J,Forster G,Mc Cloud PI.Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer:a randomised phase III noninferiority trial.Ann Oncol 2009;20:666-673[PMID:19153121 DOI:10.1093/annonc/mdn717]
11 Koizumi W,Narahara H,Hara T,Takagane A,Akiya T,Takagi M,Miyashita K,Nishizaki T,Kobayashi O,Takiyama W,Toh Y,Nagaie T,Takagi S,Yamamura Y,Yanaoka K,Orita H,Takeuchi M.S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer(SPIRITS trial):a phase III trial.Lancet Oncol 2008;9:215-221[PMID:18282805 DOI:10.1016/S1470-2045(08)70035-4]
12 Ajani JA,Rodriguez W,Bodoky G,Moiseyenko V,Lichinitser M,Gorbunova V,Vynnychenko I,Garin A,Lang I,Falcon S.Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study:the FLAGS trial.J Clin Oncol 2010;28:1547-1553[PMID:20159816 DOI:10.1200/JCO.2009.25.4706]
13 Dank M,Zaluski J,Barone C,Valvere V,Yalcin S,Peschel C,Wenczl M,Goker E,Cisar L,Wang K,Bugat R.Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction.Ann Oncol 2008;19:1450-1457[PMID:18558665 DOI:10.1093/annonc/mdn166]
14 Guimbaud R,Louvet C,Ries P,Ychou M,Maillard E,AndréT,Gornet JM,Aparicio T,Nguyen S,Azzedine A,Etienne PL,Boucher E,Rebischung C,Hammel P,Rougier P,Bedenne L,BouchéO.Prospective,randomized,multicenter,phase III study of fluorouracil,leucovorin,and irinotecan versus epirubicin,cisplatin,and capecitabine in advanced gastric adenocarcinoma:a French intergroup(Fédération Francophone de Cancérologie Digestive,Fédération Nationale des Centres de Lutte Contre le Cancer,and Groupe Coopérateur Multidisciplinaire en Oncologie)study.JClin Oncol 2014;32:3520-3526[PMID:25287828 DOI:10.1200/JCO.2013.54.1011]
15 Ford HE,Marshall A,Bridgewater JA,Janowitz T,Coxon FY,Wadsley J,Mansoor W,Fyfe D,Madhusudan S,Middleton GW,Swinson D,Falk S,Chau I,Cunningham D,Kareclas P,Cook N,Blazeby JM,Dunn JA.Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma(COUGAR-02):an open-label,phase 3 randomised controlled trial.Lancet Oncol 2014;15:78-86[PMID:24332238 DOI:10.1016/S1470-2045(13)70549-7]
16 Kang JH,Lee SI,Lim do H,Park KW,Oh SY,Kwon HC,Hwang IG,Lee SC,Nam E,Shin DB,Lee J,Park JO,Park YS,Lim HY,Kang WK,Park SH.Salvage chemotherapy for pretreated gastric cancer:a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.J Clin Oncol 2012;30:1513-1518[PMID:22412140 DOI:10.1200/JCO.2011.39.4585]
17 Thuss-Patience PC,Kretzschmar A,Bichev D,Deist T,Hinke A,Breithaupt K,Dogan Y,Gebauer B,Schumacher G,Reichardt P.Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie(AIO).Eur J Cancer 2011;47:2306-2314[PMID:21742485 DOI:10.1016/j.ejca.2011.06.002]
18 Hironaka S,Ueda S,Yasui H,Nishina T,Tsuda M,Tsumura T,Sugimoto N,Shimodaira H,Tokunaga S,Moriwaki T,Esaki T,Nagase M,Fujitani K,Yamaguchi K,Ura T,Hamamoto Y,Morita S,Okamoto I,Boku N,Hyodo I.Randomized,open-label,phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum:WJOG 4007 trial.J Clin Oncol 2013;31:4438-4444[PMID:24190112 DOI:10.1200/JCO.2012.48.5805]
19 Cancer Genome Atlas Research Network.Comprehensive molecular characterization of gastric adenocarcinoma.Nature2014;513:202-209[PMID:25079317 DOI:10.1038/nature13480]
20 Hsieh AC,Moasser MM.Targeting HER proteins in cancer therapy and the role of the non-target HER3.Br J Cancer 2007;97:453-457[PMID:17667926 DOI:10.1038/sj.bjc.6603910]
21 Okines A,Cunningham D,Chau I.Targeting the human EGFRfamily in esophagogastric cancer.Nat Rev Clin Oncol 2011;8:492-503[PMID:21468131 DOI:10.1038/nrclinonc.2011.45]
22 Li SG,Li L.Targeted therapy in HER2-positive breast cancer.Biomed Rep 2013;1:499-505[PMID:24648975 DOI:10.3892/br.2013.95]
23 Gravalos C,Jimeno A.HER2 in gastric cancer:a new prognostic factor and a novel therapeutic target.Ann Oncol 2008;19:1523-1529[PMID:18441328 DOI:10.1093/annonc/mdn169]
24 Yano T,Doi T,Ohtsu A,Boku N,Hashizume K,Nakanishi M,Ochiai A.Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer.Oncol Rep2006;15:65-71[PMID:16328035 DOI:10.3892/or.15.1.65]
25 Sheng WQ,Huang D,Ying JM,Lu N,Wu HM,Liu YH,Liu JP,Bu H,Zhou XY,Du X.HER2 status in gastric cancers:a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance.Ann Oncol2013;24:2360-2364[PMID:23788757 DOI:10.1093/annonc/mdt232]
26 Carey LA,Perou CM,Livasy CA,Dressler LG,Cowan D,Conway K,Karaca G,Troester MA,Tse CK,Edmiston S,Deming SL,Geradts J,Cheang MC,Nielsen TO,Moorman PG,Earp HS,Millikan RC.Race,breast cancer subtypes,and survival in the Carolina Breast Cancer Study.JAMA 2006;295:2492-2502[PMID:16757721 DOI:10.1001/jama.295.21.2492]
27 Hofmann M,Stoss O,Shi D,Büttner R,van de Vijver M,Kim W,Ochiai A,Rüschoff J,Henkel T.Assessment of a HER2scoring system for gastric cancer:results from a validation study.Histopathology 2008;52:797-805[PMID:18422971 DOI:10.1111/j.1365-2559.2008.03028.x]
28 Bang YJ,Van Cutsem E,Feyereislova A,Chung HC,Shen L,Sawaki A,Lordick F,Ohtsu A,Omuro Y,Satoh T,Aprile G,Kulikov E,Hill J,Lehle M,Rüschoff J,Kang YK.Trastuzumab in combination with 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.Lancet 2010;376:687-697[PMID:20728210DOI:10.1016/S0140-6736(10)61121-X]
29 Hecht JR,Bang YJ,Qin SK,Chung HC,Xu JM,Park JO,Jeziorski K,Shparyk Y,Hoff PM,Sobrero A,Salman P,Li J,Protsenko SA,Wainberg ZA,Buyse M,Afenjar K,HouéV,Garcia A,Kaneko T,Huang Y,Khan-Wasti S,Santillana S,Press MF,Slamon D.Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor2-Positive Advanced or Metastatic Gastric,Esophageal,or Gastroesophageal Adenocarcinoma:TRIO-013/LOGi C-ARandomized Phase III Trial.J Clin Oncol 2016;34:443-451[PMID:26628478 DOI:10.1200/JCO.2015.62.6598]
