2021
Deep learning trained on hematoxylin and eosin tumor region of Interest predicts HER2 status and trastuzumab treatment response in HER2+ breast cancer
Farahmand S, Fernandez AI, Ahmed FS, Rimm DL, Chuang JH, Reisenbichler E, Zarringhalam K. Deep learning trained on hematoxylin and eosin tumor region of Interest predicts HER2 status and trastuzumab treatment response in HER2+ breast cancer. Modern Pathology 2021, 35: 44-51. PMID: 34493825, PMCID: PMC10221954, DOI: 10.1038/s41379-021-00911-w.Peer-Reviewed Original ResearchConceptsHER2 statusBreast cancerTreatment responseHER2-positive breast cancerAnti-HER2 agentsPre-treatment samplesNeoadjuvant chemotherapyTrastuzumab therapyClinical outcomesClinical evaluationProtein immunohistochemistryHER2 amplificationTrastuzumab responseTumor stainTreatment selectionTCGA testPathology teamTumor regionCancer featuresCancerPatientsHER2Current standardImmunohistochemistryHematoxylinBRCA1 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 patients
2019
Multiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry
Carvajal-Hausdorf DE, Patsenker J, Stanton KP, Villarroel-Espindola F, Esch A, Montgomery RR, Psyrri A, Kalogeras KT, Kotoula V, Foutzilas G, Schalper KA, Kluger Y, Rimm DL. Multiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry. Clinical Cancer Research 2019, 25: 3054-3062. PMID: 30796036, PMCID: PMC6522272, DOI: 10.1158/1078-0432.ccr-18-2599.Peer-Reviewed Original ResearchConceptsTrastuzumab-treated patientsT cell infiltrationCD8 T cell infiltrationCohort of patientsCytotoxic T cellsMass cytometryCase-control seriesExtracellular domainMechanism of actionTrastuzumab benefitAdjuvant treatmentCD8 cellsRecurrence eventsT cellsAntibody panelImmune systemPatientsMetal-conjugated antibodiesQuantitative immunofluorescenceTrastuzumabImaging Mass CytometryHER2Signaling targetsObjective measurementsCytometry
2018
Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations
Toki MI, Mani N, Smithy JW, Liu Y, Altan M, Wasserman B, Tuktamyshov R, Schalper K, Syrigos KN, Rimm DL. Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations. Journal Of Thoracic Oncology 2018, 13: 1884-1896. PMID: 30267840, PMCID: PMC6251746, DOI: 10.1016/j.jtho.2018.09.012.Peer-Reviewed Original ResearchConceptsPD-L1 expressionPD-L1TIL activationHigh PD-L1 levelsDeath ligand 1 (PD-L1) expressionActivation statusKRAS wild-type tumorsKRAS mutantEGFR mutantsHigh PD-L1Multiplexed quantitative immunofluorescenceUnique immune profilePD-L1 levelsLigand 1 expressionDeath-1/EGFR-mutant tumorsImmunotherapy response ratesKRAS mutant tumorsWild-type tumorsHigher CD4NSCLC patientsImmune profileClinical efficacyKRAS WTLymphocyte populationsKi67 reproducibility using digital image analysis: an inter-platform and inter-operator study
Acs B, Pelekanou V, Bai Y, Martinez-Morilla S, Toki M, Leung SCY, Nielsen TO, Rimm DL. Ki67 reproducibility using digital image analysis: an inter-platform and inter-operator study. Laboratory Investigation 2018, 99: 107-117. PMID: 30181553, DOI: 10.1038/s41374-018-0123-7.Peer-Reviewed Original Research
2017
Objective, 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-HER2CarcinomaMutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function
Choi M, Kadara H, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, Zhao Z, Behrens C, Fujimoto J, Chow C, Kim K, Kalhor N, Moran C, Rimm D, Swisher S, Gibbons DL, Heymach J, Kaftan E, Townsend JP, Lynch TJ, Schlessinger J, Lee J, Lifton RP, Herbst RS, Wistuba II. Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function. Annals Of Oncology 2017, 28: 83-89. PMID: 28177435, PMCID: PMC6246501, DOI: 10.1093/annonc/mdw437.Peer-Reviewed Original ResearchConceptsLung squamous cell carcinomaEarly stage lung squamous cell carcinomaNon-small cell lung cancerSquamous cell carcinomaWhole-exome sequencingImmune markersClinical outcomesCell carcinomaPIK3CA mutationsExact testPoor recurrence-free survivalProportional hazards regression modelsTumoral PD-L1 expressionPD-L1 expressionRecurrence-free survivalCell lung cancerComprehensive immune profilingTP53 mutant tumorsHazards regression modelsNormal lung tissuesFisher's exact testLUSC cohortAdjuvant therapyImmune profilingPoor prognosis
