2020
Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer
Garrido-Castro AC, Saura C, Barroso-Sousa R, Guo H, Ciruelos E, Bermejo B, Gavilá J, Serra V, Prat A, Paré L, Céliz P, Villagrasa P, Li Y, Savoie J, Xu Z, Arteaga CL, Krop IE, Solit DB, Mills GB, Cantley LC, Winer EP, Lin NU, Rodon J. Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer. Breast Cancer Research 2020, 22: 120. PMID: 33138866, PMCID: PMC7607628, DOI: 10.1186/s13058-020-01354-y.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesAntineoplastic Combined Chemotherapy ProtocolsClass I Phosphatidylinositol 3-KinasesDisease ProgressionFemaleHigh-Throughput Nucleotide SequencingHumansMiddle AgedMorpholinesNeoplasm MetastasisPatient SafetyProtein Kinase InhibitorsProteomicsResponse Evaluation Criteria in Solid TumorsSurvival RateTreatment OutcomeTriple Negative Breast NeoplasmsConceptsTriple-negative breast cancerProgression-free survivalPan-class I PI3K inhibitorMetastatic triple-negative breast cancerStable diseasePhase 2 studyBreast cancerOverall survivalPI3K inhibitorsPI3K pathwayPartial responseComplete responseClinical benefitSingle-arm phase 2 studyTriple-negative metastatic breast cancerMedian progression-free survivalK inhibitorsClinical benefit rateEfficacy of buparlisibK pathwayFrequent adverse eventsMedian overall survivalPercent of patientsMetastatic breast cancerSubset of patients
2018
Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial
Borges VF, Ferrario C, Aucoin N, Falkson C, Khan Q, Krop I, Welch S, Conlin A, Chaves J, Bedard PL, Chamberlain M, Gray T, Vo A, Hamilton E. Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncology 2018, 4: 1214-1220. PMID: 29955792, PMCID: PMC6143009, DOI: 10.1001/jamaoncol.2018.1812.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAdultAntineoplastic Combined Chemotherapy ProtocolsArea Under CurveBreast NeoplasmsDiarrheaDrug Administration ScheduleFatigueFemaleHumansKaplan-Meier EstimateMaytansineMiddle AgedNauseaNeoplasm MetastasisProtein Kinase InhibitorsReceptor, ErbB-2Response Evaluation Criteria in Solid TumorsTrastuzumabConceptsHER2-positive metastatic breast cancerMetastatic breast cancerAdo-trastuzumab emtansineT-DM1Breast cancerTyrosine kinase inhibitorsBrain metastasesAdverse eventsClinical trialsToxic reactionsDose-limiting toxic reactionHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2Phase 1b clinical trialGrowth factor receptor 2ERBB2/HER2-positive breast cancerPreliminary antitumor activityTreatment of patientsSpecific tyrosine kinase inhibitorYears of ageDrug-drug interactionsFactor receptor 2Hepatic transaminitisHER2 therapyIncidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis
Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, Tolaney SM. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncology 2018, 4: 173-182. PMID: 28973656, PMCID: PMC5838579, DOI: 10.1001/jamaoncol.2017.3064.Peer-Reviewed Original ResearchConceptsPD-1 inhibitorsCTLA-4 inhibitorsPD-L1 inhibitorsPrimary adrenal insufficiencyInsulin-deficient diabetesAdverse eventsCombination therapyEndocrine dysfunctionSystematic reviewAdrenal insufficiencyPD-1Clinical trialsDifferent immune checkpoint inhibitorsIncidence of AEsImmune checkpoint inhibitorsAdvanced solid tumorsEndocrine adverse eventsRisk of hyperthyroidismSuch adverse eventsPreferred Reporting ItemsRandom-effects modelGrade hypothyroidismInhibitor regimensMDX-010Checkpoint inhibitors
2017
CDK4/6 inhibition triggers anti-tumour immunity
Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature 2017, 548: 471-475. PMID: 28813415, PMCID: PMC5570667, DOI: 10.1038/nature23465.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationBiological MimicryBreast NeoplasmsCell Cycle CheckpointsCell Line, TumorCell ProliferationCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Disease Models, AnimalFemaleHumansInterferonsMicePhosphorylationProtein Kinase InhibitorsRepressor ProteinsRNA, Double-StrandedSignal TransductionT-Lymphocytes, RegulatoryTranscriptomeVirusesPhase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors
Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Bohorquez S, Savage HM, Sampath D, Salphati L, Lin RS, Jin H, Parmar H, Hsu JY, Von Hoff DD, Baselga J. Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors. Cancer Discovery 2017, 7: 704-715. PMID: 28331003, PMCID: PMC5501742, DOI: 10.1158/2159-8290.cd-16-1080.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityAdverse eventsMutant tumorsHigh-grade adverse eventsTreatment-related adverse eventsConfirmed response rateMetastatic solid tumorsTumor xenograft modelPatient tumor samplesMeasurable diseasePharmacodynamic findingsPreclinical dataTumor patientsTumor growth inhibitorLow doseXenograft modelDose levelsResponse rateSolid tumorsPathway inhibitionPatientsPathway suppressionTumor samplesTumorsHotspot mutations
2016
Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant
Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, Aimi J, Derynck MK, Chen M, Chan IT, Amler LC, Hampton GM, Johnston S, Krop I, Schmid P, Lackner MR. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nature Communications 2016, 7: 11579. PMID: 27174596, PMCID: PMC4869259, DOI: 10.1038/ncomms11579.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreastBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDisease-Free SurvivalDNA Mutational AnalysisDNA, NeoplasmDrug Resistance, NeoplasmEstradiolEstrogen Receptor alphaEstrogen Receptor AntagonistsEstrogensFemaleFulvestrantHumansIndazolesMiddle AgedMutationProtein Kinase InhibitorsSulfonamidesConceptsMetastatic breast cancer patientsESR1 mutationsBreast cancer patientsCancer patientsPan-PI3K inhibitorPIK3CA-mutated tumorsProgression-free survivalMetastatic breast cancerWild-type patientsClinical trial samplesMutation allele frequencyInhibitor therapyFulvestrant treatmentBreast cancerClinical significanceClinical resistancePatientsBaseline samplesHotspot mutationsK inhibitorsTherapyLongitudinal analysisTrial samplesESR1Distinct clonesOvercoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors
Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 2016, 29: 255-269. PMID: 26977878, PMCID: PMC4794996, DOI: 10.1016/j.ccell.2016.02.006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Disease Models, AnimalDrug Resistance, NeoplasmErbB ReceptorsFemaleHumansMechanistic Target of Rapamycin Complex 1MiceMice, NudeMice, TransgenicMultiprotein ComplexesNeoplasm Recurrence, LocalPhosphorylationProtein Kinase InhibitorsReceptor, ErbB-2TOR Serine-Threonine KinasesTumor Suppressor ProteinsConceptsHER2-positive breast cancerCDK4/6 inhibitorsBreast cancerEGFR/HER2Patient-derived xenograft tumorsTransgenic mouse modelInhibition of CDK4/6Tumor recurrenceXenograft tumorsMouse modelPotent suppressionTransgenic modelClinical specimensTherapeutic resistanceDual inhibitionMediate resistanceHER2CancerTSC2 phosphorylationG1 arrestCellular senescenceTherapyRb phosphorylationTumorsCDK4/6Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases
Freedman RA, Gelman RS, Wefel JS, Melisko ME, Hess KR, Connolly RM, Van Poznak CH, Niravath PA, Puhalla SL, Ibrahim N, Blackwell KL, Moy B, Herold C, Liu MC, Lowe A, Agar NY, Ryabin N, Farooq S, Lawler E, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU. Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases. Journal Of Clinical Oncology 2016, 34: 945-952. PMID: 26834058, PMCID: PMC5070554, DOI: 10.1200/jco.2015.63.0343.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBrain NeoplasmsBreast NeoplasmsFemaleHumansMiddle AgedProtein Kinase InhibitorsQuinolinesReceptor, ErbB-2ConceptsObjective response rateWhole brain radiotherapyBrain metastasesBreast cancerHER2-positive breast cancer brain metastasesCNS objective response rateHER2-positive brain metastasesMedian progression-free survivalNeurologic signs/symptomsPrevious whole-brain radiotherapyBreast cancer brain metastasesHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2Human epidermal growth factor receptorCNS-directed therapyNon-CNS progressionNon-target lesionsOpen-label trialCancer brain metastasesPhase II trialProgression-free survivalGrowth factor receptor 2Positive breast cancerSigns/symptomsLessons from breast cancer trials of HER2-kinase inhibitors