30 Satoh T,Xu RH,Chung HC,Sun GP,Doi T,Xu JM,Tsuji A,Omuro Y,Li J,Wang JW,Miwa H,Qin SK,Chung IJ,Yeh KH,Feng JF,Mukaiyama A,Kobayashi M,Ohtsu A,Bang YJ.Lapatinib plus paclitaxel versus paclitaxel alone in the secondline treatment of HER2-amplified advanced gastric cancer in Asian populations:Ty TAN--a randomized,phase III study.J Clin Oncol 2014;32:2039-2049[PMID:24868024 DOI:10.1200/JCO.2013.53.6136]
31 Kang YK,Shah MA,Ohtsu A,Van Cutsem E,Ajani JA,van der Horst T,Harle-Yge M,Piao Y,Althaus B,Thuss-Patience PC.Arandomized,open-label,multicenter,adaptive phase 2/3 study of trastuzumab emtansine(T-DM1)versus a taxane(TAX)in patients(pts)with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma(LA/MGC/GEJC).J Clin Oncol 2016;34:5
32 Herbst RS.Review of epidermal growth factor receptor biology.Int J Radiat Oncol Biol Phys 2004;59:21-26[PMID:15142631]
33 Oda K,Matsuoka Y,Funahashi A,Kitano H.A comprehensive pathway map of epidermal growth factor receptor signaling.Mol Syst Biol 2005;1:2005.0010[PMID:16729045 DOI:10.1038/msb4100014]
34 Wang KL,Wu TT,Choi IS,Wang H,Resetkova E,Correa AM,Hofstetter WL,Swisher SG,Ajani JA,Rashid A,Albarracin CT.Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas:association with poor outcome.Cancer 2007;109:658-667[PMID:17211865 DOI:10.1002/cncr.22445]
35 Lieto E,Ferraraccio F,Orditura M,Castellano P,Mura AL,Pinto M,Zamboli A,De Vita F,Galizia G.Expression of vascular endothelial growth factor(VEGF)and epidermal growth factor receptor(EGFR)is an independent prognostic indicator of worse outcome in gastric cancer patients.Ann Surg Oncol 2008;15:69-79[PMID:17896140 DOI:10.1245/s10434-007-9596-0]
36 Lordick F,Kang YK,Chung HC,Salman P,Oh SC,Bodoky G,Kurteva G,Volovat C,Moiseyenko VM,Gorbunova V,Park JO,Sawaki A,Celik I,G?tte H,MelezínkováH,Moehler M.Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer(EXPAND):a randomised,open-label phase 3 trial.Lancet Oncol 2013;14:490-499[PMID:23594786]
37 Waddell T,Chau I,Cunningham D,Gonzalez D,Okines AF,Okines C,Wotherspoon A,Saffery C,Middleton G,Wadsley J,Ferry D,Mansoor W,Crosby T,Coxon F,Smith D,Waters J,Iveson T,Falk S,Slater S,Peckitt C,Barbachano Y.Epirubicin,oxaliplatin,and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer(REAL3):a randomised,open-label phase 3 trial.Lancet Oncol 2013;14:481-489[PMID:23594787 DOI:10.1016/S1470-2045(13)70096-2]
38 Ferrara N,Gerber HP,Le Couter J.The biology of VEGF and its receptors.Nat Med 2003;9:669-676[PMID:12778165 DOI:10.1038/nm0603-669]
39 Prins MJ,Verhage RJ,ten Kate FJ,van Hillegersberg R.Cyclooxygenase isoenzyme-2 and vascular endothelial growth f a c t o r a r e a s s o c i a t e d w i t h p o o r p r o g n o s i s i n e s o p h a g e a l adenocarcinoma.J Gastrointest Surg 2012;16:956-966[PMID:22258871 DOI:10.1007/s11605-011-1814-1]
40 Shi H,Xu JM,Hu NZ,Xie HJ.Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma.World J Gastroenterol 2003;9:1421-1426[PMID:12854133 DOI:10.3748/wjg.v9.i7.1421]
41 Ohtsu A,Shah MA,Van Cutsem E,Rha SY,Sawaki A,Park SR,Lim HY,Yamada Y,Wu J,Langer B,Starnawski M,Kang YK.Bevacizumab in combination with chemotherapy as firstline therapy in advanced gastric cancer:a randomized,doubleblind,placebo-controlled phase III study.J Clin Oncol 2011;29:3968-3976[PMID:21844504]
42 Shen L,Li J,Xu J,Pan H,Dai G,Qin S,Wang L,Wang J,Yang Z,Shu Y,Xu R,Chen L,Liu Y,Yu S,Bu L,Piao Y.Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer:randomized,double-blind,phase III study(AVATARstudy).Gastric Cancer 2015;18:168-176[PMID:24557418 DOI:10.1007/s10120-014-0351-5]
43 Fuchs CS,Tomasek J,Yong CJ,Dumitru F,Passalacqua R,Goswami C,Safran H,dos Santos LV,Aprile G,Ferry DR,Melichar B,Tehfe M,Topuzov E,Zalcberg JR,Chau I,Campbell W,Sivanandan C,Pikiel J,Koshiji M,Hsu Y,Liepa AM,Gao L,Schwartz JD,Tabernero J.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(REGARD):an international,randomised,multicentre,placebo-controlled,phase 3 trial.Lancet 2014;383:31-39[PMID:24094768 DOI:10.1016/S0140-6736(13)61719-5]
44 Wilke H,Van Cutsem E,Oh SC,Bodoky G,Shimada Y,Hironaka S,Sugimoto N,Lipatov ON,Kim TY,Cunningham D,Ohtsu A,Rougier P,Emig M,Carlesi R,Chandrawansa K,Muro K.RAINBOW:A global,phase 3,randomized,double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum-and fluoropyrimidine-containing combination therapy:Results of a multiple Cox regression analysis adjusting for prognostic factors.J Clin Oncol 2014;32:4076
45 Wilke H,Muro K,Van Cutsem E,Oh SC,Bodoky G,Shimada Y,Hironaka S,Sugimoto N,Lipatov O,Kim TY,Cunningham D,Rougier P,Komatsu Y,Ajani J,Emig M,Carlesi R,Ferry D,Chandrawansa K,Schwartz JD,Ohtsu A.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(RAINBOW):a double-blind,randomised phase3 trial.Lancet Oncol 2014;15:1224-1235[PMID:25240821 DOI:10.1016/S1470-2045(14)70420-6]
46 Yoon HH,Bendell JC,Braiteh FS,Firdaus I,Philip PA,Cohn AL,Lewis N,Anderson DM,Arrowsmith E,Schwartz JD,Xu Y,Koshiji M,Alberts SR,Wainberg ZA.Ramucirumab(RAM)plus FOLFOX as front-line therapy(Rx)for advanced gastric or esophageal adenocarcinoma(GE-AC):Randomized,double-blind,multicenter phase 2 trial.J Clin Oncol 2014;32:4004