2016
EGFR-GRB2 Protein Colocalization Is a Prognostic Factor Unrelated to Overall EGFR Expression or EGFR Mutation in Lung Adenocarcinoma
Toki MI, Carvajal-Hausdorf DE, Altan M, McLaughlin J, Henick B, Schalper KA, Syrigos KN, Rimm DL. EGFR-GRB2 Protein Colocalization Is a Prognostic Factor Unrelated to Overall EGFR Expression or EGFR Mutation in Lung Adenocarcinoma. Journal Of Thoracic Oncology 2016, 11: 1901-1911. PMID: 27449805, PMCID: PMC5075503, DOI: 10.1016/j.jtho.2016.06.025.Peer-Reviewed Original ResearchConceptsEGFR pathway activationSeries of patientsLung adenocarcinomaMutation statusEGFR expressionPathway activationProximity ligation assayKRAS wild-type tumorsEGFR-mutant patientsKRAS-mutant casesCohort of patientsWild-type tumorsInteraction of EGFREGFR expression levelsEGFR protein expressionMAPK/ERK pathwayGrowth factor receptorActive EGFRPrognostic factorsDifferent mutation statusPatient groupPrognostic valueLonger survivalEGFR mutationsPrognostic markerTriple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence
Balko JM, Schwarz LJ, Luo N, Estrada MV, Giltnane JM, Dávila-González D, Wang K, Sánchez V, Dean PT, Combs SE, Hicks D, Pinto JA, Landis MD, Doimi FD, Yelensky R, Miller VA, Stephens PJ, Rimm DL, Gómez H, Chang JC, Sanders ME, Cook RS, Arteaga CL. Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence. Science Translational Medicine 2016, 8: 334ra53. PMID: 27075627, PMCID: PMC5256931, DOI: 10.1126/scitranslmed.aad3001.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsCell Line, TumorCell ProliferationChromosomes, Human, Pair 9Cohort StudiesFemaleGene AmplificationGene Knockdown TechniquesGenetic LociHumansJanus Kinase 2Middle AgedSignal TransductionSpheroids, CellularSTAT3 Transcription FactorSTAT6 Transcription FactorTriple Negative Breast NeoplasmsConceptsTriple-negative breast cancerJAK2 amplificationBreast cancerUntreated triple-negative breast cancerEventual metastatic spreadBasal-like cancersBreast cancer subtypesTNBC cell linesAmplification of JAK2Janus kinase 2 (JAK2) geneNeoadjuvant chemotherapyOverall survivalTNBC xenograftsJAK1/2 inhibitorClinical trialsMetastatic spreadKinase 2 geneJAK2-specific inhibitorTumor growthCancer subtypesMammosphere formationPatientsPotential biomarkersTumor progressionJAK2 inhibitors
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 timeHigh 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 functionPD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer
Wimberly H, Brown JR, Schalper K, Haack H, Silver MR, Nixon C, Bossuyt V, Pusztai L, Lannin DR, Rimm DL. PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunology Research 2015, 3: 326-332. PMID: 25527356, PMCID: PMC4390454, DOI: 10.1158/2326-6066.cir-14-0133.Peer-Reviewed Original ResearchConceptsTumor-infiltrating lymphocytesPD-L1 expressionPathologic complete responseNeoadjuvant chemotherapyPD-L1Breast cancerDeath 1 ligand 1PD-L1 protein expressionYale-New Haven HospitalHigh PD-L1Antitumor immune activitySubset of patientsTriple-negative patientsBreast cancer patientsTriple-negative statusImmune checkpoint proteinsImmune regulatory moleculesNew Haven HospitalSignificant multivariate modelRabbit monoclonal antibodyTILs correlateComplete responseImmune therapyCancer patientsImmune activity
2014
Quantitative assessment of miR34a as an independent prognostic marker in breast cancer
