New Advances In Targeted Gastric Cancer Treatment

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World J Gastroenterol 2016 August 14; 22(30): 6776-6799ISSN 1007-9327 (print) ISSN 2219-2840 (online)Submit a Manuscript: http://www.wjgnet.com/esps/Help Desk: http://www.wjgnet.com/esps/helpdesk.aspxDOI: 10.3748/wjg.v22.i30.6776 2016 Baishideng Publishing Group Inc. All rights reserved.REVIEWNew advances in targeted gastric cancer treatmentDaniela Cornelia Lazăr, Sorina Tăban, Marioara Cornianu, Alexandra Faur, Adrian Goldişgastric cancer remains a major global health problem.In the more recent period, survival has shown onlyminor improvement, despite significant advances indiagnostic techniques, surgical and chemotherapeuticapproaches, the development of novel therapeuticagents and treatment by multidisciplinary teams.Because multiple genetic mutations, epigenetic altera tions, and aberrant molecular signalling pathways areinvolved in the development of gastric cancers, recentresearch has attempted to determine the molecularheterogeneity responsible for the processes of car cinogenesis, spread and metastasis. Currently, somenovel agents targeting a part of these dysfunctionalmolecular signalling pathways have already beenintegrated into the standard treatment of gastric cancer,whereas others remain in phases of investigationwithin clinical trials. It is essential to identify the uniquemolecular patterns of tumours and specific biomarkersto develop treatments targeted to the individual tumourbehaviour. This review analyses the global impact ofgastric cancer, as well as the role of Helicobacter pyloriinfection and the efficacy of bacterial eradication inpreventing gastric cancer development. Furthermore,the paper discusses the currently available targetedtreatments and future directions of research usingpromising novel classes of molecular agents foradvanced tumours.Daniela Cornelia Lazăr, Adrian Goldiş, Department ofGastroenterology and Hepatology, University of Medicine andPharmacy, “Victor Babeş”, 300041 Timişoara, Timis County,RomaniaSorina Tăban, Marioara Cornianu, Alexandra Faur, Departmentof Pathology, University of Medicine and Pharmacy, “VictorBabeş”, 300041 Timişoara, Timis County, RomaniaAuthor contributions: All of the authors contributed equally tothis work.Conflict-of-interest statement: The authors have no conflicts ofinterest to report.Open-Access: This article is an open-access article which wasselected by an in-house editor and fully peer-reviewed by externalreviewers. It is distributed in accordance with the CreativeCommons Attribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, build upon thiswork non-commercially, and license their derivative works ondifferent terms, provided the original work is properly cited andthe use is non-commercial. See: script source: Invited manuscriptCorrespondence to: Daniela Cornelia Lazăr, MD, PhD,Assistant Professor, Department of Gastroenterology andHepatology, University of Medicine and Pharmacy, “VictorBabeş”, Piata Eftimie Murgu No. 2, 300041 Timişoara, TimisCounty, Romania. lazar [email protected]: 40-356-433121Fax: 40-256-486956Key words: Gastric cancer; Helicobacter pylori infection;Chemotherapy; Targeted therapy; Clinical trials; Newtreatment advancesReceived: March 29, 2016Peer-review started: April 4, 2016First decision: May 12, 2016Revised: June 13, 2016Accepted: July 6, 2016Article in press: July 6, 2016Published online: August 14, 2016 The Author(s) 2016. Published by Baishideng PublishingGroup Inc. All rights reserved.Core tip: Recent research attempts to determine themolecular heterogeneity of gastric tumours. Currently,some novel agents targeting aberrant molecularsignalling pathways are already part of the standardtreatments for gastric cancer, whereas others remainin phases of clinical trials. By identifying the uniquemolecular patterns of tumours, new horizons in gastriccancer treatment towards personalized medicine willemerge. This review analyses the role of HelicobacterAbstractDespite a decrease in incidence over past decades,WJG www.wjgnet.com6776August 14, 2016 Volume 22 Issue 30

