2023
Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno‐Oncology Biomarker Working Group on Breast Cancer
Page D, Broeckx G, Jahangir C, Verbandt S, Gupta R, Thagaard J, Khiroya R, Kos Z, Abduljabbar K, Haab G, Acs B, Akturk G, Almeida J, Alvarado‐Cabrero I, Azmoudeh‐Ardalan F, Badve S, Baharun N, Bellolio E, Bheemaraju V, Blenman K, Fujimoto L, Bouchmaa N, Burgues O, Cheang M, Ciompi F, Cooper L, Coosemans A, Corredor G, Portela F, Deman F, Demaria S, Dudgeon S, Elghazawy M, Ely S, Fernandez‐Martín C, Fineberg S, Fox S, Gallagher W, Giltnane J, Gnjatic S, Gonzalez‐Ericsson P, Grigoriadis A, Halama N, Hanna M, Harbhajanka A, Hardas A, Hart S, Hartman J, Hewitt S, Hida A, Horlings H, Husain Z, Hytopoulos E, Irshad S, Janssen E, Kahila M, Kataoka T, Kawaguchi K, Kharidehal D, Khramtsov A, Kiraz U, Kirtani P, Kodach L, Korski K, Kovács A, Laenkholm A, Lang‐Schwarz C, Larsimont D, Lennerz J, Lerousseau M, Li X, Ly A, Madabhushi A, Maley S, Narasimhamurthy V, Marks D, McDonald E, Mehrotra R, Michiels S, Minhas F, Mittal S, Moore D, Mushtaq S, Nighat H, Papathomas T, Penault‐Llorca F, Perera R, Pinard C, Pinto‐Cardenas J, Pruneri G, Pusztai L, Rahman A, Rajpoot N, Rapoport B, Rau T, Reis‐Filho J, Ribeiro J, Rimm D, Vincent‐Salomon A, Salto‐Tellez M, Saltz J, Sayed S, Siziopikou K, Sotiriou C, Stenzinger A, Sughayer M, Sur D, Symmans F, Tanaka S, Taxter T, Tejpar S, Teuwen J, Thompson E, Tramm T, Tran W, van der Laak J, van Diest P, Verghese G, Viale G, Vieth M, Wahab N, Walter T, Waumans Y, Wen H, Yang W, Yuan Y, Adams S, Bartlett J, Loibl S, Denkert C, Savas P, Loi S, Salgado R, Stovgaard E. Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno‐Oncology Biomarker Working Group on Breast Cancer. The Journal Of Pathology 2023, 260: 514-532. PMID: 37608771, PMCID: PMC11288334, DOI: 10.1002/path.6165.Peer-Reviewed Original ResearchMeSH KeywordsBenchmarkingBiomarkersColonic NeoplasmsHumansLymphocytes, Tumor-InfiltratingSpatial AnalysisTumor MicroenvironmentPitfalls in machine learning‐based assessment of tumor‐infiltrating lymphocytes in breast cancer: A report of the International Immuno‐Oncology Biomarker Working Group on Breast Cancer
Thagaard J, Broeckx G, Page D, Jahangir C, Verbandt S, Kos Z, Gupta R, Khiroya R, Abduljabbar K, Haab G, Acs B, Akturk G, Almeida J, Alvarado‐Cabrero I, Amgad M, Azmoudeh‐Ardalan F, Badve S, Baharun N, Balslev E, Bellolio E, Bheemaraju V, Blenman K, Fujimoto L, Bouchmaa N, Burgues O, Chardas A, Cheang M, Ciompi F, Cooper L, Coosemans A, Corredor G, Dahl A, Portela F, Deman F, Demaria S, Hansen J, Dudgeon S, Ebstrup T, Elghazawy M, Fernandez‐Martín C, Fox S, Gallagher W, Giltnane J, Gnjatic S, Gonzalez‐Ericsson P, Grigoriadis A, Halama N, Hanna M, Harbhajanka A, Hart S, Hartman J, Hauberg S, Hewitt S, Hida A, Horlings H, Husain Z, Hytopoulos E, Irshad S, Janssen E, Kahila M, Kataoka T, Kawaguchi K, Kharidehal D, Khramtsov A, Kiraz U, Kirtani P, Kodach L, Korski K, Kovács A, Laenkholm A, Lang‐Schwarz C, Larsimont D, Lennerz J, Lerousseau M, Li X, Ly A, Madabhushi A, Maley S, Narasimhamurthy V, Marks D, McDonald E, Mehrotra R, Michiels S, Minhas F, Mittal S, Moore D, Mushtaq S, Nighat H, Papathomas T, Penault‐Llorca F, Perera R, Pinard C, Pinto‐Cardenas J, Pruneri G, Pusztai L, Rahman A, Rajpoot N, Rapoport B, Rau T, Reis‐Filho J, Ribeiro J, Rimm D, Roslind A, Vincent‐Salomon A, Salto‐Tellez M, Saltz J, Sayed S, Scott E, Siziopikou K, Sotiriou C, Stenzinger A, Sughayer M, Sur D, Fineberg S, Symmans F, Tanaka S, Taxter T, Tejpar S, Teuwen J, Thompson E, Tramm T, Tran W, van der Laak J, van Diest P, Verghese G, Viale G, Vieth M, Wahab N, Walter T, Waumans Y, Wen H, Yang W, Yuan Y, Zin R, Adams S, Bartlett J, Loibl S, Denkert C, Savas P, Loi S, Salgado R, Stovgaard E. Pitfalls in machine learning‐based assessment of tumor‐infiltrating lymphocytes in breast cancer: A report of the International Immuno‐Oncology Biomarker Working Group on Breast Cancer. The Journal Of Pathology 2023, 260: 498-513. PMID: 37608772, PMCID: PMC10518802, DOI: 10.1002/path.6155.