2024
State-of-the-Art Advancements in Gastroesophageal Cancer Treatment: Harnessing Biomarkers for Precision Care.
Balmaceda N, Petrillo A, Krishnan M, Zhao J, Kim S, Klute K, Sundar R. State-of-the-Art Advancements in Gastroesophageal Cancer Treatment: Harnessing Biomarkers for Precision Care. American Society Of Clinical Oncology Educational Book 2024, 44: e431060. PMID: 38771996, DOI: 10.1200/edbk_431060.Peer-Reviewed Original ResearchConceptsGastroesophageal cancerIntegration of immune checkpoint inhibitorsChimeric antigen receptor T cellsImmune checkpoint inhibitorsMetastatic gastroesophageal cancerPD-1 inhibitorsAdoptive cell therapyImmunotherapy-based approachesResectable gastroesophageal cancerAntibody-drug conjugatesCheckpoint inhibitorsPD-1Perioperative chemotherapyTargeted therapyT cellsTreatment paradigmFGFR2 inhibitorsCell therapyClinical challengeBispecific antibodiesImprove outcomesCancer treatmentReduced toxicityTherapyInhibitorsInconsistencies in the predictive value of PD-L1 in metastatic gastroesophageal cancer
Sundar R, Smyth E. Inconsistencies in the predictive value of PD-L1 in metastatic gastroesophageal cancer. The Lancet Gastroenterology & Hepatology 2024, 9: 495-497. PMID: 38492581, DOI: 10.1016/s2468-1253(24)00043-8.Peer-Reviewed Original Research
2023
Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression
Huang K, Ma H, Chong R, Uchihara T, Lian B, Zhu F, Sheng T, Srivastava S, Tay S, Sundar R, Tan A, Ong X, Lee M, Ho S, Lesluyes T, Ashktorab H, Smoot D, Van Loo P, Chua J, Ramnarayanan K, Lau L, Gotoda T, Kim H, Ang T, Khor C, Lee J, Tsao S, Yang W, Teh M, Chung H, So J, Yeoh K, Tan P, Consortium S. Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression. Cancer Cell 2023, 41: 2019-2037.e8. PMID: 37890493, PMCID: PMC10729843, DOI: 10.1016/j.ccell.2023.10.004.Peer-Reviewed Original ResearchMeSH KeywordsGastric MucosaGenomicsHumansMetaplasiaPrecancerous ConditionsProspective StudiesStomach NeoplasmsConceptsIntestinal metaplasiaProspective 10-year studyPre-malignant conditionChromatin regulationGastric cancer progressionMicrobial communitiesClinical-only modelClinical-genomic modelsCellular compartmentsIntestinal homeostasisMicrobial dysbiosisTranscriptome profilingDriver genesARID1A mutationsDiverse pathwaysIM patientsClonal dynamicsGenomic profilingSingle-cellEarly malignancyGC riskCell typesGastric cancerCancer progressionLineage heterogeneityCombining chemotherapy, trastuzumab, and immune-checkpoint inhibitors in HER2-positive gastro-oesophageal cancer
Smyth E, Sundar R. Combining chemotherapy, trastuzumab, and immune-checkpoint inhibitors in HER2-positive gastro-oesophageal cancer. The Lancet 2023, 402: 2168-2170. PMID: 37871605, DOI: 10.1016/s0140-6736(23)02296-1.Peer-Reviewed Original ResearchEffects of prior therapies on outcomes with trifluridine/tipiracil in patients with metastatic gastric/gastroesophageal junction cancer in a randomized phase III trial (TAGS)
Shitara K, George B, Taieb J, Sundar R, Fakih M, Makris L, Benhadji K, Ghidini M. Effects of prior therapies on outcomes with trifluridine/tipiracil in patients with metastatic gastric/gastroesophageal junction cancer in a randomized phase III trial (TAGS). Journal Of Cancer Research And Clinical Oncology 2023, 149: 9361-9374. PMID: 37213030, PMCID: PMC10374776, DOI: 10.1007/s00432-023-04813-z.Peer-Reviewed Original ResearchConceptsProgression-free survivalGastric/gastroesophageal junction cancerJunction cancerSurvival benefitSafety profileEastern Cooperative Oncology Group performance statusRandomized phase III trialAssociated with survival benefitMedian overall survivalPhase III trialsPost hoc exploratory analysisLater-lineTrifluridine/tipiracil treatmentHematologic toxicityPrior therapyMedian overallOverall survivalIII trialsPlacebo armPerformance statusResultsBaseline characteristicsMedian timeRamucirumabTherapy patternsClinical trialsComprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