47 Qin S.Phase III study of apatinib in advanced gastric cancer:Arandomized,double-blind,placebo-controlled trial.J Clin Oncol2014;32:4003
48 Bang YJ,Kang YK,Kang WK,Boku N,Chung HC,Chen JS,Doi T,Sun Y,Shen L,Qin S,Ng WT,Tursi JM,Lechuga MJ,Lu DR,Ruiz-Garcia A,Sobrero A.Phase II study of sunitinib as secondline treatment for advanced gastric cancer.Invest New Drugs 2011;29:1449-1458[PMID:20461441 DOI:10.1007/s10637-010-9438-y]
49 Moehler MH,Thuss-Patience PC,Schmoll HJ,HegewischBecker S,Wilke H,Al-Batran SE,Weissinger F,Kullmann F,Fischer Von Weikersthal L,Siveke JT,Kanzler S,Schimanski CC,Otte M,Schollenberger L,Koenig J,Galle PR.FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients:a randomized placebo-controlled multicentric AIO phase II trial.J Clin Oncol 2013;31:4086
50 Sun W,Powell M,O’Dwyer PJ,Catalano P,Ansari RH,Benson AB.Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma:ECOG 5203.JClin Oncol 2010;28:2947-2951[PMID:20458043 DOI:10.1200/JCO.2009.27.7988]
51 Martin-Richard M,Gallego R,Pericay C,Garcia Foncillas J,Queralt B,Casado E,Barriuso J,Iranzo V,Juez I,Visa L,Saigi E,Barnadas A,Garcia-Albeniz X,Maurel J.Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment.A GEMCAD study.Invest New Drugs 2013;31:1573-1579[PMID:24077981 DOI:10.1007/s10637-013-0020-2]
52 Thuss-Patience PC,Al-Batran SE,Siveke JT,Homann N,Malfertheiner P,Glaeser D,Stein A,Tamm I,Daum S,Potenberg J,Florschütz A,Vogel A,Ridwelski K,Ritgen M,Geissler M,Schmalenberg H,Schlattmann P,Lorenz M,Breithaupt K,Pichlmeier U.Pazopanib and 5-FU/oxaliplatin as first-line treatment in advanced gastric cancer:Pa FLO,a randomized phase II study from the AIO(Arbeitsgemeinschaft Internistische Onkologie).J Clin Oncol 2015;33:4033
53 Pavlakis N,Sjoquist KM,Tsobanis E,Martin AJ,Kang YK,Bang YJ,O’Callaghan CJ,Tebbutt NC,Rha SY,Lee J,Cho JY,Lipton LR,Burnell MJ,Alcindor T,Strickland A,Kim JW,Yip S,Simes J,Zalcberg JR,Goldstein D.INTEGRATE:A randomized,phase II,double-blind,placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer(AOGC):A study by the Australasian Gastrointestinal Trials Group(AGITG)-Final overall and subgroup results.J Clin Oncol 2015;33:4003
54 Guertin DA,Sabatini DM.Defining the role of m TOR in cancer.Cancer Cell 2007;12:9-22[PMID:17613433 DOI:10.1016/j.ccr.2007.05.008]
55 Bjornsti MA,Houghton PJ.The TOR pathway:a target for cancer therapy.Nat Rev Cancer 2004;4:335-348[PMID:15122205 DOI:10.1038/nrc1362]
56 Shi J,Yao D,Liu W,Wang N,Lv H,He N,Shi B,Hou P,Ji M.Frequent gene amplification predicts poor prognosis in gastric cancer.Int J Mol Sci 2012;13:4714-4726[PMID:22606006 DOI:10.3390/ijms13044714]
57 Yu HG,Ai YW,Yu LL,Zhou XD,Liu J,Li JH,Xu XM,Liu S,Chen J,Liu F,Qi YL,Deng Q,Cao J,Liu SQ,Luo HS,Yu JP.Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death.Int J Cancer 2008;122:433-443[PMID:17935137 DOI:10.1002/ijc.23049]
58 Ohtsu A,Ajani JA,Bai YX,Bang YJ,Chung HC,Pan HM,Sahmoud T,Shen L,Yeh KH,Chin K,Muro K,Kim YH,Ferry D,Tebbutt NC,Al-Batran SE,Smith H,Costantini C,Rizvi S,Lebwohl D,Van Cutsem E.Everolimus for previously treated advanced gastric cancer:results of the randomized,double-blind,phase III GRANITE-1 study.J Clin Oncol 2013;31:3935-3943[PMID:24043745 DOI:10.1200/JCO.2012.48.3552]
59 Gherardi E,Birchmeier W,Birchmeier C,Vande Woude G.Targeting MET in cancer:rationale and progress.Nat Rev Cancer2012;12:89-103[PMID:22270953 DOI:10.1038/nrc3205]
60 Yashiro M,Nishii T,Hasegawa T,Matsuzaki T,Morisaki T,Fukuoka T,Hirakawa K.A c-Met inhibitor increases the chemosensitivity of cancer stem cells to the irinotecan in gastric carcinoma.Br J Cancer 2013;109:2619-2628[PMID:24129235DOI:10.1038/bjc.2013.638]
61 Nakajima M,Sawada H,Yamada Y,Watanabe A,Tatsumi M,Yamashita J,Matsuda M,Sakaguchi T,Hirao T,Nakano H.The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas.Cancer 1999;85:1894-1902[PMID:10223227]
62 Graziano F,Galluccio N,Lorenzini P,Ruzzo A,Canestrari E,D’Emidio S,Catalano V,Sisti V,Ligorio C,Andreoni F,Rulli E,Di Oto E,Fiorentini G,Zingaretti C,De Nictolis M,Cappuzzo F,Magnani M.Genetic activation of the MET pathway and prognosis of patients with high-risk,radically resected gastric cancer.J Clin Oncol 2011;29:4789-4795[PMID:22042954 DOI:10.1200/JCO.2011.36.7706]
63 Lennerz JK,Kwak EL,Ackerman A,Michael M,Fox SB,Bergethon K,Lauwers GY,Christensen JG,Wilner KD,Haber DA,Salgia R,Bang YJ,Clark JW,Solomon BJ,Iafrate AJ.MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.J Clin Oncol 2011;29:4803-4810[PMID:22042947DOI:10.1200/JCO.2011.35.4928]
64 Oliner KS,Tang R,Anderson A,Lan Y,Iveson T,Donehower RC,Jiang Y,Dubey S,Loh E.Evaluation of MET pathway biomarkers in a phase II study of rilotumumab(R,AMG 102)or placebo(P)in combination with epirubicin,cisplatin,and capecitabine(ECX)in patients(pts)with locally advanced or metastatic gastric(G)or esophagogastric junction(EGJ)cancer.J Clin Oncol 2012;30:4005
65 Iveson T,Donehower RC,Davidenko I,Tjulandin S,Deptala A,Harrison M,Nirni S,Lakshmaiah K,Thomas A,Jiang Y,Zhu M,Tang R,Anderson A,Dubey S,Oliner KS,Loh E.Rilotumumab in combination with 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.Lancet Oncol 2014;15:1007-1018[PMID:24965569 DOI:10.1016/S1470-2045(14)70023-3]