Agarwal S, Hanna J, Sherman ME, Figueroa J, Rimm DL. Quantitative assessment of miR34a as an independent prognostic marker in breast cancer. British Journal Of Cancer 2014, 112: 61-68. PMID: 25474246, PMCID: PMC4453614, DOI: 10.1038/bjc.2014.573.Peer-Reviewed Original ResearchConceptsDisease-specific survivalBreast cancer cohortPoor disease-specific survivalDisease-specific deathIndependent breast cancer cohortsBreast cancerCancer cohortPoor outcomeCohort 1Multivariate Cox proportional hazards analysisCox proportional hazards analysisNode-positive populationX-tile softwareNode-negative patientsProportional hazards analysisTumor suppressorBreast cancer patientsIndependent prognostic markerExpression of miR34aReceptor statusNode statusPreclinical observationsTumor sizeCancer patientsCohort 2ERβ splice variant expression in four large cohorts of human breast cancer patient tumors
Wimberly H, Han G, Pinnaduwage D, Murphy LC, Yang XR, Andrulis IL, Sherman M, Figueroa J, Rimm DL. ERβ splice variant expression in four large cohorts of human breast cancer patient tumors. Breast Cancer Research And Treatment 2014, 146: 657-667. PMID: 25007965, PMCID: PMC6939385, DOI: 10.1007/s10549-014-3050-3.Peer-Reviewed Original ResearchConceptsBreast cancerPatient tumorsERβ variantsQuantitative immunofluorescenceBreast cancer patient tumorsTriple-negative patientsBreast cancer outcomesAbsence of ERαBreast cancer biologyCancer patient tumorsBreast cancer patient samplesSplice variant expressionCancer patient samplesParaffin-embedded tissuesQIF scoresCancer outcomesPredictive biomarkersWorse outcomesEstrogen receptorLarge cohortSurvival analysisERβPatient samplesAQUA technologyVariant expressionIn Situ Quantitative Measurement of HER2mRNA Predicts Benefit from Trastuzumab-Containing Chemotherapy in a Cohort of Metastatic Breast Cancer Patients
Vassilakopoulou M, Togun T, Dafni U, Cheng H, Bordeaux J, Neumeister VM, Bobos M, Pentheroudakis G, Skarlos DV, Pectasides D, Kotoula V, Fountzilas G, Rimm DL, Psyrri A. In Situ Quantitative Measurement of HER2mRNA Predicts Benefit from Trastuzumab-Containing Chemotherapy in a Cohort of Metastatic Breast Cancer Patients. PLOS ONE 2014, 9: e99131. PMID: 24968015, PMCID: PMC4072595, DOI: 10.1371/journal.pone.0099131.Peer-Reviewed Original ResearchConceptsBreast cancer patientsMetastatic breast cancer patientsFISH HER2Cancer patientsHER2 mRNAPrognostic factorsTrastuzumab-treated metastatic breast cancer patientsMultivariate Cox regression modelECD HER2Log rank pMetastatic breast cancerStrong prognostic factorCox regression modelKaplan-Meier estimatesHER2 mRNA levelsHER2-ICDChemotherapy regimensMetastatic cohortTrastuzumab treatmentBreast cancerTissue microarrayMRNA statusPerformance of markersHER2 receptorPredictive valueMarkers of Epithelial to Mesenchymal Transition in Association with Survival in Head and Neck Squamous Cell Carcinoma (HNSCC)
Pectasides E, Rampias T, Sasaki C, Perisanidis C, Kouloulias V, Burtness B, Zaramboukas T, Rimm D, Fountzilas G, Psyrri A. Markers of Epithelial to Mesenchymal Transition in Association with Survival in Head and Neck Squamous Cell Carcinoma (HNSCC). PLOS ONE 2014, 9: e94273. PMID: 24722213, PMCID: PMC3983114, DOI: 10.1371/journal.pone.0094273.Peer-Reviewed Original ResearchMeSH KeywordsAutomationBiomarkers, TumorCarcinoma, Squamous CellCohort StudiesEpithelial-Mesenchymal TransitionFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticHead and Neck NeoplasmsHumansImage Processing, Computer-AssistedImmunohistochemistryKaplan-Meier EstimateMaleMultivariate AnalysisNeoplasm MetastasisPhenotypePrognosisProportional Hazards ModelsSquamous Cell Carcinoma of Head and NeckTreatment OutcomeConceptsProgression-free survivalSquamous cell carcinomaOverall survivalCell carcinomaE-cadherinPrimary squamous cell carcinomaNeck squamous cell carcinomaHigh-risk HNSCCKaplan-Meier analysisNovel therapeutic approachesMesenchymal transition phenotypeHigh metastatic potentialLow E-cadherinImproved OSInferior OSIndependent predictorsPoor prognosisCarcinoma prognosisClinicopathological parametersInclusion criteriaTherapeutic approachesTransition phenotypeMetastatic potentialMesenchymal transitionProtein expression analysis
