2021
Multi-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study
Taube JM, Roman K, Engle EL, Wang C, Ballesteros-Merino C, Jensen SM, McGuire J, Jiang M, Coltharp C, Remeniuk B, Wistuba I, Locke D, Parra ER, Fox BA, Rimm DL, Hoyt C. Multi-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study. Journal For ImmunoTherapy Of Cancer 2021, 9: e002197. PMID: 34266881, PMCID: PMC8286792, DOI: 10.1136/jitc-2020-002197.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryLaboratories, ClinicalMaleTissue Array AnalysisConceptsPD-1/PD-L1 axisPD-L1 axisMultiplexed immunofluorescenceTumor cellsBreast carcinomaNon-small cell lung cancer (NSCLC) tissuesCell lung cancer tissuesCell density assessmentPD-L1 expressionLung cancer tissuesTissue sectionsPercent positive cellsAverage concordanceClinical laboratory processPDL1 expressionMIF assayPD-1PD-L1Predictive biomarkersLow-level expressionPositive cellsCancer tissuesFluorescent detection reagentMultisite trialChromogenic assayBRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort
Vassilakopoulou M, Won M, Curran WJ, Souhami L, Prados MD, Langer CJ, Rimm DL, Hanna JA, Neumeister VM, Melian E, Diaz AZ, Atkins JN, Komarnicky LT, Schultz CJ, Howard SP, Zhang P, Dicker AP, Knisely JPS. BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort. Oncology 2021, 99: 580-588. PMID: 33957633, PMCID: PMC8491475, DOI: 10.1159/000516168.Peer-Reviewed Original ResearchConceptsBRCA1 protein expressionTensin homolog (PTEN) tumor suppressor geneProtein expressionTumor suppressor geneQuantitative protein analysisDNA repairGenetic profiling studiesMolecular markersSuppressor geneProtein analysisProfiling studiesBRCA1 expressionSitu hybridizationExpression levelsTumor formationCommon malignant brain tumorCancer cellsTissue microarrayGlioblastoma tumorsExpressionPre-temozolomide eraGlioblastoma patientsBiomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass CytometryMultiplex Discovery with Imaging Mass Cytometry
Martinez-Morilla S, Villarroel-Espindola F, Wong PF, Toki MI, Aung TN, Pelekanou V, Bourke-Martin B, Schalper KA, Kluger HM, Rimm DL. Biomarker Discovery in Patients with Immunotherapy-Treated Melanoma with Imaging Mass CytometryMultiplex Discovery with Imaging Mass Cytometry. Clinical Cancer Research 2021, 27: 1987-1996. PMID: 33504554, PMCID: PMC8026677, DOI: 10.1158/1078-0432.ccr-20-3340.Peer-Reviewed Original ResearchMeSH KeywordsBeta 2-MicroglobulinBiomarkers, TumorHumansImage CytometryImmune Checkpoint InhibitorsMelanomaRNA, MessengerTissue Array AnalysisTumor Microenvironment
2020
Digital quantitative assessment of PD-L1 using digital spatial profiling
Gupta S, Zugazagoitia J, Martinez-Morilla S, Fuhrman K, Rimm DL. Digital quantitative assessment of PD-L1 using digital spatial profiling. Laboratory Investigation 2020, 100: 1311-1317. PMID: 32249818, PMCID: PMC7502436, DOI: 10.1038/s41374-020-0424-5.Peer-Reviewed Original ResearchMeSH KeywordsB7-H1 AntigenBiomarkersCell LineHumansImmunohistochemistryProtein Array AnalysisReproducibility of ResultsTissue Array AnalysisConceptsTissue microarrayPD-L1Digital spatial profilingDeath 1 ligand 1 expressionPD-L1 immunohistochemistry assaysDigital quantitative assessmentDigital Spatial ProfilerLigand 1 expressionPD-L1 assaysCompanion diagnostic testingCell linesImmune therapyPredictive markerImmune cellsImmunohistochemistry assaysQuantitative immunohistochemistryUS FoodDrug AdministrationDiagnostic testingImmunohistochemistryNCounter platformTumor cellsDifferent scoring methodsMultiple studiesDifferent antibodiesAdvances in quantitative immunohistochemistry and their contribution to breast cancer
Yaghoobi V, Martinez-Morilla S, Liu Y, Charette L, Rimm DL, Harigopal M. Advances in quantitative immunohistochemistry and their contribution to breast cancer. Expert Review Of Molecular Diagnostics 2020, 20: 509-522. PMID: 32178550, DOI: 10.1080/14737159.2020.1743178.Peer-Reviewed Original Research