66 Cunningham D,Tebbutt NC,Davidenko I,Murad AM,AlBatran SE,Ilson DH,Tjulandin S,Gotovkin E,Karaszewska B,Bondarenko I,Tejani MA,Udrea AA,Tehfe MA,Baker N,Oliner KS,Zhang Y,Hoang T,Sidhu R,Catenacci DVT.Phase III,randomized,double-blind,multicenter,placebo(P)-controlled trial of rilotumumab(R)plus epirubicin,cisplatin and capecitabine(ECX)as first-line therapy in patients(pts)with advanced MET-positive(pos)gastric or gastroesophageal junction(G/GEJ)cancer:RILOMET-1 study.J Clin Oncol 2015;33:4000
67 Shah MA,Cho JY,Huat ITB,Tebbutt NC,Yen CJ,Kang A,Shames DS,Bu L,Kang YK.Randomized Phase II Study of FOLFOX/-MET Inhibitor,Onartuzumab(O),in Advanced Gastroesophageal Adenocarcinoma(GEC).J Clin Oncol 2015;33:2
68 Shah MA,Bang YJ,Lordick F,Tabernero J,Chen M,Hack SP,Phan SC,Shames DS,Cunningham D.METGastric:A phase III study of onartuzumab plus m FOLFOX6 in patients with metastatic HER2-negative(HER2-)and MET-positive(MET)adenocarcinoma of the stomach or gastroesophageal junction(GEC).J Clin Oncol 2015;33:4012
69 Javle M,Curtin NJ.The role of PARP in DNA repair and its therapeutic exploitation.Br J Cancer 2011;105:1114-1122[PMID:21989215 DOI:10.1038/bjc.2011.382]
70 Rouleau M,Patel A,Hendzel MJ,Kaufmann SH,Poirier GG.PARP inhibition:PARP1 and beyond.Nat Rev Cancer 2010;10:293-301[PMID:20200537 DOI:10.1038/nrc2812]
71 Bang YJ,Im SA,Lee KW,Cho JY,Song EK,Lee KH,Kim YH,Park JO,Chun HG,Zang DY,Fielding A,Rowbottom J,Hodgson D,O’Connor MJ,Yin X,Kim WH.Randomized,Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.J Clin Oncol 2015;33:3858-3865[PMID:26282658 DOI:10.1200/JCO.2014.60.0320]
72 Dunn GP,Bruce AT,Ikeda H,Old LJ,Schreiber RD.Cancer immunoediting:from immunosurveillance to tumor escape.Nat Immunol 2002;3:991-998[PMID:12407406 DOI:10.1038/ni1102-991]
73 Schreiber RD,Old LJ,Smyth MJ.Cancer immunoediting:integrating immunity’s roles in cancer suppression and promotion.Science 2011;331:1565-1570[PMID:21436444 DOI:10.1126/science.1203486]
74 Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer 2012;12:252-264[PMID:22437870 DOI:10.1038/nrc3239]
75 Hodi FS,O’Day SJ,Mc Dermott DF,Weber RW,Sosman JA,Haanen JB,Gonzalez R,Robert C,Schadendorf D,Hassel JC,Akerley W,van den Eertwegh AJ,Lutzky J,Lorigan P,Vaubel JM,Linette GP,Hogg D,Ottensmeier CH,LebbéC,Peschel C,Quirt I,Clark JI,Wolchok JD,Weber JS,Tian J,Yellin MJ,Nichol GM,Hoos A,Urba WJ.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med 2010;363:711-723[PMID:20525992 DOI:10.1056/NEJMoa1003466]
76 Ralph C,Elkord E,Burt DJ,O’Dwyer JF,Austin EB,Stern PL,Hawkins RE,Thistlethwaite FC.Modulation of lymphocyte regulation for cancer therapy:a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma.Clin Cancer Res2010;16:1662-1672[PMID:20179239 DOI:10.1158/1078-0432.CCR-09-2870]
77 Muro K,Bang Y,Shankaran V,Geva R,Catenacci DVT,Gupta S,Eder JP,Berger R,Gonzalez EJ,Pulini J,Ray AB,Dolled-Filhart M,Emancipator K,Pathiraja K,Shu X,Koshiji MR,Cheng J,Chung HC.LBA15 A phase 1b study of pembrolizumab(PEMBRO;MK-3475)in patients(PTS)with advanced gastric cancer.Ann Oncol 2014;25:v1-v41[DOI:10.1093/annonc/mdu438.15]
78 Muro K,Bang YJ,Shankaran V,Geva R,Catenacci DVT,Gupta S,Eder JP,Berger R,Gonzalez EJ,Ray A,Dolled-Filhart M,Emancipator K,Pathiraja K,Lunceford JK,Cheng JD,Koshiji M,Chung HC.Relationship between PD-L1 expression and clinical outcomes in patients(Pts)with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab(Pembro;MK-3475)in KEYNOTE-012.J Clin Oncol 2015;33:3
79 Le DT,Uram JN,Wang H,Bartlett BR,Kemberling H,Eyring AD,Skora AD,Luber BS,Azad NS,Laheru D,Biedrzycki B,Donehower RC,Zaheer A,Fisher GA,Crocenzi TS,Lee JJ,Duffy SM,Goldberg RM,de la Chapelle A,Koshiji M,Bhaijee F,Huebner T,Hruban RH,Wood LD,Cuka N,Pardoll DM,Papadopoulos N,Kinzler KW,Zhou S,Cornish TC,Taube JM,Anders RA,Eshleman JR,Vogelstein B,Diaz LA.PD-1Blockade in Tumors with Mismatch-Repair Deficiency.N Engl J Med 2015;372:2509-2520[PMID:26028255 DOI:10.1056/NEJMoa1500596]
80 Lutzky J,Antonia SJ,Blake-Haskins A,Li X,Robbins PB,Shalabi AM,Vasselli J,Ibrahim RA,Khleif S,Segal NH.A phase1 study of MEDI4736,an anti-PD-L1 antibody,in patients with advanced solid tumors.J Clin Oncol 2014;32:3001
2 Jemal A,Bray F,Center MM,Ferlay J,Ward E,Forman D.Global cancer statistics.CA Cancer J Clin 2011;61:69-90[PMID:21296855 DOI:10.3322/caac.20107]
3 Ferlay J,Shin HR,Bray F,Forman D,Mathers C,Parkin DM.Estimates of worldwide burden of cancer in 2008:GLOBOCAN2008.Int J Cancer 2010;127:2893-2917[PMID:21351269 DOI:10.1002/ijc.25516]
4 Cunningham D,O kines A F,Ashley S.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl JMed 2010;362:858-859[PMID:20200397 DOI:10.1056/NEJMc0911925]
5 Kamangar F,Dores GM,Anderson WF.Patterns of cancer incidence,mortality,and prevalence across five continents:defining priorities to reduce cancer disparities in different geographic regions of the world.J Clin Oncol 2006;24:2137-2150[PMID:16682732 DOI:10.1200/JCO.2005.05.2308]
6 Wagner AD,Grothe W,Haerting J,Kleber G,Grothey A,Fleig WE.Chemotherapy in advanced gastric cancer:a systematic review and meta-analysis based on aggregate data.J Clin Oncol 2006;24:2903-2909[PMID:16782930 DOI:10.1200/JCO.2005.05.0245]
