2020
Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers
Lee S, Shimasaki N, Lim J, Wong A, Yadav K, Yong W, Tan L, Koh L, Poon M, Tan S, Ow S, Bharwani L, Yap Y, Foo M, Coustan-Smith E, Sundar R, Tan L, Chong W, Kumarakulasinghe N, Lieow J, Koe P, Goh B, Campana D. Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Clinical Cancer Research 2020, 26: 4494-4502. PMID: 32522887, DOI: 10.1158/1078-0432.ccr-20-0768.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiopsyBreast NeoplasmsCoculture TechniquesCombined Modality TherapyDose-Response Relationship, DrugFemaleHumansImmunotherapyK562 CellsKiller Cells, NaturalMaleMiddle AgedReceptor, ErbB-2Response Evaluation Criteria in Solid TumorsStomach NeoplasmsTransplantation, AutologousTrastuzumabConceptsAntibody-dependent cell cytotoxicityAutologous NK cellsNK cellsPhase I trialI trialNK cells expressed high levelsNatural killer (NK) cellsActivated autologous NK cellsHER2-positive solid tumorsPhase I dose escalationPeripheral blood NK cellsHER2-positive malignanciesNK cell infusionNK cell therapyBlood NK cellsNK cell expansionIncreased NK cellsPhase II trialPreliminary antitumor activityNK cell activityCells expressing high levelsHER2-positive cancersStable diseasePartial responseII trialCerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer
Malani R, Fleisher M, Kumthekar P, Lin X, Omuro A, Groves MD, Lin NU, Melisko M, Lassman AB, Jeyapalan S, Seidman A, Skakodub A, Boire A, DeAngelis LM, Rosenblum M, Raizer J, Pentsova E. Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer. Journal Of Neuro-Oncology 2020, 148: 599-606. PMID: 32506369, PMCID: PMC7438284, DOI: 10.1007/s11060-020-03555-z.Peer-Reviewed Original ResearchConceptsLeptomeningeal metastasesCSF cytologyCSF CTCsCTC enumerationCerebrospinal fluidIT trastuzumabPhase I/II dose escalation trialCentral nervous system compartmentTumor cellsHER2/neu positivityHER2/neu expressionDose-escalation trialHER2-positive cancersIntrathecal trastuzumabEscalation trialRadiographic responseTumor burdenPositive cancersNeu expressionNeu positivityConclusionOur studyPatientsDay 1Epithelial cancersCancer
2018
P05.10 Prospective evaluation of cerebrospinal fluid circulating tumor cells (CSF CTC) in patients with HER2 positive cancers and leptomeningeal metastases receiving treatment with intrathecal trastuzumab
Pentsova E, Malani R, Fleisher M, Lin X, Omuro A, Groves M, Lin N, Melisko M, Lassman A, Jeyapalan S, Boire A, DeAngelis L, Raizer J. P05.10 Prospective evaluation of cerebrospinal fluid circulating tumor cells (CSF CTC) in patients with HER2 positive cancers and leptomeningeal metastases receiving treatment with intrathecal trastuzumab. Neuro-Oncology 2018, 20: iii304-iii304. PMCID: PMC6144227, DOI: 10.1093/neuonc/noy139.336.Peer-Reviewed Original ResearchCSF CTCsLeptomeningeal metastasesCellSearch systemCTC enumerationCSF cytologyTreatment responsePhase I/II dose escalation trialDose-escalation trialPositive CSF cytologyCycles of treatmentHER2-positive cancersCycle 1Number of CTCsIntrathecal trastuzumabIT trastuzumabLM progressionEscalation trialIntrathecal therapyRadiographic responseVentricular reservoirRadiographic worseningProspective evaluationPositive cancersHER2 expressionCerebrospinal fluid
2017
Long-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy.
