2023
Intratumor spatial heterogeneity in programmed death-ligand 1 (PD-L1) protein expression in early-stage breast cancer
Kahn A, Golestani R, Harigopal M, Pusztai L. Intratumor spatial heterogeneity in programmed death-ligand 1 (PD-L1) protein expression in early-stage breast cancer. Breast Cancer Research And Treatment 2023, 201: 289-298. PMID: 37378695, DOI: 10.1007/s10549-023-06977-1.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerPD-L1 expressionBreast cancerPD-L1Metastatic triple-negative breast cancerPD-L1 positive casesEarly-stage breast cancerPD-L1 protein expressionImmune checkpoint inhibitorsPD-L1 positivityPD-L1 statusProtein expressionWhole study populationPrimary breast tumorsNegative breast cancerConcordant negative resultsCheckpoint inhibitorsMultiple biopsiesPositive cancersCohen's kappa coefficientStudy populationE1L3N antibodyDiscordance rateBreast tumorsPositive casesNeoadjuvant Immunotherapy in Early, Triple-Negative Breast Cancers: Catching Up with the Rest
Kim L, Coman M, Pusztai L, Park T. Neoadjuvant Immunotherapy in Early, Triple-Negative Breast Cancers: Catching Up with the Rest. Annals Of Surgical Oncology 2023, 30: 6441-6449. PMID: 37349612, DOI: 10.1245/s10434-023-13714-x.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerTumor mutational burdenBreast cancerAdjuvant therapyPathological complete response rateImmune checkpoint modulationComplete response rateExcellent clinical outcomesCombination immunochemotherapyNeoadjuvant immunotherapyNeoadjuvant settingNeoadjuvant chemotherapyOverall survivalPD-L1Checkpoint modulationClinical outcomesMajor trialsMutational burdenResponse rateCancer typesCancerTherapyBiomarkersOutcomesExciting advancesVariable Landscape of PD-L1 Expression in Breast Carcinoma as Detected by the DAKO 22C3 Immunohistochemistry Assay
Danziger N, Sokol E, Graf R, Hiemenz M, Maule J, Parimi V, Palmieri C, Pusztai L, Ross J, Huang R. Variable Landscape of PD-L1 Expression in Breast Carcinoma as Detected by the DAKO 22C3 Immunohistochemistry Assay. The Oncologist 2023, 28: 319-326. PMID: 36866462, PMCID: PMC10078903, DOI: 10.1093/oncolo/oyad025.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerPD-L1 expressionNegative triple negative breast cancerTNBC tissue samplesPD-L1 positivityPD-L1Dako 22C3Breast cancerDeath ligand 1 (PD-L1) immunohistochemistry (IHC) assaysPD-L1 groupNon-TNBC patientsTissue samplesComprehensive genomic profilingBreast cancer subtypesFoundationOne CDxImmunotherapy efficacyMetastatic sitesTNBC casesBC patientsBreast carcinomaPositive statusImmunohistochemistry assaysOptimum cutoffCancer subtypesGenomic profiling
2022
PD-L1 protein expression in relation to recurrence score values in early-stage ER + breast cancer
Rozenblit M, Blenman K, Harigopal M, Reisenbichler E, Singh K, Qing T, Ibrahim E, Ramkissoon S, Asmelash S, Lin HK, Roberts M, Ross J, Huang RSP, Pusztai L. PD-L1 protein expression in relation to recurrence score values in early-stage ER + breast cancer. Breast Cancer Research And Treatment 2022, 196: 221-227. PMID: 36028784, DOI: 10.1007/s10549-022-06712-2.Peer-Reviewed Original ResearchConceptsPD-L1 positivityPD-L1 protein expressionPD-L1 expressionGrade 3 cancersPD-L1TIL scoreTumor gradeMultivariate analysisHigher PD-L1 positivityTumor-infiltrating lymphocyte countsConclusionPD-L1 expressionProtein expressionPD-L1 immunohistochemistryChi-square testResultsPD-L1T1 cancersLymphocyte countT3 tumorsIndependent predictorsTumor sizeLarge tumorsPositivity rateCell positivityBreast cancerGrade 2Tumor immune microenvironment of self-identified African American and non-African American triple negative breast cancer
Marczyk M, Qing T, O’Meara T, Yagahoobi V, Pelekanou V, Bai Y, Reisenbichler E, Cole KS, Li X, Gunasekharan V, Ibrahim E, Fanucci K, Wei W, Rimm DL, Pusztai L, Blenman KRM. Tumor immune microenvironment of self-identified African American and non-African American triple negative breast cancer. Npj Breast Cancer 2022, 8: 88. PMID: 35869114, PMCID: PMC9307813, DOI: 10.1038/s41523-022-00449-3.Peer-Reviewed Original ResearchTumor immune microenvironmentImmune microenvironmentTriple-negative breast cancer tissuesTriple-negative breast cancerAfrican AmericansImmune checkpoint inhibitorsTumor mutation burdenNegative breast cancerBreast cancer tissuesImmune-related pathwaysStromal TILsCheckpoint inhibitorsImmune exclusionClinical outcomesPD-L1Self-identified African AmericansCancer patientsImmune infiltrationBreast cancerMutation burdenCancer tissuesPredictive signatureMRNA expressionTherapeutic agentsPatients