Lazăr DC et al . Gastric cancer in 2016pylori infection and the efficacy of bacterial eradicationintervention is more effective in patients who do not[11-13]have atrophic gastritis or IM at the same time. Ina pooled analysis of six studies including 6695 patients(most of them from Asia) followed up for 4-10 years,Fuccio and collaborators showed that the relative riskfor gastric cancer after H. pylori eradication was 0.65[14](95%CI: 0.43-0.98) .[15]De Vries et alfound out that the incidence ofpremalignant gastric lesions was declining, and theyconcluded that a further decrease of at least 24% inthe incidence of gastric cancer in the coming decadecould be anticipated in Western countries.The study by Lee showed that mass eradicationof H. pylori infection led to an important reductionin the incidence of gastric atrophy shortly afterimplementation, supporting the use of this strategyto prevent gastric cancer in populations in whom H.pylori is endemic and the incidence of gastric cancer is[16]high .Usually, the diagnosis of gastric cancer is delayedby a lack of early specific symptoms, and mostpatients are diagnosed in advanced stages, resulting in[17]poor 5-year survival rates , with median survival of[18-20]less than 1 year for metastatic disease.Based on the evidence that exists regardingprognostic factors and the management of specifictypes of gastric cancer, there is an imperative need toimprove the tumour node metastasis (TNM) stagingthsystem. The 7 edition of the TNM staging systememphasizes the importance of both depth of invasionand the number of locoregional lymph nodes involvedas major prognostic factors, as a consensus approach[21,22]of Eastern and Western countries. Currently,gastro-oesophageal (GE) junction cancers are nowclassified as oesophageal cancers because of thesimilarity. However, we should bear in mind that it issometimes difficult to interpret data from the literatureand to implement them because many gastric cancerclinical trials include a significant proportion of GEjunction tumours, while many trials designed foroesophageal cancer have also included some proximalgastric tumours.Surgical resection is the mainstay of stomachcancer treatment, with adjuvant chemotherapy or[23,24]chemoradiation. In recent years, the survivalrate has shown only minor improvement despitesignificant progress in diagnostic techniques, surgicaland chemotherapy approaches, the discovery of noveltherapeutic agents and treatment of gastric cancerpatients by multidisciplinary teams. In patients withlocally advanced or metastatic cancers, treatmentrelies mainly on chemotherapy, although the resultsare often limited by the high grade toxicity ofaggressive regimens associating three agents or by[25]the poor performance status of patients . In suchcases, palliatives and BSC are unfortunately the onlyappropriate treatments.Because the pathogenesis of gastric cancersinvolves many different genetic mutations, as wellin gastric cancer prevention, as well as the currentlyavailable targeted treatments and future directions ofresearch using promising novel classes of molecularagents.Lazăr DC, Tăban S, Cornianu M, Faur A, Goldiş A. New advancesin targeted gastric cancer treatment. World J Gastroenterol 2016;22(30): 6776-6799 Available from: URL: htm DOI: TIONGastric cancer represents a major health problem[1,2]worldwide . Despite a decrease in incidence in pastdecades, stomach cancer remains the fifth mostcommon type of cancer and the third leading cause of[3]cancer-related mortality worldwide . There is broadvariation in the geographic distribution of gastriccarcinoma, with this neoplasia being the most commonmalignancy in some regions, such as Japan.In developed countries, the incidence of cardiatumours has paralleled the trend in oesophagealcancer, while distal cancers have tended to decrease in[4,5]incidence . In contrast, the incidence of non-cardianeoplasias remains high in Japan and other parts of[6]the world .There are differences in environmental factors, suchas dietary patterns and salt intake, the prevalenceof Helicobacter pylori (H. pylori) infection and thevirulence of strains, as well as host factors, whichdetermine the regional variations in the incidence ofstomach cancer.Data from the literature, based on epidemiologicaldata and observational and therapeutic trials, as wellas in vitro and in vivo models, have revealed that H.pylori infection is the most important proven risk factorfor human non-cardia gastric neoplasia. The risk ofdeveloping stomach cancer proved to be 20-fold higher[7-10]or more in the presence of H. pylori infection.H. pylori prevalence has demonstrated greatvariability determined by factors such as geographiclocation, age, ethnicity and socioeconomic conditions.For these reasons, its prevalence is usually high indeveloping regions, where H. pylori infection representsa public-health issue, and lower in developed countries.Its prevalence can show variability within regions ofdifferent countries and between more crowded urbanpopulations and rural populations, mostly due tosocioeconomic differences between populations.H. pylori eradication is an effective method forpreventing gastric cancer if it is performed before thedevelopment of premalignant lesions. There have beennumerous studies suggesting that H. pylori eradicationis the most effective approach to gastric cancerprevention, but we should bear in mind that thisWJG www.wjgnet.com6777August 14, 2016 Volume 22 Issue 30

