2023
Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial
Rodler E, Sharma P, Barlow W, Gralow J, Puhalla S, Anders C, Goldstein L, Tripathy D, Brown-Glaberman U, Huynh T, Szyarto C, Godwin A, Pathak H, Swisher E, Radke M, Timms K, Lew D, Miao J, Pusztai L, Hayes D, Hortobagyi G. Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Oncology 2023, 24: 162-174. PMID: 36623515, PMCID: PMC9924094, DOI: 10.1016/s1470-2045(22)00739-2.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerMedian progression-free survivalProgression-free survivalMetastatic breast cancerMetastatic triple-negative breast cancerGermline BRCA1/2Phase 2 trialVeliparib groupPlacebo groupPlatinum-based chemotherapyBreast cancerHomologous recombination deficiencyAdverse eventsPARP inhibitorsEligible patientsMetastatic diseaseEastern Cooperative Oncology Group performance statusBRCA mutation-associated breast cancerInvestigator-assessed progression-free survivalTreatment-related adverse eventsRecurrent triple-negative breast cancerAcademic clinical sitesAddition of veliparibCommon grade 3Lines of chemotherapy
2022
Cancer Relevance of Human Genes
Qing T, Mohsen H, Cannataro VL, Marczyk M, Rozenblit M, Foldi J, Murray M, Townsend J, Kluger Y, Gerstein M, Pusztai L. Cancer Relevance of Human Genes. Journal Of The National Cancer Institute 2022, 114: 988-995. PMID: 35417011, PMCID: PMC9275765, DOI: 10.1093/jnci/djac068.Peer-Reviewed Original ResearchConceptsCore cancer genesHuman genesFunctional importanceSomatic mutation frequencySelection pressureGene/protein networksCancer genesHigher somatic mutation frequencyNegative selection pressureGene-gene interaction networksMutation frequencyProtein-truncating variantsGenomic contextCell viabilityGenes decreasesCancer Genome AtlasInteraction networksProtein networkCancer relevanceCancer cell viabilityCell survivalGenesCancer biologyGenome AtlasSearch tools
2021
Network propagation-based prioritization of long tail genes in 17 cancer types
Mohsen H, Gunasekharan V, Qing T, Seay M, Surovtseva Y, Negahban S, Szallasi Z, Pusztai L, Gerstein MB. Network propagation-based prioritization of long tail genes in 17 cancer types. Genome Biology 2021, 22: 287. PMID: 34620211, PMCID: PMC8496153, DOI: 10.1186/s13059-021-02504-x.Peer-Reviewed Original ResearchConceptsCancer-relevant genesTail genesMobility genesNetwork propagation approachGenome-wide RNAiNetwork propagation methodCancer developmentPotential functional impactCancer cell survivalNew genesUnreported genesFunctional screeningCancer typesFunctional importanceCancer genesNovel potential therapeutic targetDriver genesCell survivalGenesMutational distributionsBiological interactionsPotential therapeutic targetFunctional impactGenomic alterationsInfrequent mutationsDiverse immune response of DNA damage repair-deficient tumors
Qing T, Jun T, Lindblad KE, Lujambio A, Marczyk M, Pusztai L, Huang KL. Diverse immune response of DNA damage repair-deficient tumors. Cell Reports Medicine 2021, 2: 100276. PMID: 34095878, PMCID: PMC8149377, DOI: 10.1016/j.xcrm.2021.100276.Peer-Reviewed Original ResearchConceptsCancer typesDDR-deficient tumorsImmune checkpoint inhibitorsHigh neoantigen loadDifferent immune phenotypesDiverse immune responsesAdaptive immune markersRepair-deficient tumorsDDR deficiencyCheckpoint inhibitorsImmunotherapy outcomesDNA damage repair deficiencyImmune infiltratesImmune markersNeoantigen loadSurvival outcomesImmune phenotypeTumor neoantigensImmune responseAnimal modelsGenomic biomarkersGermline mutationsPathway mutationsTumorsRepair deficiencyWhole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers
Li X, Kumar S, Harmanci A, Li S, Kitchen RR, Zhang Y, Wali VB, Reddy SM, Woodward WA, Reuben JM, Rozowsky J, Hatzis C, Ueno NT, Krishnamurthy S, Pusztai L, Gerstein M. Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers. Genome Medicine 2021, 13: 70. PMID: 33902690, PMCID: PMC8077918, DOI: 10.1186/s13073-021-00879-x.Peer-Reviewed Original ResearchConceptsSingle nucleotide variantsWhole-genome sequencingGermline single nucleotide variantsInternational Cancer Genome ConsortiumGenomic featuresGenomic alterationsGenome ConsortiumClonal architectureWhole Genomes (PCAWG) ConsortiumNon-coding regionsCancer-related pathwaysNon-IBC samplesCancer Genome Atlas ProgramMAST2 geneCopy number profilesPan-cancer analysisTGF-β pathwayGenomic architectureGenomic regionsSimilar genomic alterationsSimilar genomic characteristicsComplex SVsIBC samplesGenomic differencesOverall mutational loadTargeted RNAseq assay incorporating unique molecular identifiers for improved quantification of gene expression signatures and transcribed mutation fraction in fixed tumor samples
Fu C, Marczyk M, Samuels M, Trevarton AJ, Qu J, Lau R, Du L, Pappas T, Sinn BV, Gould RE, Pusztai L, Hatzis C, Symmans WF. Targeted RNAseq assay incorporating unique molecular identifiers for improved quantification of gene expression signatures and transcribed mutation fraction in fixed tumor samples. BMC Cancer 2021, 21: 114. PMID: 33541297, PMCID: PMC7860187, DOI: 10.1186/s12885-021-07814-8.Peer-Reviewed Original ResearchConceptsPolymerase chain reactionParaffin-embedded tumor tissue samplesConcordance correlation coefficientFresh frozenFFPE samplesPrimary breast cancerMulti-gene signatureTumor tissue samplesActivating point mutationMutant allele fractionReverse transcriptionKey breast cancer genesGene expression signaturesBreast cancer genesPIK3CA mutationsBackgroundOur objectiveBreast cancerWhole transcriptome RNAseqTumor samplesLin's concordance correlation coefficientHormone receptorsFF samplesTissue samplesExpression signaturesChain reaction
2020
Analysis of Pre- and Posttreatment Tissues from the SWOG S0800 Trial Reveals an Effect of Neoadjuvant Chemotherapy on the Breast Cancer Genome
Powles RL, Wali VB, Li X, Barlow WE, Nahleh Z, Thompson AM, Godwin AK, Hatzis C, Pusztai L. Analysis of Pre- and Posttreatment Tissues from the SWOG S0800 Trial Reveals an Effect of Neoadjuvant Chemotherapy on the Breast Cancer Genome. Clinical Cancer Research 2020, 26: 1977-1984. PMID: 31919134, PMCID: PMC7717064, DOI: 10.1158/1078-0432.ccr-19-2405.Peer-Reviewed Original Research
2019
Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure
Criscione J, Ji W, Jeffries L, McGrath JM, Soloway S, Pusztai L, Lakhani S. Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure. Molecular Case Studies 2019, 5: a004374. PMID: 31653660, PMCID: PMC6913140, DOI: 10.1101/mcs.a004374.Peer-Reviewed Original ResearchConceptsPrimary open-angle glaucomaEarly-onset primary open-angle glaucomaOpen-angle glaucomaGenetic testingElevated intraocular pressureJuvenile-onset primary open-angle glaucomaFurther genetic testingAutosomal dominant patternFemale patientsIntraocular pressureIrreversible blindnessFamily historyEye disordersMYOC variantsMyocilin geneGlaucomaPOAG phenotypeHispanic familiesOlfactomedin domainPrevious findingsDominant patternVariant segregatesMost casesPatientsEtiology
2018