2021
Quantitative assessment of the immune microenvironment in African American Triple Negative Breast Cancer: a case–control study
Yaghoobi V, Moutafi M, Aung TN, Pelekanou V, Yaghoubi S, Blenman K, Ibrahim E, Vathiotis IA, Shafi S, Sharma A, O’Meara T, Fernandez AI, Pusztai L, Rimm DL. Quantitative assessment of the immune microenvironment in African American Triple Negative Breast Cancer: a case–control study. Breast Cancer Research 2021, 23: 113. PMID: 34906209, PMCID: PMC8670126, DOI: 10.1186/s13058-021-01493-w.Peer-Reviewed Original ResearchConceptsNegative breast cancerT cellsTumor microenvironmentAA patientsImmune cellsAA tumorsBreast cancerPurposeTriple-negative breast cancerAfrican AmericansTriple-negative breast cancerCase-control studySignificant differencesActivated T cellsImmunologic biomarkersPD-L1Lymphocytic infiltrationLymphoid infiltrationImmune microenvironmentControl cohortTNBC tumorsMyeloid markersQuantitative immunofluorescenceMean expression levelPatientsTNBCNeoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer
Foldi J, Silber A, Reisenbichler E, Singh K, Fischbach N, Persico J, Adelson K, Katoch A, Horowitz N, Lannin D, Chagpar A, Park T, Marczyk M, Frederick C, Burrello T, Ibrahim E, Qing T, Bai Y, Blenman K, Rimm DL, Pusztai L. Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer. Npj Breast Cancer 2021, 7: 9. PMID: 33558513, PMCID: PMC7870853, DOI: 10.1038/s41523-021-00219-7.Peer-Reviewed Original ResearchStromal tumor-infiltrating lymphocytesWeekly nab-paclitaxelTriple-negative breast cancerPD-L1Nab-paclitaxelAdverse eventsBreast cancerGrade 3/4 treatment-related adverse eventsPhase I/II trialGrade 3/4 adverse eventsTreatment-related adverse eventsDoxorubicin/cyclophosphamidePhase II studyGuillain-Barre syndromeMononuclear inflammatory cellsPathologic complete responseTumor-infiltrating lymphocytesTumor cell stainingEvaluable patientsNeoadjuvant durvalumabSP263 antibodyII trialNeoadjuvant chemotherapyNeoadjuvant therapyPrimary endpoint
2020
Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers
Rozenblit M, Huang R, Danziger N, Hegde P, Alexander B, Ramkissoon S, Blenman K, Ross JS, Rimm DL, Pusztai L. Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers. Journal For ImmunoTherapy Of Cancer 2020, 8: e001558. PMID: 33239417, PMCID: PMC7689582, DOI: 10.1136/jitc-2020-001558.Peer-Reviewed Original ResearchConceptsPD-L1 positivity ratePD-L1 positivityPD-L1 expressionDifferent metastatic sitesPrimary tumorMetastatic sitesPositivity rateImmune cellsMetastatic lesionsTumor cellsPD-L1 protein expressionTriple-negative breast cancerMore primary tumorsTriple negative breast cancer tumorsPrimary breast lesionsPrimary outcome measureSoft tissueNegative breast cancerLow positivity rateBreast cancer tumorsBone metastasesFoundation MedicineLymph nodesPD-L1Spearman correlation coefficientPD-L1 Protein Expression on Both Tumor Cells and Macrophages are Associated with Response to Neoadjuvant Durvalumab with Chemotherapy in Triple-negative Breast Cancer
Ahmed FS, Gaule P, McGuire J, Patel K, Blenman K, Pusztai L, Rimm DL. PD-L1 Protein Expression on Both Tumor Cells and Macrophages are Associated with Response to Neoadjuvant Durvalumab with Chemotherapy in Triple-negative Breast Cancer. Clinical Cancer Research 2020, 26: 5456-5461. PMID: 32709714, PMCID: PMC7572612, DOI: 10.1158/1078-0432.ccr-20-1303.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntigens, CDAntigens, Differentiation, MyelomonocyticAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenBiomarkers, TumorCell ProliferationFemaleGene Expression Regulation, NeoplasticHumansLymphocytes, Tumor-InfiltratingMacrophagesMiddle AgedNeoadjuvant TherapyProgrammed Cell Death 1 ReceptorTriple Negative Breast NeoplasmsConceptsTriple-negative breast cancerPD-L1 expressionNeoadjuvant durvalumabTumor cellsImmune cellsBreast cancerPretreatment core-needle biopsiesPhase I/II clinical trialsPD-L1 protein expressionIMpassion 130 trialCore needle biopsyAmount of CD68Neoadjuvant settingMetastatic settingPD-L1Clinical trialsNeedle biopsyInsufficient tissuePatientsCD68Stromal compartmentQuantitative immunofluorescenceChemotherapyFinal analysisProtein expressionBiomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD‐L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer
Huang RSP, Li X, Haberberger J, Sokol E, Severson E, Duncan DL, Hemmerich A, Edgerly C, Williams E, Elvin J, Vergilio J, Killian J, Lin D, Hiemenz M, Xiao J, McEwan D, Holmes O, Danziger N, Erlich R, Frampton G, Cohen M, McGregor K, Reddy P, Cardeiro D, Anhorn R, Venstrom J, Alexander B, Brown C, Pusztai L, Ross J, Ramkissoon S. Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD‐L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer. The Oncologist 2020, 25: 943-953. PMID: 32869930, PMCID: PMC7648336, DOI: 10.1634/theoncologist.2020-0449.Peer-Reviewed Original ResearchConceptsComprehensive genomic profilingPD-L1 immunohistochemistryPotential therapeutic optionBreast cancerPD-L1Therapeutic optionsTriple negative breast cancer cohortDrug AdministrationHormone receptor-positive breast cancerReceptor-positive breast cancerGenomic profilingTriple-negative breast cancerPD-L1 positivityRoutine clinical careMutations/MbBreast cancer cohortBiomarker landscapeTNBC cohortNab-paclitaxelGermline testingConsecutive patientsReceptor negativeHER2-positiveClinical trialsPIK3CA mutationsProspective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer
Reisenbichler ES, Han G, Bellizzi A, Bossuyt V, Brock J, Cole K, Fadare O, Hameed O, Hanley K, Harrison BT, Kuba MG, Ly A, Miller D, Podoll M, Roden AC, Singh K, Sanders MA, Wei S, Wen H, Pelekanou V, Yaghoobi V, Ahmed F, Pusztai L, Rimm DL. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer. Modern Pathology 2020, 33: 1746-1752. PMID: 32300181, PMCID: PMC8366569, DOI: 10.1038/s41379-020-0544-x.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerNegative breast cancerOverall percent agreementPD-L1Intraclass correlation coefficientBreast cancerAdvanced triple-negative breast cancerPD-L1 positive casesImmune cell stainingMultiple pathologistsPD-L1 scoringMulti-institutional evaluationLung cancer studiesAtezolizumab therapySP142 assaySP263 assaysPatient selectionSP263SP142US FoodDrug AdministrationPathologist's assessmentPositive casesReal-world settingPercent agreement
2019
LBA8_PR KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)
Schmid P, Cortés J, Dent R, Pusztai L, McArthur H, Kuemmel S, Bergh J, Denkert C, Park Y, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching P, Cardoso F, Jia L, Karantza V, Zhao J, Aktan G, O’Shaughnessy J. LBA8_PR KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Annals Of Oncology 2019, 30: v853-v854. DOI: 10.1093/annonc/mdz394.003.Peer-Reviewed Original ResearchEarly triple-negative breast cancerTriple-negative breast cancerEvent-free survivalSubsidiary of MerckGerman Study GroupBristol-Myers SquibbPD-L1Dohme Corp.Daiichi SankyoSeattle GeneticsChemo groupYpT0 ypN0Merck SharpGenomic HealthStudy groupFavorable trendF. Hoffmann-La Roche LtdCycles of paclitaxelDual primary endpointsI-SPY 2Cycles of doxorubicinPhase III studyWolters Kluwer HealthEli LillyKyowa Hakko KirinReanalysis of the NCCN PD-L1 companion diagnostic assay study for lung cancer in the context of PD-L1 expression findings in triple-negative breast cancer
Rimm DL, Han G, Taube JM, Yi ES, Bridge JA, Flieder DB, Homer R, Roden AC, Hirsch FR, Wistuba II, Pusztai L. Reanalysis of the NCCN PD-L1 companion diagnostic assay study for lung cancer in the context of PD-L1 expression findings in triple-negative breast cancer. Breast Cancer Research 2019, 21: 72. PMID: 31196152, PMCID: PMC6567382, DOI: 10.1186/s13058-019-1156-6.Peer-Reviewed Original ResearchConceptsPD-L1 expressionImmune cell PD-L1 expressionLung cancerImmune cellsTriple-negative breast cancerEasy scoring methodCompanion diagnostic testsPD-L1Immune therapyBreast cancerImmunohistochemical testsBetter outcomesLarger studyTumor cellsDiagnostic testsCancerExpression findingsCellsExpressionPoor agreementScoring methodTherapyTrialsQuantitative assessment of immune cell populations and associations with clinical outcomes in African-American (AA) versus Caucasian triple-negative breast cancer (TNBC).