2019
Quantitative Assessment of CMTM6 in the Tumor Microenvironment and Association with Response to PD-1 Pathway Blockade in Advanced-Stage Non–Small Cell Lung Cancer
Zugazagoitia J, Liu Y, Toki M, McGuire J, Ahmed FS, Henick BS, Gupta R, Gettinger S, Herbst R, Schalper KA, Rimm DL. Quantitative Assessment of CMTM6 in the Tumor Microenvironment and Association with Response to PD-1 Pathway Blockade in Advanced-Stage Non–Small Cell Lung Cancer. Journal Of Thoracic Oncology 2019, 14: 2084-2096. PMID: 31605795, PMCID: PMC6951804, DOI: 10.1016/j.jtho.2019.09.014.Peer-Reviewed Original ResearchConceptsPD-L1CMTM6 expressionPathway blockadeAdvanced stage non-small cell lung cancerNon-small cell lung cancerPD-1 pathway blockadeTumor cellsAbsence of immunotherapyMultiplexed quantitative immunofluorescencePD-L1 coexpressionStromal immune cellsPD-L1 expressionT cell infiltrationLonger overall survivalCell lung cancerIndependent retrospective cohortsKRAS mutational statusExpression of CMTM6MARVEL transmembrane domainNSCLC cohortOverall survivalRetrospective cohortAxis blockadeClinical featuresImmunotherapy outcomesHigh-Plex Predictive Marker Discovery for Melanoma Immunotherapy–Treated Patients Using Digital Spatial Profiling
Toki MI, Merritt CR, Wong PF, Smithy JW, Kluger HM, Syrigos KN, Ong GT, Warren SE, Beechem JM, Rimm DL. High-Plex Predictive Marker Discovery for Melanoma Immunotherapy–Treated Patients Using Digital Spatial Profiling. Clinical Cancer Research 2019, 25: 5503-5512. PMID: 31189645, PMCID: PMC6744974, DOI: 10.1158/1078-0432.ccr-19-0104.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Agents, ImmunologicalBiomarkers, TumorFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryImmunotherapyLymphocytes, Tumor-InfiltratingMaleMelanomaMolecular Diagnostic TechniquesMolecular Targeted TherapyPrognosisProportional Hazards ModelsTissue Array AnalysisTreatment OutcomeConceptsNon-small cell lung cancerProlonged progression-free survivalDigital spatial profilingOverall survivalPD-L1Predictive markerPD-L1 expressionProgression-free survivalProtein expressionCell lung cancerNovel predictive markerCD68-positive cellsStromal CD3Melanoma immunotherapyImmune markersImmune therapyPrognostic valueLung cancerAntibody cocktailTissue microarrayQuantitative fluorescenceOutcome assessmentTumor cellsHigh concordanceMultiple biomarkersQuantitative assessment of PD-L1 as an analyte in immunohistochemistry diagnostic assays using a standardized cell line tissue microarray
Martinez-Morilla S, McGuire J, Gaule P, Moore L, Acs B, Cougot D, Gown AM, Yaziji H, Wang WL, Cartun RW, Hornick JL, Sholl LM, Qiu J, Mino-Kenudson M, Yi ES, Beasley MB, Merrick DT, Ambaye AB, Zhang ZJ, Walker J, Rimm DL. Quantitative assessment of PD-L1 as an analyte in immunohistochemistry diagnostic assays using a standardized cell line tissue microarray. Laboratory Investigation 2019, 100: 4-15. PMID: 31409885, PMCID: PMC6920558, DOI: 10.1038/s41374-019-0295-9.Peer-Reviewed Original ResearchConceptsTissue microarrayPD-L1Quantitative immunofluorescencePD-L1 expressionPD-L1 immunohistochemistryMulti-institutional settingRoutine clinical samplesCell linesPredictive markerClinical trialsTumor typesIHC assaysQuantitative digital image analysisImmunohistochemistryCut pointsClinical samplesAntibodiesFDAInter-assay comparisonsDiagnostic assaysIsogenic cell linesAssaysDigital image analysisSubjective assessmentLow levels
2018
CD68, CD163, and matrix metalloproteinase 9 (MMP-9) co-localization in breast tumor microenvironment predicts survival differently in ER-positive and -negative cancers