Krop IE. Lessons from breast cancer trials of HER2-kinase inhibitors. The Lancet Oncology 2016, 17: 267-268. PMID: 26822399, DOI: 10.1016/s1470-2045(16)00004-8.Peer-Reviewed Original ResearchAntineoplastic AgentsBreast NeoplasmsHumansProtein Kinase InhibitorsQuinazolinesReceptor, ErbB-2Trastuzumab
2015
The Evolving Landscape of HER2 Targeting in Breast Cancer
Moasser MM, Krop IE. The Evolving Landscape of HER2 Targeting in Breast Cancer. JAMA Oncology 2015, 1: 1154. PMID: 26204261, DOI: 10.1001/jamaoncol.2015.2286.Peer-Reviewed Original ResearchConceptsTreatment of HER2Breast cancerImmunologic effectorsHER2 targetingSubstantial single-agent activityHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Value of HER2Lines of therapyGrowth factor receptor 2Single-agent activityLate-stage diseaseStage of diseaseUseful predictive biomarkerHER2 inhibitor lapatinibFactor receptor 2Variety of cytotoxicModest efficacyTrastuzumab resistancePredictive biomarkersCell surface expressionImmunologic activityInhibitor lapatinibReceptor 2Advanced stagePI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2015, 35: 3607-3612. PMID: 26500061, PMCID: PMC4846581, DOI: 10.1038/onc.2015.406.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmFemaleHumansLapatinibMammary Neoplasms, ExperimentalMice, KnockoutMolecular Targeted TherapyPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2Signal TransductionThiazolesTumor BurdenXenograft Model Antitumor AssaysConceptsBreast tumorsP110β inhibitorsHuman epidermal growth factor receptor 2 (HER2) amplificationP110α inhibitionPTEN lossInhibition of HER2Treatment of HER2Human cancersPI3K pathway activationPTEN-deficient breast cancersGenetic mouse modelsPI3K/Akt signalingPTEN-deficient tumorsPI3K/AktDual HER2Therapeutic regimenHER2 inhibitionPIK3CA mutationsTumor regressionBreast cancerMouse modelXenograft modelHER2Null tumorsHER2 activation
2013
HER2-positive breast cancer—sifting through many good options
Krop IE. HER2-positive breast cancer—sifting through many good options. Nature Reviews Clinical Oncology 2013, 10: 312-313. PMID: 23629473, DOI: 10.1038/nrclinonc.2013.72.Peer-Reviewed Original ResearchBeyond trastuzumab and lapatinib: new options for HER2-positive breast cancer .
Zardavas D, Cameron D, Krop I, Piccart M. Beyond trastuzumab and lapatinib: new options for HER2-positive breast cancer . American Society Of Clinical Oncology Educational Book 2013, 33: e2-e11. PMID: 23714441, DOI: 10.1200/edbook_am.2013.33.e2.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBreast NeoplasmsChemotherapy, AdjuvantDrug Resistance, NeoplasmFemaleHumansLapatinibMolecular Targeted TherapyNeoadjuvant TherapyProtein Kinase InhibitorsQuinazolinesReceptor, ErbB-2Signal TransductionTrastuzumabTreatment OutcomeConceptsHER2-positive breast cancerDual HER2 blockadeAntibody-drug conjugatesHER2 blockadeBreast cancerMetastatic settingClinical trialsAnti-HER2 resistanceAnti-HER2 agentsLarge randomized trialsHER2-targeted agentsNew treatment optionsAggressive biologic behaviorMajor clinical issueImproved treatment outcomesNew therapeutic avenuesDevelopment of agentsAdjuvant settingNeoadjuvant settingAdvanced diseaseTrastuzumab-DM1Randomized trialsTreatment optionsBiologic rationaleHER2 inhibition
2010
Advances in Targeting Src in the Treatment of Breast Cancer and Other Solid Malignancies