7 Van Cutsem E,Moiseyenko VM,Tjulandin S,Majlis A,Constenla M,Boni C,Rodrigues A,Fodor M,Chao Y,Voznyi E,Risse ML,Ajani JA.Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer:a report of the V325 Study Group.J Clin Oncol 2006;24:4991-4997[PMID:17075117 DOI:10.1200/JCO.2006.06.8429]
8 Al-Batran SE,Hartmann JT,Probst S,Schmalenberg H,Hollerbach S,Hofheinz R,Rethwisch V,Seipelt G,Homann N,Wilhelm G,Schuch G,Stoehlmacher J,Derigs HG,HegewischBecker S,Grossmann J,Pauligk C,Atmaca A,Bokemeyer C,Knuth A,J?ger E.Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil,leucovorin plus either oxaliplatin or cisplatin:a study of the Arbeitsgemeinschaft Internistische Onkologie.J Clin Oncol 2008;26:1435-1442[PMID:18349393 DOI:10.1200/JCO.2007.13.9378]
9 Cunningham D,Starling N,Rao S,Iveson T,Nicolson M,Coxon F,Middleton G,Daniel F,Oates J,Norman AR.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med 2008;358:36-46[PMID:18172173 DOI:10.1056/NEJMoa073149]
10 Kang YK,Kang WK,Shin DB,Chen J,Xiong J,Wang J,Lichinitser M,Guan Z,Khasanov R,Zheng L,Philco-Salas M,Suarez T,Santamaria J,Forster G,Mc Cloud PI.Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer:a randomised phase III noninferiority trial.Ann Oncol 2009;20:666-673[PMID:19153121 DOI:10.1093/annonc/mdn717]
11 Koizumi W,Narahara H,Hara T,Takagane A,Akiya T,Takagi M,Miyashita K,Nishizaki T,Kobayashi O,Takiyama W,Toh Y,Nagaie T,Takagi S,Yamamura Y,Yanaoka K,Orita H,Takeuchi M.S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer(SPIRITS trial):a phase III trial.Lancet Oncol 2008;9:215-221[PMID:18282805 DOI:10.1016/S1470-2045(08)70035-4]
12 Ajani JA,Rodriguez W,Bodoky G,Moiseyenko V,Lichinitser M,Gorbunova V,Vynnychenko I,Garin A,Lang I,Falcon S.Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study:the FLAGS trial.J Clin Oncol 2010;28:1547-1553[PMID:20159816 DOI:10.1200/JCO.2009.25.4706]
13 Dank M,Zaluski J,Barone C,Valvere V,Yalcin S,Peschel C,Wenczl M,Goker E,Cisar L,Wang K,Bugat R.Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction.Ann Oncol 2008;19:1450-1457[PMID:18558665 DOI:10.1093/annonc/mdn166]
14 Guimbaud R,Louvet C,Ries P,Ychou M,Maillard E,AndréT,Gornet JM,Aparicio T,Nguyen S,Azzedine A,Etienne PL,Boucher E,Rebischung C,Hammel P,Rougier P,Bedenne L,BouchéO.Prospective,randomized,multicenter,phase III study of fluorouracil,leucovorin,and irinotecan versus epirubicin,cisplatin,and capecitabine in advanced gastric adenocarcinoma:a French intergroup(Fédération Francophone de Cancérologie Digestive,Fédération Nationale des Centres de Lutte Contre le Cancer,and Groupe Coopérateur Multidisciplinaire en Oncologie)study.JClin Oncol 2014;32:3520-3526[PMID:25287828 DOI:10.1200/JCO.2013.54.1011]
15 Ford HE,Marshall A,Bridgewater JA,Janowitz T,Coxon FY,Wadsley J,Mansoor W,Fyfe D,Madhusudan S,Middleton GW,Swinson D,Falk S,Chau I,Cunningham D,Kareclas P,Cook N,Blazeby JM,Dunn JA.Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma(COUGAR-02):an open-label,phase 3 randomised controlled trial.Lancet Oncol 2014;15:78-86[PMID:24332238 DOI:10.1016/S1470-2045(13)70549-7]
16 Kang JH,Lee SI,Lim do H,Park KW,Oh SY,Kwon HC,Hwang IG,Lee SC,Nam E,Shin DB,Lee J,Park JO,Park YS,Lim HY,Kang WK,Park SH.Salvage chemotherapy for pretreated gastric cancer:a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.J Clin Oncol 2012;30:1513-1518[PMID:22412140 DOI:10.1200/JCO.2011.39.4585]
17 Thuss-Patience PC,Kretzschmar A,Bichev D,Deist T,Hinke A,Breithaupt K,Dogan Y,Gebauer B,Schumacher G,Reichardt P.Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie(AIO).Eur J Cancer 2011;47:2306-2314[PMID:21742485 DOI:10.1016/j.ejca.2011.06.002]
18 Hironaka S,Ueda S,Yasui H,Nishina T,Tsuda M,Tsumura T,Sugimoto N,Shimodaira H,Tokunaga S,Moriwaki T,Esaki T,Nagase M,Fujitani K,Yamaguchi K,Ura T,Hamamoto Y,Morita S,Okamoto I,Boku N,Hyodo I.Randomized,open-label,phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum:WJOG 4007 trial.J Clin Oncol 2013;31:4438-4444[PMID:24190112 DOI:10.1200/JCO.2012.48.5805]
19 Cancer Genome Atlas Research Network.Comprehensive molecular characterization of gastric adenocarcinoma.Nature2014;513:202-209[PMID:25079317 DOI:10.1038/nature13480]
20 Hsieh AC,Moasser MM.Targeting HER proteins in cancer therapy and the role of the non-target HER3.Br J Cancer 2007;97:453-457[PMID:17667926 DOI:10.1038/sj.bjc.6603910]
21 Okines A,Cunningham D,Chau I.Targeting the human EGFRfamily in esophagogastric cancer.Nat Rev Clin Oncol 2011;8:492-503[PMID:21468131 DOI:10.1038/nrclinonc.2011.45]
22 Li SG,Li L.Targeted therapy in HER2-positive breast cancer.Biomed Rep 2013;1:499-505[PMID:24648975 DOI:10.3892/br.2013.95]
23 Gravalos C,Jimeno A.HER2 in gastric cancer:a new prognostic factor and a novel therapeutic target.Ann Oncol 2008;19:1523-1529[PMID:18441328 DOI:10.1093/annonc/mdn169]
24 Yano T,Doi T,Ohtsu A,Boku N,Hashizume K,Nakanishi M,Ochiai A.Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer.Oncol Rep2006;15:65-71[PMID:16328035 DOI:10.3892/or.15.1.65]
25 Sheng WQ,Huang D,Ying JM,Lu N,Wu HM,Liu YH,Liu JP,Bu H,Zhou XY,Du X.HER2 status in gastric cancers:a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance.Ann Oncol2013;24:2360-2364[PMID:23788757 DOI:10.1093/annonc/mdt232]