Pelekanou V, Villarroel-Espindola F, Schalper KA, Pusztai L, Rimm DL. CD68, CD163, and matrix metalloproteinase 9 (MMP-9) co-localization in breast tumor microenvironment predicts survival differently in ER-positive and -negative cancers. Breast Cancer Research 2018, 20: 154. PMID: 30558648, PMCID: PMC6298021, DOI: 10.1186/s13058-018-1076-x.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CDAntigens, Differentiation, MyelomonocyticAntineoplastic AgentsBiomarkers, TumorBreastBreast NeoplasmsDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansMacrophagesMatrix Metalloproteinase 9Middle AgedPatient SelectionPrognosisReceptors, Cell SurfaceReceptors, EstrogenRetrospective StudiesSurvival AnalysisTissue Array AnalysisTumor MicroenvironmentConceptsTumor-associated macrophagesOverall survivalQuantitative immunofluorescenceMacrophage markersBreast cancerHigh expressionPan-macrophage marker CD68Triple-negative breast cancerCD163/CD68Multiplexed quantitative immunofluorescenceImproved overall survivalProtein expressionWorse overall survivalPoor overall survivalMMP-9 protein expressionSubclass of patientsMacrophage-targeted therapiesMatrix metalloproteinase-9Tissue microarray formatMMP-9 proteinBreast tumor microenvironmentModulator of responseParaffin-embedded tissuesBreast cancer biomarkersCohort B
2017
PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors
Kluger HM, Zito CR, Turcu G, Baine M, Zhang H, Adeniran A, Sznol M, Rimm DL, Kluger Y, Chen L, Cohen JV, Jilaveanu LB. PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clinical Cancer Research 2017, 23: 4270-4279. PMID: 28223273, PMCID: PMC5540774, DOI: 10.1158/1078-0432.ccr-16-3146.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPD-L1 expressionRenal cell carcinomaPD-1 inhibitorsCell carcinomaImmune-infiltrating cellsMelanoma patientsPD-L1Tumor cellsTumor typesTumor-associated inflammatory cellsCTLA-4 inhibitorsCell lung cancerRenal cell carcinoma cellsHigh response rateClin Cancer ResCell linesMelanoma tumor cellsPD-1Multivariable analysisNSCLC specimensInflammatory cellsLung cancerTissue microarrayResponse rateObjective, domain-specific HER2 measurement in uterine and ovarian serous carcinomas and its clinical significance
Carvajal-Hausdorf DE, Schalper KA, Bai Y, Black J, Santin AD, Rimm DL. Objective, domain-specific HER2 measurement in uterine and ovarian serous carcinomas and its clinical significance. Gynecologic Oncology 2017, 145: 154-158. PMID: 28196634, PMCID: PMC5941302, DOI: 10.1016/j.ygyno.2017.02.002.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAfatinibAntibodies, Monoclonal, HumanizedAntineoplastic AgentsCohort StudiesExtracellular SpaceFemaleFluorescent Antibody TechniqueHumansIntracellular SpaceLapatinibMaytansineMiddle AgedNeoplasms, Cystic, Mucinous, and SerousOvarian NeoplasmsProtein DomainsQuinazolinesReceptor, ErbB-2Retrospective StudiesTissue Array AnalysisTrastuzumabUterine NeoplasmsConceptsUterine serous carcinomaOvarian serous carcinomaHER2 intracellular domainSerous carcinomaECD levelsECD statusTissue microarrayHER2 measurementQuantitative immunofluorescenceHER2 overexpression/amplificationClinico-pathologic characteristicsClinico-pathological featuresHER2-targeted agentsIntracellular domainOverexpression/amplificationHER2 extracellular domainExtracellular domainOSC patientsClinical trialsBreast cancerClinical significancePatientsHER2 assaysP95-HER2CarcinomaProof of the quantitative potential of immunofluorescence by mass spectrometry
Toki MI, Cecchi F, Hembrough T, Syrigos KN, Rimm DL. Proof of the quantitative potential of immunofluorescence by mass spectrometry. Laboratory Investigation 2017, 97: 329-334. PMID: 28092364, PMCID: PMC5334147, DOI: 10.1038/labinvest.2016.148.Peer-Reviewed Original Research
2016
Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo
Cocco E, Lopez S, Black J, Bellone S, Bonazzoli E, Predolini F, Ferrari F, Schwab CL, Menderes G, Zammataro L, Buza N, Hui P, Wong S, Zhao S, Bai Y, Rimm DL, Ratner E, Litkouhi B, Silasi DA, Azodi M, Schwartz PE, Santin AD. Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo. British Journal Of Cancer 2016, 115: 303-311. PMID: 27351214, PMCID: PMC4973158, DOI: 10.1038/bjc.2016.198.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorClass I Phosphatidylinositol 3-KinasesCyclin EDNA Copy Number VariationsFemaleGene Knockdown TechniquesHeterograftsHumansIn Situ Hybridization, FluorescenceIn Vitro TechniquesMiceMutationOncogene ProteinsPhosphatidylinositol 3-KinasesRNA, MessengerTissue Array AnalysisUterine NeoplasmsConceptsUterine serous carcinomaSerous carcinomaTumor growthCyclin E1 (CCNE1) gene amplificationRecurrent uterine serous carcinomaPrimary USC cell linesNovel therapeutic optionsSingle-agent treatmentIdeal therapeutic targetUSC cell linesCyclin E1 expressionUSC patientsUSC xenograftsInhibited cell growthCell cycle analysisAggressive variantTherapeutic optionsCCNE1 amplificationEndometrial tumorsCYC065Therapeutic targetClinical optionPIK3CA driver mutationsDriver mutationsXenograftsAutomated measurement of estrogen receptor in breast cancer: a comparison of fluorescent and chromogenic methods of measurement
Zarrella ER, Coulter M, Welsh AW, Carvajal DE, Schalper KA, Harigopal M, Rimm D, Neumeister V. Automated measurement of estrogen receptor in breast cancer: a comparison of fluorescent and chromogenic methods of measurement. Laboratory Investigation 2016, 96: 1016-1025. PMID: 27348626, PMCID: PMC5008858, DOI: 10.1038/labinvest.2016.73.Peer-Reviewed Original ResearchQuantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer
McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelakanou V, Rehman J, Velcheti V, Herbst R, LoRusso P, Rimm DL. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer. JAMA Oncology 2016, 2: 1-9. PMID: 26562159, PMCID: PMC4941982, DOI: 10.1001/jamaoncol.2015.3638.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntibodies, MonoclonalAntibody SpecificityB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryLung NeoplasmsMaleObserver VariationPredictive Value of TestsReproducibility of ResultsRetrospective StudiesTissue Array AnalysisConceptsTumor-infiltrating lymphocytesPD-L1 expressionPD-L1 antibodiesPD-L1 protein expressionCell lung cancerPD-L1Whole tissue sectionsQuantitative immunofluorescenceLung cancerChromogenic immunohistochemistryPoor concordanceDifferent PD-L1 antibodiesHigh tumor-infiltrating lymphocytesTumor PD-L1 expressionPD-L1 protein levelsCell lung cancer biopsiesMonoclonal antibodiesCurrent consensus guidelinesProtein expressionDurable clinical responsesMain outcome measuresEarly phase trialsLung cancer biopsiesRabbit monoclonal antibodyCorresponding tissue microarrays
2015
Loss of antigenicity with tissue age in breast cancer
Combs SE, Han G, Mani N, Beruti S, Nerenberg M, Rimm DL. Loss of antigenicity with tissue age in breast cancer. Laboratory Investigation 2015, 96: 264-269. PMID: 26568292, DOI: 10.1038/labinvest.2015.138.Peer-Reviewed Original ResearchConceptsHuman epidermal growth receptor 2Estrogen receptorQuantitative immunofluorescenceProtein expressionSeries of formalinRandom-effects modelHuman breast carcinomaLarge cooperative groupsParaffin-embedded tissuesKi67 expressionBreast carcinomaBreast cancerIndividual patientsTissue microarrayClinical investigationClinical questionsReceptor 2Tumor specimensPositive casesLoss of antigenicityFFPE biospecimensQuantitative protein expressionBiomarkersCooperative groupsPreservation timeMeasurement of Domain-Specific HER2 (ERBB2) Expression May Classify Benefit From Trastuzumab in Breast Cancer