Xu C, Huang K, Law J, Chua J, Sheng T, Flores N, Pizzi M, Okabe A, Tan A, Zhu F, Kumar V, Lu X, Benitez A, Lian B, Ma H, Ho S, Ramnarayanan K, Anene-Nzelu C, Razavi-Mohseni M, Ghani S, Tay S, Ong X, Lee M, Guo Y, Ashktorab H, Smoot D, Li S, Skanderup A, Beer M, Foo R, Wong J, Sanghvi K, Yong W, Sundar R, Kaneda A, Prabhakar S, Mazur P, Ajani J, Yeoh K, So J, Tan P. Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities. Gut 2023, 72: 1651-1663. PMID: 36918265, DOI: 10.1136/gutjnl-2022-328332.Peer-Reviewed Original ResearchConceptsGastric cancerMolecular subtypesPromoter activityMutational signaturesProinflammatory tumor microenvironmentTumor microenvironmental changesMutated driver genesSingle-cell transcriptome profilingCTCF occupancyGC molecular subtypesChromatin profilingDistal enhancerRegulatory networksEpigenetic landscapeBRD4 bindingEpigenomic reprogrammingEpigenomic levelsTumor-intrinsicTumor inflammationTumor microenvironmentTherapeutic vulnerabilitiesTranscriptome profilingDriver genesNFkB inhibitorGene expressionClinical relevance of PD-1 positive CD8 T-cells in gastric cancer
Choo J, Kua L, Soe M, Asuncion B, Tan B, Teo C, Tay R, So J, Shabbir A, Guowei K, Tan H, Chan G, Ma H, Ramachandran G, Lum J, Chee C, Sridharan S, Tan P, Sundar R, Yong W. Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer. Gastric Cancer 2023, 26: 393-404. PMID: 36781556, PMCID: PMC10115710, DOI: 10.1007/s10120-023-01364-7.Peer-Reviewed Original ResearchConceptsCD8 T cellsPD-1+CD8+ T cellsT cellsTumor microenvironmentPD-1Overall survivalGastric cancerMultiplex immunohistochemistryT cell-inflamed tumor microenvironmentAssociated with improved OSIncreased PD-1 expressionClinical relevanceGranzyme-B expressionInflamed tumor microenvironmentPD-1 expressionInfluence overall survivalNK cell proportionTreated with immunotherapyPhase 2 trialAssociated with chemotherapyCox proportional hazards modelsProportional hazards modelImproved OSImmunotherapy sensitivityNK cells
2022
Outcomes of a Phase II Study of Intraperitoneal Paclitaxel Plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases
Chia D, Sundar R, Kim G, Ang J, Shabbir A, So J, Yong W. Outcomes of a Phase II Study of Intraperitoneal Paclitaxel Plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases. Annals Of Surgical Oncology 2022, 30: 1889-1890. PMID: 36564654, DOI: 10.1245/s10434-022-12877-3.Peer-Reviewed Original ResearchASO Author Reflections: Combination Intra-Peritoneal and Systemic Chemotherapy for Gastric Cancer with Peritoneal Metastases
Chia D, Ang J, Sundar R, Kim G, Shabbir A, So J, Yong W. ASO Author Reflections: Combination Intra-Peritoneal and Systemic Chemotherapy for Gastric Cancer with Peritoneal Metastases. Annals Of Surgical Oncology 2022, 29: 8606-8607. PMID: 36192514, DOI: 10.1245/s10434-022-12102-1.Peer-Reviewed Original ResearchReply to: Letter to editor on the article “Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy”
Yeong J, Teo C, Tay R, Tan B, Chan Y, Smyth E, Sundar R. Reply to: Letter to editor on the article “Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy”. Gastric Cancer 2022, 25: 1133-1135. PMID: 36152122, DOI: 10.1007/s10120-022-01343-4.Peer-Reviewed Original ResearchOutcomes of a Phase II Study of Intraperitoneal Paclitaxel plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases
Chia D, Sundar R, Kim G, Ang J, Lum J, Nga M, Goh G, Seet J, Chee C, Tan H, Ho J, Ngoi N, Lee M, Muthu V, Chan G, Pang A, Ang Y, Choo J, Lim J, Teh J, Lwin A, Soon Y, Shabbir A, So J, Yong W. Outcomes of a Phase II Study of Intraperitoneal Paclitaxel plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases. Annals Of Surgical Oncology 2022, 29: 8597-8605. PMID: 36070113, DOI: 10.1245/s10434-022-11998-z.Peer-Reviewed Original ResearchConceptsGastric cancer peritoneal metastasisIP-PTXConversion surgeryIntraperitoneal paclitaxelMedian OSSystemic chemotherapyPeritoneal metastasisSC groupConversion to negative cytologyResultsThe median OSProgression-free survivalPhase II studyMethodsForty-four patientsIntravenous oxaliplatinMedian PFSOral capecitabineSystemic capecitabineExtraperitoneal metastasesNegative cytologyPeritoneal diseaseOverall survivalPerformance statusPrimary endpointSecondary endpointsIP cohortRegulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities
Ho S, Sheng T, Xing M, Ooi W, Xu C, Sundar R, Huang K, Li Z, Kumar V, Ramnarayanan K, Zhu F, Srivastava S, Bin Adam Isa Z, Anene-Nzelu C, Razavi-Mohseni M, Shigaki D, Ma H, Tan A, Ong X, Lee M, Tay S, Guo Y, Huang W, Li S, Beer M, Foo R, Teh M, Skanderup A, Teh B, Tan P. Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities. Gut 2022, 72: 226-241. PMID: 35817555, DOI: 10.1136/gutjnl-2021-326483.Peer-Reviewed Original ResearchConceptsEpigenomic landscapeGastric cancerEnhancer landscapeGenome-wide epigenomic profilesDownstream targetsPharmacological inhibitionCell linesClinically aggressive subtypeTargetable genomic alterationsMultiple molecular subtypesChIP-seqPoor patient survivalGenomic associationsGC cell linesTranscriptomic scenarioEpigenomic profilingSuper-enhancersChromatin immunoprecipitationRNA sequencingTranscriptome profilingUpstream regulatorGenomic alterationsTherapy resistanceCRISPR/Cas9 editingPatient survivalChoice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy
Yeong J, Lum H, Teo C, Tan B, Chan Y, Tay R, Choo J, Jeyasekharan A, Miow Q, Loo L, Yong W, Sundar R. Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy. Gastric Cancer 2022, 25: 741-750. PMID: 35661944, PMCID: PMC9226082, DOI: 10.1007/s10120-022-01301-0.Peer-Reviewed Original ResearchMeSH KeywordsB7-H1 AntigenBiomarkers, TumorCross-Sectional StudiesHumansImmunohistochemistryImmunotherapyStomach NeoplasmsConceptsCombined positive scorePD-L1 combined positive scoreTumor proportion scorePD-L1Gastric cancerImmune cellsPD-L1 immunohistochemistry assaysProgrammed death-ligand 1Resection of gastric cancerStandard-of-care treatmentBackgroundImmune checkpoint inhibitorsGastric cancer immunotherapyPD-L1 positivityPD-L1 scoringPD-L1 immunohistochemistryDeath-ligand 1Metastatic gastric cancerPD-L1-positive samplesInter-assay concordanceCheckpoint inhibitorsDako 22C3ICI therapyCross-sectional studyCancer immunotherapyPatient selectionIntegration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis
Gwee Y, Chia D, So J, Ceelen W, Yong W, Tan P, Ong C, Sundar R. Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis. Journal Of Clinical Oncology 2022, 40: 2830. PMID: 35649219, PMCID: PMC9390822, DOI: 10.1200/jco.21.02745.Peer-Reviewed Original ResearchMeSH KeywordsGenomicsHumansNeoplasm StagingPeritoneal NeoplasmsPeritoneumStomach NeoplasmsTumor MicroenvironmentConceptsPeritoneal metastasisSystemic therapyClinical trialsGastric cancerTherapeutic strategiesEmergence of novel therapiesSynchronous peritoneal metastasesKnowledge of cancer biologyTraditional systemic therapiesCurrent standard-of-careSite of metastasisGastric cancer peritoneal metastasisAdvanced gastric cancerSurrounding tumor microenvironmentStandard-of-careInternational clinical guidelinesLocoregional therapeutic strategiesDiagnostic laparoscopyDismal prognosisTumor microenvironmentClinical entityNovel therapiesSurgical techniqueDisease stageMolecular profilingChromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer.