26 Carey LA,Perou CM,Livasy CA,Dressler LG,Cowan D,Conway K,Karaca G,Troester MA,Tse CK,Edmiston S,Deming SL,Geradts J,Cheang MC,Nielsen TO,Moorman PG,Earp HS,Millikan RC.Race,breast cancer subtypes,and survival in the Carolina Breast Cancer Study.JAMA 2006;295:2492-2502[PMID:16757721 DOI:10.1001/jama.295.21.2492]
27 Hofmann M,Stoss O,Shi D,Büttner R,van de Vijver M,Kim W,Ochiai A,Rüschoff J,Henkel T.Assessment of a HER2scoring system for gastric cancer:results from a validation study.Histopathology 2008;52:797-805[PMID:18422971 DOI:10.1111/j.1365-2559.2008.03028.x]
28 Bang YJ,Van Cutsem E,Feyereislova A,Chung HC,Shen L,Sawaki A,Lordick F,Ohtsu A,Omuro Y,Satoh T,Aprile G,Kulikov E,Hill J,Lehle M,Rüschoff J,Kang YK.Trastuzumab in combination with 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.Lancet 2010;376:687-697[PMID:20728210DOI:10.1016/S0140-6736(10)61121-X]
29 Hecht JR,Bang YJ,Qin SK,Chung HC,Xu JM,Park JO,Jeziorski K,Shparyk Y,Hoff PM,Sobrero A,Salman P,Li J,Protsenko SA,Wainberg ZA,Buyse M,Afenjar K,HouéV,Garcia A,Kaneko T,Huang Y,Khan-Wasti S,Santillana S,Press MF,Slamon D.Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor2-Positive Advanced or Metastatic Gastric,Esophageal,or Gastroesophageal Adenocarcinoma:TRIO-013/LOGi C-ARandomized Phase III Trial.J Clin Oncol 2016;34:443-451[PMID:26628478 DOI:10.1200/JCO.2015.62.6598]
30 Satoh T,Xu RH,Chung HC,Sun GP,Doi T,Xu JM,Tsuji A,Omuro Y,Li J,Wang JW,Miwa H,Qin SK,Chung IJ,Yeh KH,Feng JF,Mukaiyama A,Kobayashi M,Ohtsu A,Bang YJ.Lapatinib plus paclitaxel versus paclitaxel alone in the secondline treatment of HER2-amplified advanced gastric cancer in Asian populations:Ty TAN--a randomized,phase III study.J Clin Oncol 2014;32:2039-2049[PMID:24868024 DOI:10.1200/JCO.2013.53.6136]
31 Kang YK,Shah MA,Ohtsu A,Van Cutsem E,Ajani JA,van der Horst T,Harle-Yge M,Piao Y,Althaus B,Thuss-Patience PC.Arandomized,open-label,multicenter,adaptive phase 2/3 study of trastuzumab emtansine(T-DM1)versus a taxane(TAX)in patients(pts)with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma(LA/MGC/GEJC).J Clin Oncol 2016;34:5
32 Herbst RS.Review of epidermal growth factor receptor biology.Int J Radiat Oncol Biol Phys 2004;59:21-26[PMID:15142631]
33 Oda K,Matsuoka Y,Funahashi A,Kitano H.A comprehensive pathway map of epidermal growth factor receptor signaling.Mol Syst Biol 2005;1:2005.0010[PMID:16729045 DOI:10.1038/msb4100014]
34 Wang KL,Wu TT,Choi IS,Wang H,Resetkova E,Correa AM,Hofstetter WL,Swisher SG,Ajani JA,Rashid A,Albarracin CT.Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas:association with poor outcome.Cancer 2007;109:658-667[PMID:17211865 DOI:10.1002/cncr.22445]
35 Lieto E,Ferraraccio F,Orditura M,Castellano P,Mura AL,Pinto M,Zamboli A,De Vita F,Galizia G.Expression of vascular endothelial growth factor(VEGF)and epidermal growth factor receptor(EGFR)is an independent prognostic indicator of worse outcome in gastric cancer patients.Ann Surg Oncol 2008;15:69-79[PMID:17896140 DOI:10.1245/s10434-007-9596-0]
36 Lordick F,Kang YK,Chung HC,Salman P,Oh SC,Bodoky G,Kurteva G,Volovat C,Moiseyenko VM,Gorbunova V,Park JO,Sawaki A,Celik I,G?tte H,MelezínkováH,Moehler M.Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer(EXPAND):a randomised,open-label phase 3 trial.Lancet Oncol 2013;14:490-499[PMID:23594786]
37 Waddell T,Chau I,Cunningham D,Gonzalez D,Okines AF,Okines C,Wotherspoon A,Saffery C,Middleton G,Wadsley J,Ferry D,Mansoor W,Crosby T,Coxon F,Smith D,Waters J,Iveson T,Falk S,Slater S,Peckitt C,Barbachano Y.Epirubicin,oxaliplatin,and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer(REAL3):a randomised,open-label phase 3 trial.Lancet Oncol 2013;14:481-489[PMID:23594787 DOI:10.1016/S1470-2045(13)70096-2]
38 Ferrara N,Gerber HP,Le Couter J.The biology of VEGF and its receptors.Nat Med 2003;9:669-676[PMID:12778165 DOI:10.1038/nm0603-669]
39 Prins MJ,Verhage RJ,ten Kate FJ,van Hillegersberg R.Cyclooxygenase isoenzyme-2 and vascular endothelial growth f a c t o r a r e a s s o c i a t e d w i t h p o o r p r o g n o s i s i n e s o p h a g e a l adenocarcinoma.J Gastrointest Surg 2012;16:956-966[PMID:22258871 DOI:10.1007/s11605-011-1814-1]
40 Shi H,Xu JM,Hu NZ,Xie HJ.Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma.World J Gastroenterol 2003;9:1421-1426[PMID:12854133 DOI:10.3748/wjg.v9.i7.1421]
41 Ohtsu A,Shah MA,Van Cutsem E,Rha SY,Sawaki A,Park SR,Lim HY,Yamada Y,Wu J,Langer B,Starnawski M,Kang YK.Bevacizumab in combination with chemotherapy as firstline therapy in advanced gastric cancer:a randomized,doubleblind,placebo-controlled phase III study.J Clin Oncol 2011;29:3968-3976[PMID:21844504]
42 Shen L,Li J,Xu J,Pan H,Dai G,Qin S,Wang L,Wang J,Yang Z,Shu Y,Xu R,Chen L,Liu Y,Yu S,Bu L,Piao Y.Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer:randomized,double-blind,phase III study(AVATARstudy).Gastric Cancer 2015;18:168-176[PMID:24557418 DOI:10.1007/s10120-014-0351-5]
43 Fuchs CS,Tomasek J,Yong CJ,Dumitru F,Passalacqua R,Goswami C,Safran H,dos Santos LV,Aprile G,Ferry DR,Melichar B,Tehfe M,Topuzov E,Zalcberg JR,Chau I,Campbell W,Sivanandan C,Pikiel J,Koshiji M,Hsu Y,Liepa AM,Gao L,Schwartz JD,Tabernero J.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(REGARD):an international,randomised,multicentre,placebo-controlled,phase 3 trial.Lancet 2014;383:31-39[PMID:24094768 DOI:10.1016/S0140-6736(13)61719-5]