Carvajal-Hausdorf DE, Schalper KA, Pusztai L, Psyrri A, Kalogeras KT, Kotoula V, Fountzilas G, Rimm DL. Measurement of Domain-Specific HER2 (ERBB2) Expression May Classify Benefit From Trastuzumab in Breast Cancer. Journal Of The National Cancer Institute 2015, 107: djv136. PMID: 25991002, PMCID: PMC4554192, DOI: 10.1093/jnci/djv136.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, Monoclonal, HumanizedAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsChemotherapy, AdjuvantClinical Trials as TopicDisease-Free SurvivalExtracellular SpaceFemaleFluorescent Antibody TechniqueGene Expression Regulation, NeoplasticHumansIntracellular SpaceKaplan-Meier EstimateMiddle AgedPredictive Value of TestsPrognosisReceptor, ErbB-2Sensitivity and SpecificityTissue Array AnalysisTrastuzumabTreatment OutcomeConceptsHuman epidermal growth factor receptor 2ECD expressionICD statusLonger DFSQuantitative immunofluorescenceTrastuzumab therapyPrognostic valueBreast cancerTissue microarrayEpidermal growth factor receptor 2Adjuvant trastuzumab therapyDisease-free survival analysisTrastuzumab-treated patientsGrowth factor receptor 2High positive predictive valueHER2-positive tumorsKaplan-Meier estimatesFactor receptor 2ERBB2 gene amplificationHER2 protein expressionPositive predictive valueExtracellular domainAdjuvant chemotherapyHER2-ICDBetter DFSHigh level PHGDH expression in breast is predominantly associated with keratin 5‐positive cell lineage independently of malignancy
Gromova I, Gromov P, Honma N, Kumar S, Rimm D, Talman ML, Wielenga VT, Moreira JM. High level PHGDH expression in breast is predominantly associated with keratin 5‐positive cell lineage independently of malignancy. Molecular Oncology 2015, 9: 1636-1654. PMID: 26026368, PMCID: PMC5528790, DOI: 10.1016/j.molonc.2015.05.003.Peer-Reviewed Original ResearchConceptsOverexpression of PhgdhPHGDH expressionMammary epithelial cellsTriple-negative breast cancer patientsNegative breast cancer patientsEpithelial cellsBreast cancer patientsNormal breast tissueCell lineagesMammary tissue samplesHigh-level expressionExpression of PHGDHProspective cohortCancer patientsCK5-positive cellsBasal phenotypeProteomic profilingTNBC samplesIHC analysisQuantitative IHC analysisCancer typesBreast tissueMalignancyCandidate oncogeneOncogenic functionPLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis
Jilaveanu LB, Parisi F, Barr ML, Zito CR, Cruz-Munoz W, Kerbel RS, Rimm DL, Bosenberg MW, Halaban R, Kluger Y, Kluger HM. PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis. Clinical Cancer Research 2015, 21: 2138-2147. PMID: 25316811, PMCID: PMC4397107, DOI: 10.1158/1078-0432.ccr-14-0861.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBrain NeoplasmsCell Line, TumorFemaleFluorescent Antibody TechniqueGene Expression ProfilingHumansImage Processing, Computer-AssistedIntracellular Signaling Peptides and ProteinsMaleMelanomaMiddle AgedNeoplasm InvasivenessTissue Array AnalysisTranscriptomeYoung AdultConceptsCell line modelsBlood-brain barrierBrain metastasesGene expression profilesGene expression profilingExpression profilingExpression profilesPLEKHA5Brain metastasis-free survivalA375P cellsQuantitative immunofluorescenceEarly brain metastasisMelanoma brain metastasesMetastasis-free survivalProfile of patientsPotential mediatorsProtein levelsMetastatic melanoma casesEarly developmentMelanoma cellsKnockdownDecrease proliferationBBB transmigrationExtracerebral sitesMetastatic sites
2014
Preanalytical variables and phosphoepitope expression in FFPE tissue: quantitative epitope assessment after variable cold ischemic time
Vassilakopoulou M, Parisi F, Siddiqui S, England AM, Zarella ER, Anagnostou V, Kluger Y, Hicks DG, Rimm DL, Neumeister VM. Preanalytical variables and phosphoepitope expression in FFPE tissue: quantitative epitope assessment after variable cold ischemic time. Laboratory Investigation 2014, 95: 334-341. PMID: 25418580, DOI: 10.1038/labinvest.2014.139.Peer-Reviewed Original ResearchConceptsCold ischemic timeIschemic timeFormalin fixationCompanion diagnostic testingCancer patientsBreast cancerTissue microarrayPhospho-HSP27Breast tumorsDiagnostic testingQuantitative immunofluorescenceAQUA technologyPreanalytical variablesGene expression profilingLoss of antigenicityTissue samplesReproducible assessmentProtein levelsConfidence intervalsSpecimen collectionExpression levelsPhosphorylation levelsAntigenicityRoutine usageResearch settings