O'Meara T, Yaghoobi V, Blenman K, Pelekanou V, Silber A, Rimm D, Pusztai L. Quantitative assessment of immune cell populations and associations with clinical outcomes in African-American (AA) versus Caucasian triple-negative breast cancer (TNBC). Journal Of Clinical Oncology 2019, 37: e14180-e14180. DOI: 10.1200/jco.2019.37.15_suppl.e14180.Peer-Reviewed Original ResearchTriple-negative breast cancerDisease-free survivalBetter disease-free survivalPD-L1 expressionCD68 expressionAA TNBCStromal PD-L1 expressionPD-L1 protein expressionCaucasian casesHigher TIL countsTumor immune microenvironmentImmune cell populationsHigh CD68 expressionHigh CD68Similar CD8Stromal TILsClinical characteristicsDiagnosis dateTIL countPD-L1Clinical outcomesPredictive factorsCD8 expressionClinical variablesImmune microenvironment
2018
Immunological differences between primary and metastatic breast cancer
Szekely B, Bossuyt V, Li X, Wali VB, Patwardhan GA, Frederick C, Silber A, Park T, Harigopal M, Pelekanou V, Zhang M, Yan Q, Rimm DL, Bianchini G, Hatzis C, Pusztai L. Immunological differences between primary and metastatic breast cancer. Annals Of Oncology 2018, 29: 2232-2239. PMID: 30203045, DOI: 10.1093/annonc/mdy399.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAntineoplastic Agents, ImmunologicalB7-H1 AntigenBiomarkers, TumorBiopsyBreast NeoplasmsDisease ProgressionDrug Resistance, NeoplasmFemaleGene Expression RegulationHumansImmunologic SurveillanceLymphocyte CountLymphocytes, Tumor-InfiltratingMiddle AgedMutation RateTumor EscapeTumor MicroenvironmentYoung AdultConceptsMetastatic breast cancerBreast cancerTherapeutic targetToll-like receptor pathway genesImmuno-oncology therapeutic targetsBreast cancer evolvesImmune proteasome expressionPD-L1 positivityCorresponding primary tumorsPotential therapeutic targetMHC class IImmune-related genesMetastatic cancer samplesLigand/receptor pairLymphocyte countT helperT-regsPD-L1Immune microenvironmentCytotoxic TPrimary tumorMastoid cellsDisease progressionTherapeutic combinationsMacrophage markersTumor infiltrating lymphocytes and PD-L1 expression in pre- and post-treatment breast cancers in the SWOG S0800 Phase II neoadjuvant chemotherapy trial
Pelekanou V, Barlow WE, Nahleh Z, Wasserman B, Lo YC, von Wahlde MK, Hayes D, Hortobagyi GN, Gralow J, Tripathy D, Porter P, Szekely B, Hatzis C, Rimm DL, Pusztai L. Tumor infiltrating lymphocytes and PD-L1 expression in pre- and post-treatment breast cancers in the SWOG S0800 Phase II neoadjuvant chemotherapy trial. Molecular Cancer Therapeutics 2018, 17: molcanther.1005.2017. PMID: 29588392, PMCID: PMC6548451, DOI: 10.1158/1535-7163.mct-17-1005.Peer-Reviewed Original ResearchConceptsPD-L1 expressionPathologic complete responseTIL countPosttreatment tissuePD-L1Estrogen receptorImmune checkpoint inhibitor therapyPD-L1 positivity rateTumor-infiltrating lymphocyte countsDoxorubicin/cyclophosphamideCheckpoint inhibitor therapyPD-L1 levelsMol Cancer TherNab-paclitaxelLymphocyte countResidual cancerComplete responseER statusImmune changesInhibitor therapyCox regressionPatient populationControl armClinical trialsPositivity rate
2016
Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. Journal Of Clinical Oncology 2016, 34: 2460-2467. PMID: 27138582, PMCID: PMC6816000, DOI: 10.1200/jco.2015.64.8931.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerAdvanced triple-negative breast cancerPD-L1Antitumor activityBreast cancerCell death protein 1 (PD-1) inhibitorsSingle-agent phase II studyAdvanced PD-L1Single-agent pembrolizumabStudy of immunotherapyTreatment-related deathsImmune checkpoint inhibitionPhase Ib studyPhase Ib trialPhase II studyAcceptable safety profilePD-L1 expressionOverall response rateProtein 1 inhibitorCommon toxicitiesIb trialKEYNOTE-012TNBC cohortII studyMedian duration
2015
PD-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