Wong Y, Raghavendra A, Hatzis C, Irizarry J, Vega T, Barcenas C, Chavez-Mac Gregor M, Valero V, Tripathy D, Pusztai L, Murthy R. Long-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy. Journal Of Clinical Oncology 2017, 35: 1021-1021. DOI: 10.1200/jco.2017.35.15_suppl.1021.Peer-Reviewed Original ResearchProgression-free survivalLonger progression-free survivalPositive breast cancerHER2-positive cancersMedian OSNED patientsOS ratesFree survivalOverall survivalPositive cancersBreast cancerDe novo stage IV diseaseHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2MD Anderson Cancer CenterStage IV diseaseAggressive multimodality therapyEvidence of diseaseFirst-line therapyGrowth factor receptor 2Year of diagnosisEarly-stage patientsAnderson Cancer CenterLong-term survival
2016
New Strategies in Breast Cancer: Immunotherapy
Pusztai L, Karn T, Safonov A, Abu-Khalaf MM, Bianchini G. New Strategies in Breast Cancer: Immunotherapy. Clinical Cancer Research 2016, 22: 2105-2110. PMID: 26867935, PMCID: PMC9359478, DOI: 10.1158/1078-0432.ccr-15-1315.Peer-Reviewed Original ResearchConceptsBreast cancerClinical trialsEffective immune checkpoint inhibitorsObjective tumor response rateEstrogen receptor-positive cancersLocal antitumor immune responsePhase I clinical trialImmune checkpoint inhibitorsTumor response rateAntitumor immune responseReceptor-positive cancersTriple-negative cancersLocal immune microenvironmentHER2-positive cancersMost breast cancersNew treatment modalitiesCheckpoint inhibitorsDurable responsesL1 antibodyLymphocytic infiltrationImmune microenvironmentImmune infiltrationTreatment modalitiesImmune responsePreclinical studies
2015
PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling
Cheng H, Liu P, Ohlson C, Xu E, Symonds L, Isabella A, Muller WJ, Lin NU, Krop IE, Roberts TM, Winer EP, Arteaga CL, Zhao JJ. PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 2015, 35: 2961-2970. PMID: 26640141, PMCID: PMC4896860, DOI: 10.1038/onc.2015.377.Peer-Reviewed Original ResearchConceptsBreast cancerPIK3CA mutationsMammary tumorsHER2 amplification/overexpressionHER2-positive breast cancerHER2-positive cancersPrimary mammary tumorsHER2/HER3PIK3CA-activating mutationsHER2/neuHuman breast cancerEffective treatment approachAmplification/overexpressionCompound mouse modelMEK-ERK signalingMouse mammary glandWorse prognosisCombination therapyMammary tumorigenesisMouse modelMutant PIK3CATreatment approachesHER2Combined inhibitionCompensatory activationCCR 20th Anniversary Commentary: Divide and Conquer—Breast Cancer Subtypes and Response to Therapy
Pusztai L, Rouzier R, Symmans WF. CCR 20th Anniversary Commentary: Divide and Conquer—Breast Cancer Subtypes and Response to Therapy. Clinical Cancer Research 2015, 21: 3575-3577. PMID: 26275950, DOI: 10.1158/1078-0432.ccr-14-3121.Peer-Reviewed Original ResearchConceptsBreast cancerPathologic complete response rateTriple-negative breast cancerAdjuvant treatment optionsResidual invasive diseaseComplete response rateHER2-positive cancersDifferent molecular subtypesClin Cancer ResClinical cancer researchAnniversary CommentaryNeoadjuvant therapyTreatment optionsInvasive diseaseClinical trialsMolecular subtypesResponse rateCancer subtypesCancer ResExtent of responseCancerSubtypesTherapyCancer researchChemotherapyThe Influence of Host Factors on the Prognosis of Breast Cancer: Stroma and Immune Cell Components as Cancer Biomarkers.
Karn T, Pusztai L, Rody A, Holtrich U, Becker S. The Influence of Host Factors on the Prognosis of Breast Cancer: Stroma and Immune Cell Components as Cancer Biomarkers. Current Cancer Drug Targets 2015, 15: 652-64. PMID: 26452382, DOI: 10.2174/156800961508151001101209.Peer-Reviewed Original ResearchConceptsBreast cancerPredictive markerImmune cellsStromal componentsHER2-positive breast cancerHigh lymphocytic infiltrationPositive breast cancerHER2-positive cancersImmune cell componentsNovel therapeutic optionsType breast cancerBreast cancer subtypesHost immunological responseImmunotherapeutic regimensClinical courseImmune markersLymphocytic infiltrationPositive cancersTherapeutic optionsInflammatory cellsClinical subtypingImmunological parametersClinical trialsImmune parametersImmunological response
2012
Trastuzumab Emtansine (T-DM1) for the Treatment of HER2-Positive Cancer with a Focus on Breast Cancer
Rugo H, Krop I, Chu Y. Trastuzumab Emtansine (T-DM1) for the Treatment of HER2-Positive Cancer with a Focus on Breast Cancer. Cancer Drug Discovery And Development 2012, 179-210. DOI: 10.1007/978-1-4614-5456-4_11.Peer-Reviewed Original ResearchBreast cancerHER2 overexpressionHuman epidermal growth factor receptor type 2Epidermal growth factor receptor type 2Factor receptor type 2Important histopathologic featureHER2-positive cancersReceptor type 2Epidermal growth factor receptorHuman solid tumorsProgression of tumorsGrowth factor receptorHistopathologic featuresPoor prognosisOncologic unitsTrastuzumab emtansinePancreatic cancerHER receptorsSolid tumorsType 2Malignant transformationCancerTyrosine kinase familyFactor receptorSubsequent activationA phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive (HER2+) breast cancer.