44 Wilke H,Van Cutsem E,Oh SC,Bodoky G,Shimada Y,Hironaka S,Sugimoto N,Lipatov ON,Kim TY,Cunningham D,Ohtsu A,Rougier P,Emig M,Carlesi R,Chandrawansa K,Muro K.RAINBOW:A global,phase 3,randomized,double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum-and fluoropyrimidine-containing combination therapy:Results of a multiple Cox regression analysis adjusting for prognostic factors.J Clin Oncol 2014;32:4076
45 Wilke H,Muro K,Van Cutsem E,Oh SC,Bodoky G,Shimada Y,Hironaka S,Sugimoto N,Lipatov O,Kim TY,Cunningham D,Rougier P,Komatsu Y,Ajani J,Emig M,Carlesi R,Ferry D,Chandrawansa K,Schwartz JD,Ohtsu A.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(RAINBOW):a double-blind,randomised phase3 trial.Lancet Oncol 2014;15:1224-1235[PMID:25240821 DOI:10.1016/S1470-2045(14)70420-6]
46 Yoon HH,Bendell JC,Braiteh FS,Firdaus I,Philip PA,Cohn AL,Lewis N,Anderson DM,Arrowsmith E,Schwartz JD,Xu Y,Koshiji M,Alberts SR,Wainberg ZA.Ramucirumab(RAM)plus FOLFOX as front-line therapy(Rx)for advanced gastric or esophageal adenocarcinoma(GE-AC):Randomized,double-blind,multicenter phase 2 trial.J Clin Oncol 2014;32:4004
47 Qin S.Phase III study of apatinib in advanced gastric cancer:Arandomized,double-blind,placebo-controlled trial.J Clin Oncol2014;32:4003
48 Bang YJ,Kang YK,Kang WK,Boku N,Chung HC,Chen JS,Doi T,Sun Y,Shen L,Qin S,Ng WT,Tursi JM,Lechuga MJ,Lu DR,Ruiz-Garcia A,Sobrero A.Phase II study of sunitinib as secondline treatment for advanced gastric cancer.Invest New Drugs 2011;29:1449-1458[PMID:20461441 DOI:10.1007/s10637-010-9438-y]
49 Moehler MH,Thuss-Patience PC,Schmoll HJ,HegewischBecker S,Wilke H,Al-Batran SE,Weissinger F,Kullmann F,Fischer Von Weikersthal L,Siveke JT,Kanzler S,Schimanski CC,Otte M,Schollenberger L,Koenig J,Galle PR.FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients:a randomized placebo-controlled multicentric AIO phase II trial.J Clin Oncol 2013;31:4086
50 Sun W,Powell M,O’Dwyer PJ,Catalano P,Ansari RH,Benson AB.Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma:ECOG 5203.JClin Oncol 2010;28:2947-2951[PMID:20458043 DOI:10.1200/JCO.2009.27.7988]
51 Martin-Richard M,Gallego R,Pericay C,Garcia Foncillas J,Queralt B,Casado E,Barriuso J,Iranzo V,Juez I,Visa L,Saigi E,Barnadas A,Garcia-Albeniz X,Maurel J.Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment.A GEMCAD study.Invest New Drugs 2013;31:1573-1579[PMID:24077981 DOI:10.1007/s10637-013-0020-2]
52 Thuss-Patience PC,Al-Batran SE,Siveke JT,Homann N,Malfertheiner P,Glaeser D,Stein A,Tamm I,Daum S,Potenberg J,Florschütz A,Vogel A,Ridwelski K,Ritgen M,Geissler M,Schmalenberg H,Schlattmann P,Lorenz M,Breithaupt K,Pichlmeier U.Pazopanib and 5-FU/oxaliplatin as first-line treatment in advanced gastric cancer:Pa FLO,a randomized phase II study from the AIO(Arbeitsgemeinschaft Internistische Onkologie).J Clin Oncol 2015;33:4033
53 Pavlakis N,Sjoquist KM,Tsobanis E,Martin AJ,Kang YK,Bang YJ,O’Callaghan CJ,Tebbutt NC,Rha SY,Lee J,Cho JY,Lipton LR,Burnell MJ,Alcindor T,Strickland A,Kim JW,Yip S,Simes J,Zalcberg JR,Goldstein D.INTEGRATE:A randomized,phase II,double-blind,placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer(AOGC):A study by the Australasian Gastrointestinal Trials Group(AGITG)-Final overall and subgroup results.J Clin Oncol 2015;33:4003
54 Guertin DA,Sabatini DM.Defining the role of m TOR in cancer.Cancer Cell 2007;12:9-22[PMID:17613433 DOI:10.1016/j.ccr.2007.05.008]
55 Bjornsti MA,Houghton PJ.The TOR pathway:a target for cancer therapy.Nat Rev Cancer 2004;4:335-348[PMID:15122205 DOI:10.1038/nrc1362]
56 Shi J,Yao D,Liu W,Wang N,Lv H,He N,Shi B,Hou P,Ji M.Frequent gene amplification predicts poor prognosis in gastric cancer.Int J Mol Sci 2012;13:4714-4726[PMID:22606006 DOI:10.3390/ijms13044714]
57 Yu HG,Ai YW,Yu LL,Zhou XD,Liu J,Li JH,Xu XM,Liu S,Chen J,Liu F,Qi YL,Deng Q,Cao J,Liu SQ,Luo HS,Yu JP.Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death.Int J Cancer 2008;122:433-443[PMID:17935137 DOI:10.1002/ijc.23049]
58 Ohtsu A,Ajani JA,Bai YX,Bang YJ,Chung HC,Pan HM,Sahmoud T,Shen L,Yeh KH,Chin K,Muro K,Kim YH,Ferry D,Tebbutt NC,Al-Batran SE,Smith H,Costantini C,Rizvi S,Lebwohl D,Van Cutsem E.Everolimus for previously treated advanced gastric cancer:results of the randomized,double-blind,phase III GRANITE-1 study.J Clin Oncol 2013;31:3935-3943[PMID:24043745 DOI:10.1200/JCO.2012.48.3552]
59 Gherardi E,Birchmeier W,Birchmeier C,Vande Woude G.Targeting MET in cancer:rationale and progress.Nat Rev Cancer2012;12:89-103[PMID:22270953 DOI:10.1038/nrc3205]
60 Yashiro M,Nishii T,Hasegawa T,Matsuzaki T,Morisaki T,Fukuoka T,Hirakawa K.A c-Met inhibitor increases the chemosensitivity of cancer stem cells to the irinotecan in gastric carcinoma.Br J Cancer 2013;109:2619-2628[PMID:24129235DOI:10.1038/bjc.2013.638]
61 Nakajima M,Sawada H,Yamada Y,Watanabe A,Tatsumi M,Yamashita J,Matsuda M,Sakaguchi T,Hirao T,Nakano H.The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas.Cancer 1999;85:1894-1902[PMID:10223227]
62 Graziano F,Galluccio N,Lorenzini P,Ruzzo A,Canestrari E,D’Emidio S,Catalano V,Sisti V,Ligorio C,Andreoni F,Rulli E,Di Oto E,Fiorentini G,Zingaretti C,De Nictolis M,Cappuzzo F,Magnani M.Genetic activation of the MET pathway and prognosis of patients with high-risk,radically resected gastric cancer.J Clin Oncol 2011;29:4789-4795[PMID:22042954 DOI:10.1200/JCO.2011.36.7706]