2013
Programmed death ligand-1 expression in non-small cell lung cancer
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Laboratory Investigation 2013, 94: 107-116. PMID: 24217091, PMCID: PMC6125250, DOI: 10.1038/labinvest.2013.130.Peer-Reviewed Original ResearchMeSH KeywordsAgedB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungCell Line, TumorChi-Square DistributionCohort StudiesConnecticutFemaleGreeceHumansImmunohistochemistryLung NeoplasmsLymphocytes, Tumor-InfiltratingMalePrognosisReproducibility of ResultsRNA, MessengerSurvival AnalysisTissue Array AnalysisConceptsNon-small cell lung cancerPD-L1 expressionCell lung cancerPD-L1Tissue microarrayBetter outcomesNSCLC casesLung cancerDeath ligand 1 (PD-L1) expressionCell death ligand 1PD-L1 protein expressionEarly phase clinical trialsLigand 1 expressionTumor-infiltrating lymphocytesDeath ligand 1Significant better outcomePD-L1 mRNAPD-L1 proteinPhase clinical trialsNormal human placentaPrediction of responseQuantitative fluorescence approachesFrequency of expressionPD-1Prognostic valueQuantitative assessment Ki-67 score for prediction of response to neoadjuvant chemotherapy in breast cancer
Brown JR, DiGiovanna MP, Killelea B, Lannin DR, Rimm DL. Quantitative assessment Ki-67 score for prediction of response to neoadjuvant chemotherapy in breast cancer. Laboratory Investigation 2013, 94: 98-106. PMID: 24189270, DOI: 10.1038/labinvest.2013.128.Peer-Reviewed Original ResearchConstruction and Analysis of Multiparameter Prognostic Models for Melanoma Outcome
Rothberg BE, Rimm DL. Construction and Analysis of Multiparameter Prognostic Models for Melanoma Outcome. Methods In Molecular Biology 2013, 1102: 227-258. PMID: 24258982, PMCID: PMC3912557, DOI: 10.1007/978-1-62703-727-3_13.Peer-Reviewed Original ResearchConceptsAdjuvant regimensNegative sentinel lymph node biopsyAdverse risk-benefit ratioPrognostic modelStage II melanoma patientsSentinel lymph node biopsyConventional clinicopathologic criteriaLymph node biopsyStage II melanomaMelanoma-specific survivalWide local excisionRisk-benefit ratioKi-67 assaysTumor molecular profilesComposite prognostic indicesMost patientsNode biopsyLocal excisionMelanoma patientsPrognostic indexRisk stratificationClinicopathologic criteriaMelanoma outcomesPrognostic biomarkerIndependent cohortA Retrospective Population-Based Comparison of HER2 Immunohistochemistry and Fluorescence In Situ Hybridization in Breast Carcinomas: Impact of 2007 American Society of Clinical Oncology/ College of American Pathologists Criteria
Schalper KA, Kumar S, Hui P, Rimm DL, Gershkovich P. A Retrospective Population-Based Comparison of HER2 Immunohistochemistry and Fluorescence In Situ Hybridization in Breast Carcinomas: Impact of 2007 American Society of Clinical Oncology/ College of American Pathologists Criteria. Archives Of Pathology & Laboratory Medicine 2013, 138: 213-9. PMID: 24164555, DOI: 10.5858/arpa.2012-0617-oa.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBreast NeoplasmsCarcinomaCohort StudiesConnecticutFemaleHospitals, UniversityHumansImmunohistochemistryIn Situ Hybridization, FluorescenceMammary Glands, HumanMiddle AgedNeoplasm GradingNeoplasm InvasivenessNeoplasm ProteinsPractice Guidelines as TopicReceptor, ErbB-2Retrospective StudiesSocieties, MedicalUnited StatesUnited States Food and Drug Administration