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiomarkersHumansLymphocytes, Tumor-InfiltratingMachine LearningMammary Neoplasms, AnimalTriple Negative Breast NeoplasmsConceptsTumor-infiltrating lymphocytesTriple-negative breast cancerBreast cancerTIL assessmentHER2-positive breast cancerRoutine clinical managementTIL evaluationTumor-immune interactionsClinical managementDiscordant assessmentsClinical significancePrognostic biomarkerTIL quantificationCancerDaily practicePatientsTrialsTissue patternsAssessmentLymphocytesBiomarkers
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 ResearchMeSH KeywordsB7-H1 AntigenBiomarkers, TumorBreast NeoplasmsFemaleHumansLymphocyte CountLymphocytes, Tumor-InfiltratingPrognosisConceptsPD-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 2
2020
PD-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 expression
2019
Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial.
Sharma P, Barlow WE, Godwin AK, Parkes EE, Knight LA, Walker SM, Kennedy RD, Harkin DP, Logan GE, Steele CJ, Lambe SM, Badve S, Gökmen-Polar Y, Pathak HB, Isakova K, Linden HM, Porter P, Pusztai L, Thompson AM, Tripathy D, Hortobagyi GN, Hayes DF. Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial. Journal Of Clinical Oncology 2019, 37: 3484-3492. PMID: 31657982, PMCID: PMC7194448, DOI: 10.1200/jco.19.00693.Peer-Reviewed Original ResearchConceptsStromal tumor-infiltrating lymphocytesTriple-negative breast cancerDisease-free survivalOverall survivalImmune response signaturesBreast cancerEarly-stage triple-negative breast cancerThree-year disease-free survivalParaffin-embedded tumor tissueThird of patientsTumor-infiltrating lymphocytesSubgroup of patientsCox regression modelResponse signatureAdjuvant ACAdjuvant doxorubicinSTIL densityT2N0 diseaseAC chemotherapyNodal statusPrognostic roleImproved prognosisPrognostic valueTumor sizePrognostic markerImmune profiling of pre- and post-treatment breast cancer tissues from the SWOG S0800 neoadjuvant trial
Li X, Warren S, Pelekanou V, Wali V, Cesano A, Liu M, Danaher P, Elliott N, Nahleh ZA, Hayes DF, Hortobagyi GN, Barlow WE, Hatzis C, Pusztai L. Immune profiling of pre- and post-treatment breast cancer tissues from the SWOG S0800 neoadjuvant trial. Journal For ImmunoTherapy Of Cancer 2019, 7: 88. PMID: 30967156, PMCID: PMC6457012, DOI: 10.1186/s40425-019-0563-7.Peer-Reviewed Original ResearchConceptsPathologic complete responseResidual diseaseTIL countGene expression levelsHigh expressionCellular stressNeoadjuvant chemotherapyImmune genesImmune-related genesStromal genesImmune functionImmune microenvironment changesMost immune functionsGenesCell typesPD-L1 protein expressionStem cellsHigher TIL countsPD-L1 expressionExpression levelsPrimary breast cancerT-cell markersImmune cell typesProtein expressionStromal functionImmune microenvironment of triple-negative breast cancer in African-American and Caucasian women