Mayer EL, Krop IE. Advances in Targeting Src in the Treatment of Breast Cancer and Other Solid Malignancies. Clinical Cancer Research 2010, 16: 3526-3532. PMID: 20634194, DOI: 10.1158/1078-0432.ccr-09-1834.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsFemaleHumansMaleNeovascularization, PathologicProstatic NeoplasmsProtein Kinase InhibitorsSrc-Family KinasesConceptsMultiple solid tumor typesVascular endothelial growth factor receptorEndothelial growth factor receptorEarly phase trialsSolid tumor typesMultiple human malignanciesTargeting SrcEndocrine therapyGrowth factor receptorCombination regimensOngoing trialsFuture trialsSolid malignanciesProstate cancerBreast cancerEstrogen receptorPreclinical studiesAntitumor effectsTumor typesAngiogenesis inhibitorsCell-signaling pathwaysInhibitor dasatinibInvestigation of combinationsHuman malignanciesModest activityDisruption of Laminin-Integrin-CD151-Focal Adhesion Kinase Axis Sensitizes Breast Cancer Cells to ErbB2 Antagonists
Yang XH, Flores LM, Li Q, Zhou P, Xu F, Krop IE, Hemler ME. Disruption of Laminin-Integrin-CD151-Focal Adhesion Kinase Axis Sensitizes Breast Cancer Cells to ErbB2 Antagonists. Cancer Research 2010, 70: 2256-2263. PMID: 20197472, PMCID: PMC3310185, DOI: 10.1158/0008-5472.can-09-4032.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntigens, CDAntineoplastic AgentsBreast NeoplasmsCell Adhesion MoleculesCell Line, TumorDrug SynergismEnzyme ActivationFocal Adhesion Protein-Tyrosine KinasesHumansIntegrin alpha3beta1Integrin alpha6beta4LapatinibProtein Kinase InhibitorsQuinazolinesReceptor, ErbB-2Signal TransductionTetraspanin 24TrastuzumabConceptsAnti-ErbB2 agentsBreast cancer cellsHuman ErbB2Cancer cellsSensitizes breast cancer cellsTetraspanin protein CD151Mammary tumor cellsFocal adhesion kinaseLaminin-5ErbB2 antagonistTrastuzumab treatmentBreast cancerLaminin-binding integrinsDrug resistanceTumor cellsCD151 knockdownLaminin-integrinErbB2TrastuzumabCancerCD151CellsTreatmentKnockdownAgents
2009
Managing trastuzumab-resistant breast cancer.
Krop I. Managing trastuzumab-resistant breast cancer. Clinical Advances In Hematology And Oncology 2009, 7: 108-10. PMID: 19367251.Peer-Reviewed Original Research
2008
Ten years of HER2-directed therapy: still questions after all these years
Krop IE, Winer EP. Ten years of HER2-directed therapy: still questions after all these years. Breast Cancer Research And Treatment 2008, 113: 207-209. PMID: 18463974, DOI: 10.1007/s10549-008-0041-2.Peer-Reviewed Original ResearchAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCapecitabineClinical Trials, Phase III as TopicDeoxycytidineDisease-Free SurvivalDrug Delivery SystemsDrug Resistance, NeoplasmErbB ReceptorsFemaleFluorouracilForecastingHumansLapatinibNeoplasm ProteinsProtein Kinase InhibitorsQuinazolinesRandomized Controlled Trials as TopicReceptor, ErbB-2TrastuzumabShort Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers
Guix M, de Matos Granja N, Meszoely I, Adkins TB, Wieman BM, Frierson KE, Sanchez V, Sanders ME, Grau AM, Mayer IA, Pestano G, Shyr Y, Muthuswamy S, Calvo B, Krontiras H, Krop IE, Kelley MC, Arteaga CL. Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers. Journal Of Clinical Oncology 2008, 26: 897-906. PMID: 18180460, DOI: 10.1200/jco.2007.13.5939.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnimalsAntineoplastic AgentsBiomarkers, TumorBreast NeoplasmsCell ProliferationChemotherapy, AdjuvantErbB ReceptorsErlotinib HydrochlorideFemaleHumansImmunohistochemistryIn Situ Nick-End LabelingKi-67 AntigenMiceMice, NudeMiddle AgedNeoadjuvant TherapyNeoplasm StagingNeoplasms, Hormone-DependentProtein Kinase InhibitorsProtein-Tyrosine KinasesQuinazolinesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneSignal TransductionTandem Mass SpectrometryTreatment OutcomeXenograft Model Antitumor AssaysConceptsTumor cell proliferationBreast cancerPreoperative treatmentCell proliferationHormone receptor-positive breast cancerP-S6P-AktEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinibHormone receptor-positive cancersReceptor-positive breast cancerHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2ER-positive breast cancerP-EGFRTyrosine kinase inhibitor erlotinibTriple-negative breast cancerP-MAPKImmediate preoperative periodUntreated breast cancerGrowth factor receptor 2Day of surgeryInvasive breast cancerReceptor-positive cancersTriple-negative cancersKinase inhibitor erlotinib