TQuest, A Web-Based Platform to Enable Precision Medicine by Linking a Tumor’s Genetic Defects to Therapeutic Options
Gershkovich P, Platt J, Knopf J, Tasoulis MK, Shi W, Pusztai L, Hatzis C. TQuest, A Web-Based Platform to Enable Precision Medicine by Linking a Tumor’s Genetic Defects to Therapeutic Options. JCO Clinical Cancer Informatics 2018, 2: 1-13. PMID: 30652574, DOI: 10.1200/cci.17.00120.Peer-Reviewed Original ResearchConceptsData acquisition layerFull-text indexAcquisition layerUser interfaceData layersPrototype web applicationWeb-based platformWeb applicationRelevance scoresSearch enginesSource codeSoftware toolsSearch resultsInterventional clinical trialsLabel dataClinical trialsTherapeutic optionsPlatformUS FoodMolecular abnormalitiesMetastatic breast cancerPotential therapeutic optionPotential treatment optionTumor DNA sequencingWeb-based modulesReliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity
Shi W, Ng CKY, Lim RS, Jiang T, Kumar S, Li X, Wali VB, Piscuoglio S, Gerstein MB, Chagpar AB, Weigelt B, Pusztai L, Reis-Filho JS, Hatzis C. Reliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity. Cell Reports 2018, 25: 1446-1457. PMID: 30404001, PMCID: PMC6261536, DOI: 10.1016/j.celrep.2018.10.046.Peer-Reviewed Original ResearchPhase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer
Dickler MN, Saura C, Richards DA, Krop IE, Cervantes A, Bedard PL, Patel MR, Pusztai L, Oliveira M, Cardenas AK, Cui N, Wilson TR, Stout TJ, Wei MC, Hsu JY, Baselga J. Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer. Clinical Cancer Research 2018, 24: 4380-4387. PMID: 29793946, PMCID: PMC6139036, DOI: 10.1158/1078-0432.ccr-18-0613.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDisease-Free SurvivalDrug-Related Side Effects and Adverse ReactionsFemaleFulvestrantHumansImidazolesMiddle AgedMutationOxazepinesReceptor, ErbB-2Receptors, EstrogenConceptsAdverse eventsClinical activityBreast cancerMutation statusOpen-label phase II studyHR-positive breast cancerHigher objective response rateConfirmatory phase III trialNCI CTCAE v4.0Median treatment durationObjective response ratePhase II studySerious adverse eventsNew safety signalsPhase III trialsPositive breast cancerClin Cancer ResIntramuscular fulvestrantMeasurable diseaseRECIST v1.1II studyIII trialsPostmenopausal womenUnacceptable toxicityTumor response
2017
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer
Chung JH, Pavlick D, Hartmaier R, Schrock AB, Young L, Forcier B, Ye P, Levin MK, Goldberg M, Burris H, Gay LM, Hoffman AD, Stephens PJ, Frampton GM, Lipson DM, Nguyen DM, Ganesan S, Park BH, Vahdat LT, Leyland-Jones B, Mughal TI, Pusztai L, O’Shaughnessy J, Miller VA, Ross JS, Ali SM. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer. Annals Of Oncology 2017, 28: 2866-2873. PMID: 28945887, PMCID: PMC5834148, DOI: 10.1093/annonc/mdx490.Peer-Reviewed Original ResearchConceptsEstrogen receptor-positive metastatic breast cancerMetastatic breast cancerBreast cancerGenomic profilingGenomic alterationsEstrogen receptor-positive breast cancerMetastatic breast cancer managementReceptor-positive breast cancerTumor DNACo-occurring genomic alterationsMetastatic tissue biopsiesTissue samplesRoutine clinical careBreast cancer managementCourse of diseasePeripheral blood samplesMetastatic tumor tissueMetastatic diseaseFemale patientsInvasive alternativeCtDNA fractionCancer managementClinical careBlood samplesPatientsPhylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations
Brown D, Smeets D, Székely B, Larsimont D, Szász AM, Adnet PY, Rothé F, Rouas G, Nagy ZI, Faragó Z, Tőkés AM, Dank M, Szentmártoni G, Udvarhelyi N, Zoppoli G, Pusztai L, Piccart M, Kulka J, Lambrechts D, Sotiriou C, Desmedt C. Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations. Nature Communications 2017, 8: 14944. PMID: 28429735, PMCID: PMC5474888, DOI: 10.1038/ncomms14944.Peer-Reviewed Original ResearchConceptsDistant metastasisPrimary tumorClonal frequency analysisMultiple metastatic lesionsBreast cancer disseminationBreast cancer progressionSomatic mutationsWhole-exome sequencingAvailable metastasesMetastatic lesionsMetastatic precursorsPrimary lesionMetastatic tumorsDisease progressionBreast cancerPatterns of disseminationMetastasisMetastatic progressionCancer disseminationPatientsCancer progressionCopy number profilingCopy number aberrationsTumorsMonoclonal originStructural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer
Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, Fan C, Huang M, Wong CC, Gong Q, Kumar-Sinha C, Zhang R, Pusztai L, Rai R, Chang S, Lei M. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nature Communications 2017, 8: 14929. PMID: 28393832, PMCID: PMC5394241, DOI: 10.1038/ncomms14929.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsConserved SequenceDNA DamageDNA Mutational AnalysisDNA RepairGenomic InstabilityHumansMiceModels, MolecularMolecular ChaperonesMutationNeoplasmsPhosphoproteinsProstaglandin-E SynthasesProtein BindingProtein Structure, SecondaryScattering, Small AngleShelterin ComplexStructure-Activity RelationshipTelomere-Binding ProteinsX-Ray DiffractionConceptsTelomerase-mediated telomere extensionHuman cancersDNA damage responseC-terminal mutationsOB foldsHuman POT1Chromosome endsGenome instabilityPOT1-TPP1Telomere extensionDamage responseStable heterodimerA-NHEJStructural insightsC-terminusInappropriate repairTPP1POT1Heart-shaped structureMissense mutationsTerminal portionMutationsDomainMutantsTelomeresIntratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer
von Wahlde MK, Timms KM, Chagpar A, Wali VB, Jiang T, Bossuyt V, Saglam O, Reid J, Gutin A, Neff C, Lanchbury JS, Hatzis C, Hofstatter E, Pusztai L. Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer. Clinical Cancer Research 2017, 23: 1193-1199. PMID: 27601588, DOI: 10.1158/1078-0432.ccr-16-0889.Peer-Reviewed Original ResearchPathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial
Shi W, Jiang T, Nuciforo P, Hatzis C, Holmes E, Harbeck N, Sotiriou C, Peña L, Loi S, Rosa DD, Chia S, Wardley A, Ueno T, Rossari J, Eidtmann H, Armour A, Piccart-Gebhart M, Rimm DL, Baselga J, Pusztai L. Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial. Annals Of Oncology 2017, 28: 128-135. PMID: 28177460, PMCID: PMC5834036, DOI: 10.1093/annonc/mdw434.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiopsy, Fine-NeedleBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDNA, NeoplasmExome SequencingFemaleHumansLapatinibMolecular Targeted TherapyMutationProportional Hazards ModelsProtein Kinase InhibitorsQuinazolinesReceptor, ErbB-2RhoA GTP-Binding ProteinTrastuzumabConceptsPathologic complete response
2016
Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer
Santarpia L, Bottai G, Kelly CM, Győrffy B, Székely B, Pusztai L. Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer. The Oncologist 2016, 21: 1063-1078. PMID: 27384237, PMCID: PMC5016060, DOI: 10.1634/theoncologist.2015-0369.Peer-Reviewed Original ResearchConceptsBreast cancerCancer-causing genesCopy number variationsRNA speciesRNA editingGenomic variationNext-generation sequencingRNA sequencingGenomic complexityGenomic portraitGreater genomic complexityOncogenic mutationsOncogenic eventsTarget profilingRare mutationsMutationsRecurrent mutationsSomatic variantsGenetic aberrationsFormal clinical trialsPotential therapeutic implicationsDriver mutationsSequencingGermline variantsMolecular abnormalities
2015
A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients
Pongor L, Kormos M, Hatzis C, Pusztai L, Szabó A, Győrffy B. A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients. Genome Medicine 2015, 7: 104. PMID: 26474971, PMCID: PMC4609150, DOI: 10.1186/s13073-015-0228-1.Peer-Reviewed Original ResearchConceptsRNA-seq dataNext-generation sequencingBreast cancer patientsTranscriptomic fingerprintGenome-wide approachesGeneration sequencingClinical outcomesCancer patientsHuman gene mutationsTumor suppressor geneGene chip dataSuch genesRNA-seqGene mutationsLarge breast cancer cohortGene expressionChip dataSuppressor geneBreast cancer cohortGenesMicroarray dataMutationsSomatic mutationsClinical characteristicsCox regressionCharacterization of DNA variants in the human kinome in breast cancer
Agarwal D, Qi Y, Jiang T, Liu X, Shi W, Wali VB, Turk B, Ross JS, Fraser Symmans W, Pusztai L, Hatzis C. Characterization of DNA variants in the human kinome in breast cancer. Scientific Reports 2015, 5: 14736. PMID: 26420498, PMCID: PMC4588561, DOI: 10.1038/srep14736.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBreast NeoplasmsFemaleGene Expression Regulation, NeoplasticGenetic Predisposition to DiseaseGenetic VariationHigh-Throughput Nucleotide SequencingHumansMiddle AgedMutationNeoplasm GradingNeoplasm MetastasisNeoplasm StagingPhosphotransferasesPolymorphism, Single NucleotideReproducibility of ResultsTranscriptomeConceptsBreast cancerHuman kinomeKinase geneGreater mutational loadNucleic acid variationPrimary cancer samplesPrimary breast cancerHistologic grade 1Major functional impactSOLiD sequencing platformIndividual breast cancersNon-synonymous variantsFine-needle biopsyGrade 3 casesCancer-related genesNucleotide variationsDNA variantsSequencing platformsMetastatic lesionsMutational loadAcid variationsCancer biologyGenesNeedle biopsyAdditional cancers
2014
A Targeted Next‐Generation Sequencing Assay Detects a High Frequency of Therapeutically Targetable Alterations in Primary and Metastatic Breast Cancers: Implications for Clinical Practice
Vasan N, Yelensky R, Wang K, Moulder S, Dzimitrowicz H, Avritscher R, Wang B, Wu Y, Cronin MT, Palmer G, Symmans WF, Miller VA, Stephens P, Pusztai L. A Targeted Next‐Generation Sequencing Assay Detects a High Frequency of Therapeutically Targetable Alterations in Primary and Metastatic Breast Cancers: Implications for Clinical Practice. The Oncologist 2014, 19: 453-458. PMID: 24710307, PMCID: PMC4012963, DOI: 10.1634/theoncologist.2013-0377.Peer-Reviewed Original ResearchConceptsBreast cancerGenomic alterationsV-akt murine thymoma viral oncogene homolog 1Stage IV cancerMetastatic breast cancerActionable genomic alterationsPotential treatment optionOncogene homolog 1Primary tumor biopsiesCancer-related genesClinical Laboratory Improvement AmendmentsDependent kinasesMedian sequencing depthGene fusionsSequencing depthBase substitutionsHER2 mutationsHomolog 1Actionable alterationsTargetable alterationsTreatment optionsClinical trialsHER2 amplificationMetastatic cancerTumor biopsies