Lazăr DC et al . Gastric cancer in 2016as epigenetic alterations, and the dysfunction ofmolecular signalling pathways, many efforts havebeen undertaken in recent years to emphasize themolecular heterogeneity responsible not only for theprocess of carcinogenesis but also for cancer spreadand metastasis. Each of these molecular alterationsis involved in a different stage of cancerous disease.Currently, some of these aberrant molecular signallingpathways are used as targets of interventions withnovel therapeutic agents, some of which are alreadyapproved for the treatment of gastric cancer, while[26]others remain in the phase of clinical trials . It isessential to identify the unique molecular patterns oftumour carcinogenesis and progression in to developspecific treatments targeted to the individual tumourbiology and behaviour.the IHC 3 . IHC of 2 requires confirmatory testing[28]with fluorescence in situ hybridization (FISH) .Anti-HER2 therapies have demonstrated efficiency[29]for both in vitro and in vivo gastric cancer models .Therapies evaluated in clinical trials of patients withgastric cancer have included inhibition by monoclonalantibodies (trastuzumab and pertuzumab) andtyrosine kinase inhibitors (TKIs) (lapatinib).Monoclonal antibodies targeting HER-2Trastuzumab (trade names Herclon, Herceptin) isa humanized monoclonal antibody that targets theextracellular binding domain of the HER2 receptor;the first therapeutic indication for this agent was forbreast cancer (FDA approval since 1998). The efficacyof trastuzumab for gastric cancer was assessed inan international, open-label, phase Ⅲ trial (ToGA)that randomized naïve patients with metastatic orlocally advanced unresectable gastric or gastrooesophageal junction adenocarcinoma with overexpressed HER2 to chemotherapy associated with[30]trastuzumab vs chemotherapy alone . Becausethis study demonstrated an improvement in medianoverall survival (OS) (2.7 mo), as well as significantlybetter response rates, time to progression of disease,and duration of response for patients who receivedtrastuzumab, the FDA approved this drug as atargeted therapy for gastric and gastro-oesophagealjunction adenocarcinoma in 2010. The results ofthis study demonstrated that adding trastuzumabto classic chemotherapy could increase the OS ofpatients with advanced gastric cancer to more than 1year, thus proving the essential role of trastuzumab inthe treatment of patients with this advanced stage ofdisease. Currently, trastuzumab in combination withcapecitabine or 5-fluorouracil and cisplatin is indicatedfor the treatment of patients with HER2-positivemetastatic adenocarcinoma of the stomach or gastrooesophageal junction; it is approved for use only inpatients with HER2 overexpression, which is defined asan IHC 3 positive result or an IHC 2 and FISH doublepositive result.There are several other ongoing studies of trastu zumab, such as the HELOISE trial (trastuzumabplus chemotherapy in patients with HER2-positivemetastatic gastric or gastro-oesophageal junction[31]cancer) , the phase Ⅱ study NCT01130337 in nonmetastatic gastric cancer using trastuzumab and[32]chemotherapy in perioperative setting , the TOXAGstudy (a combination of chemotherapeutic agents plustrastuzumab and chemoradiotherapy in an adjuvantsetting in operated patients with HER2 gastric or[33]gastro-oesophageal junction cancer) , the HERFLOT study (chemotherapy plus trastuzumab as aperioperative treatment for patients with HER2-positive[34]locally advanced oesophago-gastric adenocarcinoma)and the phase Ⅲ trial RTOG 1010 for locally advancedoesophageal or gastro-oesophageal junction adeno METHODSA literature search modality was applied for all Englishlanguage literature published in the last 16 years,before March 2016, by assessing the PubMed electronicdatabase. The keywords used for our researchpurposes were “gastric cancer”, “stomach neoplasm”,“treatment”, “targeted treatment”, and “moleculartreatment”. The specific search was also performedto identify clinical studies involving novel agents forgastric cancer treatment using the ClinicalTrials.govdatabase. Furthermore, the search was also performedon different cancer-related Web sites.TARGETED THERAPIESNumerous targeted therapies belonging to