O’Meara T, Safonov A, Casadevall D, Qing T, Silber A, Killelea B, Hatzis C, Pusztai L. Immune microenvironment of triple-negative breast cancer in African-American and Caucasian women. Breast Cancer Research And Treatment 2019, 175: 247-259. PMID: 30725384, PMCID: PMC6666415, DOI: 10.1007/s10549-019-05156-5.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerCaucasian breast cancersER-positive cancersBreast cancerTIL countImmune microenvironmentCaucasian patientsMolecular subtypesAA TNBCHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Pathologic complete responseGrowth factor receptor 2Immune cell distributionImmune cell populationsCancer Genome Atlas (TCGA) databaseConsistent racial differencesFactor receptor 2Immune gene expressionImmune attenuationNeoadjuvant chemotherapyLymphocyte countLymphocyte infiltrationComplete responseTNBC cases
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
2017
Association Between Genomic Metrics and Immune Infiltration in Triple-Negative Breast Cancer
Karn T, Jiang T, Hatzis C, Sänger N, El-Balat A, Rody A, Holtrich U, Becker S, Bianchini G, Pusztai L. Association Between Genomic Metrics and Immune Infiltration in Triple-Negative Breast Cancer. JAMA Oncology 2017, 3: 1707-1711. PMID: 28750120, PMCID: PMC5824276, DOI: 10.1001/jamaoncol.2017.2140.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorCohort StudiesGene DosageGene Expression ProfilingGene Expression Regulation, NeoplasticGenetic HeterogeneityHumansImmunologic SurveillanceLymphocyte CountLymphocytes, Tumor-InfiltratingPrognosisSequence Analysis, DNASequence Analysis, RNASurvival AnalysisTriple Negative Breast NeoplasmsConceptsTriple-negative breast cancerImmune infiltrationTNBC cohortBetter prognosisPrognostic categoriesPoor prognosisInverse associationBreast cancerImmune surveillanceImmune checkpoint inhibitor therapyMore effective immunotherapy strategiesSubset of TNBCLow immune cell infiltrationClonal heterogeneityCheckpoint inhibitor therapySelection of patientsImmune cell infiltrationEffective immunotherapy strategiesIndependent validation cohortPatient survival informationLymphocyte countImmunotherapy strategiesInhibitor therapyNeoantigen loadValidation cohortEffect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance
Pelekanou V, Carvajal-Hausdorf DE, Altan M, Wasserman B, Carvajal-Hausdorf C, Wimberly H, Brown J, Lannin D, Pusztai L, Rimm DL. Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance. Breast Cancer Research 2017, 19: 91. PMID: 28784153, PMCID: PMC5547502, DOI: 10.1186/s13058-017-0884-8.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedB7-H1 AntigenBreast NeoplasmsCD8-Positive T-LymphocytesDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansLymphocytes, Tumor-InfiltratingMiddle AgedNeoadjuvant TherapyPrognosisConceptsStromal tumor-infiltrating lymphocytesPD-L1 expressionTumor-infiltrating lymphocytesRecurrence-free survivalNeoadjuvant chemotherapyResidual cancer tissueTIL countBreast cancerCancer tissuesDeath ligand 1 (PD-L1) protein expressionNode-positive breast cancerImproved recurrence-free survivalPD-L1 protein expressionHigher TIL countsPD-L1 statusProtein expressionBreast cancer patientsBreast cancer tissuesPost-treatment samplesPrechemotherapy samplesTIL infiltrationResidual cancerImmune markersResidual diseasePatient cohortImmune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer
Safonov A, Jiang T, Bianchini G, Győrffy B, Karn T, Hatzis C, Pusztai L. Immune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer. Cancer Research 2017, 77: 3317-3324. PMID: 28428277, DOI: 10.1158/0008-5472.can-16-3478.Peer-Reviewed Original ResearchMeSH KeywordsBreast NeoplasmsChromosome AberrationsFemaleGene Expression ProfilingGene Expression RegulationHumansLymphocytes, Tumor-InfiltratingTranscriptomeConceptsTumor-infiltrating lymphocytesBreast cancer subtypesImmune infiltrationNeoantigen loadImmune surveillanceLower clonal heterogeneityCancer subtypesHigher immune gene expressionClonal heterogeneityImmune checkpoint inhibitorsMajor breast cancer subtypesFavorable prognostic factorTriple-negative cancersOverall mutation loadImmune gene expressionCheckpoint inhibitorsCancer Genome AtlasPrognostic factorsImmune metagenesBreast cancerCNV loadMutation loadGermline polymorphismsCancerCancer Res
2016
Quantitative assessment of the spatial heterogeneity of tumor-infiltrating lymphocytes in breast cancer
Mani NL, Schalper KA, Hatzis C, Saglam O, Tavassoli F, Butler M, Chagpar AB, Pusztai L, Rimm DL. Quantitative assessment of the spatial heterogeneity of tumor-infiltrating lymphocytes in breast cancer. Breast Cancer Research 2016, 18: 78. PMID: 27473061, PMCID: PMC4966732, DOI: 10.1186/s13058-016-0737-x.Peer-Reviewed Original ResearchConceptsIntraclass correlation coefficientQuantitative immunofluorescenceBreast cancerSame cancerSingle biopsyMultiplexed quantitative immunofluorescenceTumor-infiltrating lymphocytesPotential predictive markerPrimary breast carcinomaCytokeratin-positive epithelial cellsCD20-positive lymphocytesCD8 levelsLymphocyte scoreQIF scoresLymphocyte countLymphocyte subpopulationsMultiple biopsiesSubpopulation countsPredictive markerPrognostic informationBreast carcinomaBiopsyB lymphocytesCD3Breast tumors
2015
Immunotherapy opportunities in breast cancer.
Pusztai L, Ladányi A, Székely B, Dank M. Immunotherapy opportunities in breast cancer. Magyar Onkológia 2015, 60: 34-40. PMID: 26934349.Peer-Reviewed Original ResearchMeSH KeywordsBreast NeoplasmsFemaleHumansImmunotherapyLymphocytes, Tumor-InfiltratingPrognosisProgrammed Cell Death 1 ReceptorConceptsAnti-tumor immune responseLocal anti-tumour immune responseBreast cancerImmune responseClinical trialsEffective immune checkpoint inhibitorsEarly-stage breast cancerTriple-negative breast cancerPhase I clinical trialImmune checkpoint inhibitorsTumor response rateExtensive lymphocytic infiltrationPD-L1 antibodiesDirect clinical evidenceBreast cancer patientsStage breast cancerNew treatment modalitiesNegative breast cancerCheckpoint inhibitorsChemotherapy regimensMetastatic settingNeoadjuvant chemotherapyLymphocytic infiltrationClinical benefitClinical evidencePD-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 ResearchMeSH KeywordsAgedB7-H1 AntigenBiomarkers, TumorBreast NeoplasmsChemotherapy, AdjuvantCohort StudiesFemaleHumansLymphocytes, Tumor-InfiltratingMiddle AgedNeoadjuvant TherapyNeoplasm ProteinsPrognosisTreatment OutcomeConceptsTumor-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
In Situ Tumor PD-L1 mRNA Expression Is Associated with Increased TILs and Better Outcome in Breast Carcinomas
Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, Rimm DL. In Situ Tumor PD-L1 mRNA Expression Is Associated with Increased TILs and Better Outcome in Breast Carcinomas. Clinical Cancer Research 2014, 20: 2773-2782. PMID: 24647569, DOI: 10.1158/1078-0432.ccr-13-2702.Peer-Reviewed Original ResearchB7-H1 AntigenBreast NeoplasmsCell Line, TumorFemaleFluorescent Antibody TechniqueGene Expression Regulation, NeoplasticHumansIn Situ HybridizationKaplan-Meier EstimateLymphatic MetastasisLymphocytes, Tumor-InfiltratingMiddle AgedMultivariate AnalysisNeoplasm Recurrence, LocalPrognosisReceptor, ErbB-2Receptors, EstrogenRNA, MessengerTissue Array Analysis