Munster P, Miller K, Krop I, Dhindsa N, Reynolds J, Geretti E, Niyikiza C, Nielsen U, Hendriks B, Wickham T, Moyo V, LoRusso P. A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive (HER2+) breast cancer. Journal Of Clinical Oncology 2012, 30: tps663-tps663. DOI: 10.1200/jco.2012.30.15_suppl.tps663.Peer-Reviewed Original ResearchAdvanced breast cancerMaximum feasible doseBreast cancerMM-302Liposomal doxorubicinHER2-positive breast cancerTumor cellsAdequate performance statusAnthracycline-free regimensBone marrow reserveDose-escalation portionClinical benefit rateDose-limiting toxicityDose-escalation designHER2-positive cancersPreliminary efficacy dataHuman phase IStandard therapy existsBreast cancer therapyAvailable anthracyclinesPrimary endpointSecondary endpointsMarrow reservePerformance statusStandard therapyClinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer
Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL, Burris III HA, LoRusso PM, Yi JH, Saad O, Tong B, Chu YW, Holden S, Joshi A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemotherapy And Pharmacology 2012, 69: 1229-1240. PMID: 22271209, PMCID: PMC3337408, DOI: 10.1007/s00280-011-1817-3.Peer-Reviewed Original ResearchConceptsSingle-agent T-DM1Anti-therapeutic antibodiesT-DM1 exposureTotal trastuzumabT-DM1Positive metastatic breast cancerHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Standard noncompartmental approachT-DM1 pharmacokineticsGrowth factor receptor 2Key adverse eventsMetastatic breast cancerHER2-positive cancersStable thioether linkerConcentrations of transaminasesFactor receptor 2Enzyme-linked immunosorbent assayEnzyme-linked immunosorbentHER2 extracellular domainAntibody-drug conjugatesEvaluable patientsPrior therapyClinical responseAdverse events
2011
Coping with uncertainty: T1a,bN0M0 HER2-positive breast cancer, do we have a treatment threshold?
Kelly CM, Pritchard KI, Trudeau M, Andreopoulou E, Hess K, Pusztai L. Coping with uncertainty: T1a,bN0M0 HER2-positive breast cancer, do we have a treatment threshold? Annals Of Oncology 2011, 22: 2387-2393. PMID: 21406473, DOI: 10.1093/annonc/mdq786.Peer-Reviewed Original ResearchConceptsHER2-positive breast cancerBreast cancerHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Baseline risk estimatesBN0M0 breast cancerHER2-positive cohortNode-negative T1aStudy end pointDisease-free survivalRisks of therapyGrowth factor receptor 2Subset of patientsPositive breast cancerRetrospective database analysisHER2-negative cancersRecent retrospective studiesHER2-positive cancersFactor receptor 2Small cohort sizeAdjuvant therapyAdjuvant trastuzumabComorbid illnessesCardiac eventsAbsolute benefit
2005
Optimizing outcomes in HER2-positive breast cancer: the molecular rationale.
Esteva FJ, Pusztai L. Optimizing outcomes in HER2-positive breast cancer: the molecular rationale. Oncology 2005, 19: 5-16. PMID: 19364051.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBreast NeoplasmsCell ProliferationCombined Modality TherapyDisease ProgressionDrug Resistance, NeoplasmErbB ReceptorsFemaleGenetic TherapyHSP90 Heat-Shock ProteinsHumansProtein Kinase InhibitorsReceptor, ErbB-2TrastuzumabConceptsAnti-HER2 therapyHER2-positive breast cancerBreast cancerEpidermal growth factor receptor HER2Small molecule tyrosine kinase inhibitorsGrowth factor receptor HER2Common chemotherapy regimensSuppression of HER2Anti-HER2 agentsHER2-positive cancersStandard of careOverexpression of HER2Use of therapiesTyrosine kinase inhibitorsHER2 blockersChemotherapy regimensSequential regimensRandomized trialsMaximum antitumor effectMechanisms of resistanceClinical trialsOptimizing outcomesAntitumor effectsReceptor HER2HER2 activity
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