Nargund A, Xu C, Mandoli A, Okabe A, Chen G, Huang K, Sheng T, Yao X, Teo J, Sundar R, Kok Y, See Y, Xing M, Li Z, Yong C, Anand A, Bin Adam Isa Z, Poon L, Ng M, Koh J, Ooi W, Tay S, Ong X, Tan A, Smoot D, Ashktorab H, Grabsch H, Fullwood M, Teh B, Bi X, Kaneda A, Li S, Tan P. Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer. Cancer Research 2022, 82: 2538-2551. PMID: 35583999, DOI: 10.1158/0008-5472.can-21-2072.Peer-Reviewed Original ResearchConceptsEnhancer-promoter interactionsCell adhesion genesGenomic bindingAdhesion genesExpression of cell adhesion genesPathway expressionBET inhibitionCell adhesion pathwaysFunction of MSH2DNA mismatch repair genes MSH2Mismatch repair genes MSH2Sensitivity to BET inhibitionTumorigenesis in vitroHistone acetylation levelsChromatin rewiringChromatin functionEpigenomic functionsDNA repair genesSuper-enhancersGene locusEpigenomic regulationFunctional screeningSynthetic lethalityDNA repairAdhesion pathwaysSingle-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric CancerSingle-Cell Atlas of Gastric Cancer Subtypes
Kumar V, Ramnarayanan K, Sundar R, Padmanabhan N, Srivastava S, Koiwa M, Yasuda T, Koh V, Huang K, Tay S, Ho S, Tan A, Ishimoto T, Kim G, Shabbir A, Chen Q, Zhang B, Xu S, Lam K, Lum H, Teh M, Yong W, So J, Tan P. Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric CancerSingle-Cell Atlas of Gastric Cancer Subtypes. Cancer Discovery 2022, 12: 670-691. PMID: 34642171, PMCID: PMC9394383, DOI: 10.1158/2159-8290.cd-21-0683.Peer-Reviewed Original ResearchMeSH KeywordsCancer-Associated FibroblastsEcosystemHumansSingle-Cell AnalysisStomach NeoplasmsTranscriptomeTumor MicroenvironmentConceptsPatient-derived organoidsPlasma cell proportionsGastric cancer subtypesLineage statePredictors of poor clinical prognosisCancer subtypesSingle-cell atlasCell proportionCancer-associated fibroblasts' subtypesCell populationsDiffuse-type tumorsPoor clinical prognosisIn vivo modelsComprehensive single-cell atlasPrimary tumorHistological subtypesRNA-sequencing cohortsTumor microenvironmentClinical stageClinical prognosisGastric malignancyTumor ecosystemGastric cancerCancer heterogeneityTumor
2021
Low Programmed Death-Ligand 1–Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma
Zhao J, Yap D, Chan Y, Tan B, Teo C, Syn N, Smyth E, Soon Y, Sundar R. Low Programmed Death-Ligand 1–Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma. Journal Of Clinical Oncology 2021, 40: 392-402. PMID: 34860570, DOI: 10.1200/jco.21.01862.Peer-Reviewed Original ResearchConceptsProgrammed death-ligand 1Combined positive scoreImmune checkpoint inhibitorsKEYNOTE-062First-line treatmentCheckMate-649Checkpoint inhibitorsEsophageal adenocarcinomaKaplan-MeierEstimate time-to-event outcomesFirst-line immune checkpoint inhibitorsPD-L1 combined positive scoreProgrammed death ligand 1 subgroupsPatients treated with pembrolizumabPD-L1-expressing tumorsRandomized phase III trialEfficacy of ICIsPD-L1 subgroupsProgression-free survivalDeath-ligand 1Phase III trialsUS Food and Drug AdministrationPrimary manuscriptsFood and Drug AdministrationCPS-1Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