63 Lennerz JK,Kwak EL,Ackerman A,Michael M,Fox SB,Bergethon K,Lauwers GY,Christensen JG,Wilner KD,Haber DA,Salgia R,Bang YJ,Clark JW,Solomon BJ,Iafrate AJ.MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.J Clin Oncol 2011;29:4803-4810[PMID:22042947DOI:10.1200/JCO.2011.35.4928]
64 Oliner KS,Tang R,Anderson A,Lan Y,Iveson T,Donehower RC,Jiang Y,Dubey S,Loh E.Evaluation of MET pathway biomarkers in a phase II study of rilotumumab(R,AMG 102)or placebo(P)in combination with epirubicin,cisplatin,and capecitabine(ECX)in patients(pts)with locally advanced or metastatic gastric(G)or esophagogastric junction(EGJ)cancer.J Clin Oncol 2012;30:4005
65 Iveson T,Donehower RC,Davidenko I,Tjulandin S,Deptala A,Harrison M,Nirni S,Lakshmaiah K,Thomas A,Jiang Y,Zhu M,Tang R,Anderson A,Dubey S,Oliner KS,Loh E.Rilotumumab in combination with 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.Lancet Oncol 2014;15:1007-1018[PMID:24965569 DOI:10.1016/S1470-2045(14)70023-3]
66 Cunningham D,Tebbutt NC,Davidenko I,Murad AM,AlBatran SE,Ilson DH,Tjulandin S,Gotovkin E,Karaszewska B,Bondarenko I,Tejani MA,Udrea AA,Tehfe MA,Baker N,Oliner KS,Zhang Y,Hoang T,Sidhu R,Catenacci DVT.Phase III,randomized,double-blind,multicenter,placebo(P)-controlled trial of rilotumumab(R)plus epirubicin,cisplatin and capecitabine(ECX)as first-line therapy in patients(pts)with advanced MET-positive(pos)gastric or gastroesophageal junction(G/GEJ)cancer:RILOMET-1 study.J Clin Oncol 2015;33:4000
67 Shah MA,Cho JY,Huat ITB,Tebbutt NC,Yen CJ,Kang A,Shames DS,Bu L,Kang YK.Randomized Phase II Study of FOLFOX/-MET Inhibitor,Onartuzumab(O),in Advanced Gastroesophageal Adenocarcinoma(GEC).J Clin Oncol 2015;33:2
68 Shah MA,Bang YJ,Lordick F,Tabernero J,Chen M,Hack SP,Phan SC,Shames DS,Cunningham D.METGastric:A phase III study of onartuzumab plus m FOLFOX6 in patients with metastatic HER2-negative(HER2-)and MET-positive(MET)adenocarcinoma of the stomach or gastroesophageal junction(GEC).J Clin Oncol 2015;33:4012
69 Javle M,Curtin NJ.The role of PARP in DNA repair and its therapeutic exploitation.Br J Cancer 2011;105:1114-1122[PMID:21989215 DOI:10.1038/bjc.2011.382]
70 Rouleau M,Patel A,Hendzel MJ,Kaufmann SH,Poirier GG.PARP inhibition:PARP1 and beyond.Nat Rev Cancer 2010;10:293-301[PMID:20200537 DOI:10.1038/nrc2812]
71 Bang YJ,Im SA,Lee KW,Cho JY,Song EK,Lee KH,Kim YH,Park JO,Chun HG,Zang DY,Fielding A,Rowbottom J,Hodgson D,O’Connor MJ,Yin X,Kim WH.Randomized,Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.J Clin Oncol 2015;33:3858-3865[PMID:26282658 DOI:10.1200/JCO.2014.60.0320]
72 Dunn GP,Bruce AT,Ikeda H,Old LJ,Schreiber RD.Cancer immunoediting:from immunosurveillance to tumor escape.Nat Immunol 2002;3:991-998[PMID:12407406 DOI:10.1038/ni1102-991]
73 Schreiber RD,Old LJ,Smyth MJ.Cancer immunoediting:integrating immunity’s roles in cancer suppression and promotion.Science 2011;331:1565-1570[PMID:21436444 DOI:10.1126/science.1203486]
74 Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer 2012;12:252-264[PMID:22437870 DOI:10.1038/nrc3239]
75 Hodi FS,O’Day SJ,Mc Dermott DF,Weber RW,Sosman JA,Haanen JB,Gonzalez R,Robert C,Schadendorf D,Hassel JC,Akerley W,van den Eertwegh AJ,Lutzky J,Lorigan P,Vaubel JM,Linette GP,Hogg D,Ottensmeier CH,LebbéC,Peschel C,Quirt I,Clark JI,Wolchok JD,Weber JS,Tian J,Yellin MJ,Nichol GM,Hoos A,Urba WJ.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med 2010;363:711-723[PMID:20525992 DOI:10.1056/NEJMoa1003466]
76 Ralph C,Elkord E,Burt DJ,O’Dwyer JF,Austin EB,Stern PL,Hawkins RE,Thistlethwaite FC.Modulation of lymphocyte regulation for cancer therapy:a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma.Clin Cancer Res2010;16:1662-1672[PMID:20179239 DOI:10.1158/1078-0432.CCR-09-2870]
77 Muro K,Bang Y,Shankaran V,Geva R,Catenacci DVT,Gupta S,Eder JP,Berger R,Gonzalez EJ,Pulini J,Ray AB,Dolled-Filhart M,Emancipator K,Pathiraja K,Shu X,Koshiji MR,Cheng J,Chung HC.LBA15 A phase 1b study of pembrolizumab(PEMBRO;MK-3475)in patients(PTS)with advanced gastric cancer.Ann Oncol 2014;25:v1-v41[DOI:10.1093/annonc/mdu438.15]
78 Muro K,Bang YJ,Shankaran V,Geva R,Catenacci DVT,Gupta S,Eder JP,Berger R,Gonzalez EJ,Ray A,Dolled-Filhart M,Emancipator K,Pathiraja K,Lunceford JK,Cheng JD,Koshiji M,Chung HC.Relationship between PD-L1 expression and clinical outcomes in patients(Pts)with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab(Pembro;MK-3475)in KEYNOTE-012.J Clin Oncol 2015;33:3
79 Le DT,Uram JN,Wang H,Bartlett BR,Kemberling H,Eyring AD,Skora AD,Luber BS,Azad NS,Laheru D,Biedrzycki B,Donehower RC,Zaheer A,Fisher GA,Crocenzi TS,Lee JJ,Duffy SM,Goldberg RM,de la Chapelle A,Koshiji M,Bhaijee F,Huebner T,Hruban RH,Wood LD,Cuka N,Pardoll DM,Papadopoulos N,Kinzler KW,Zhou S,Cornish TC,Taube JM,Anders RA,Eshleman JR,Vogelstein B,Diaz LA.PD-1Blockade in Tumors with Mismatch-Repair Deficiency.N Engl J Med 2015;372:2509-2520[PMID:26028255 DOI:10.1056/NEJMoa1500596]
80 Lutzky J,Antonia SJ,Blake-Haskins A,Li X,Robbins PB,Shalabi AM,Vasselli J,Ibrahim RA,Khleif S,Segal NH.A phase1 study of MEDI4736,an anti-PD-L1 antibody,in patients with advanced solid tumors.J Clin Oncol 2014;32:3001