Sheng T, Ho S, Ooi W, Xu C, Xing M, Padmanabhan N, Huang K, Ma L, Ray M, Guo Y, Sim N, Anene-Nzelu C, Chang M, Razavi-Mohseni M, Beer M, Foo R, Sundar R, Chan Y, Tan A, Ong X, Skanderup A, White K, Jha S, Tan P. Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer. Genome Medicine 2021, 13: 158. PMID: 34635154, PMCID: PMC8504099, DOI: 10.1186/s13073-021-00970-3.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationADP-Ribosylation FactorsCell Line, TumorCell ProliferationChromatinEnhancer Elements, GeneticEpigenomicsGene Expression Regulation, NeoplasticGenomicsHistonesHumansInhibitor of Growth Protein 1OncogenesPromoter Regions, GeneticRNA-SeqStomach NeoplasmsTranscriptomeWhole Genome SequencingConceptsSingle nucleotide polymorphismsActivity-by-contactEnhancer-promoter interactionsSomatic copy number alterationsGermline single nucleotide polymorphismsHistone modificationsDistal cis-regulatory elementsLow somatic mutation rateCell-specific gene expressionCis-regulatory elementsFunctional enhancer activityHistone modification profilesWhole-genome sequencingRegulatory region sequencingCell fate determinationSuper-enhancer regionsCopy number alterationsGenome copy numberEffect of histone acetylationSomatic mutation rateCancer-relevant genesFunctional assay dataEnhanced activityGC cell linesRegion sequencesEpigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition
Sundar R, Huang K, Kumar V, Ramnarayanan K, Demircioglu D, Her Z, Ong X, Bin Adam Isa Z, Xing M, Tan A, Tai D, Choo S, Zhai W, Lim J, Thakur M, Molinero L, Cha E, Fasso M, Niger M, Pietrantonio F, Lee J, Jeyasekharan A, Qamra A, Patnala R, Fabritius A, De Simone M, Yeong J, Ng C, Rha S, Narita Y, Muro K, Guo Y, Skanderup A, So J, Yong W, Chen Q, Göke J, Tan P. Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut 2021, 71: 1277-1288. PMID: 34433583, PMCID: PMC9185816, DOI: 10.1136/gutjnl-2021-324420.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitionImmune microenvironmentHuman immune systemCheckpoint inhibitionActive human immune systemGastric cancerHuman T-cell infiltrationT cell cytolytic activityResistance to immune checkpoint inhibitionImmune systemProgression-free survivalImmunotherapy-treated patientsT cell infiltrationTumor immune microenvironmentT cell proportionsImmune-editingImmunotherapy resistanceFunctional in vivo studiesTumor kineticsHumanised miceAlternative promoter useTumor microenvironmentTherapeutic responseCytolytic activityImmune depletionMachine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial
Sundar R, Kumarakulasinghe N, Chan Y, Yoshida K, Yoshikawa T, Miyagi Y, Rino Y, Masuda M, Guan J, Sakamoto J, Tanaka S, Tan A, Hoppe M, Jeyasekharan A, Ng C, De Simone M, Grabsch H, Lee J, Oshima T, Tsuburaya A, Tan P. Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial. Gut 2021, 71: 676-685. PMID: 33980610, PMCID: PMC8921574, DOI: 10.1136/gutjnl-2021-324060.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAntineoplastic Combined Chemotherapy ProtocolsDisease-Free SurvivalHumansMachine LearningPaclitaxelStomach NeoplasmsConceptsDisease free survivalValidation cohortGastric cancerGene signatureSurvival benefitPac-SensitiveNo survival differenceSelection of patientsGC trialsFree survivalPaclitaxel chemotherapyCurative surgeryMetastatic patientsPredictive biomarkersTraining cohortSurvival differencesIndependent cohortNanoString panelGC patientsPaclitaxelPatientsNanoString profilingCohortGroup trialUFT