2021
Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer
Keenan TE, Guerriero JL, Barroso-Sousa R, Li T, O’Meara T, Giobbie-Hurder A, Tayob N, Hu J, Severgnini M, Agudo J, Vaz-Luis I, Anderson L, Attaya V, Park J, Conway J, He MX, Reardon B, Shannon E, Wulf G, Spring LM, Jeselsohn R, Krop I, Lin NU, Partridge A, Winer EP, Mittendorf EA, Liu D, Van Allen EM, Tolaney SM. Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer. Nature Communications 2021, 12: 5563. PMID: 34548479, PMCID: PMC8455578, DOI: 10.1038/s41467-021-25769-z.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, Monoclonal, HumanizedAntigen PresentationAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenBreast NeoplasmsCytokinesDrug Resistance, NeoplasmEstrogensFemaleFuransGene Expression ProfilingGenetic HeterogeneityGenome, HumanGenomicsHumansImmune Checkpoint InhibitorsKetonesLymphocytes, Tumor-InfiltratingMaleMiddle AgedMutationNeoplasm MetastasisReceptors, EstrogenReceptors, ProgesteroneSignal TransductionSurvival RateTreatment OutcomeConceptsImmune checkpoint inhibitorsBreast cancerHormone receptor-positive metastatic breast cancerHormone receptor-positive breast cancerFinal overall survival resultsRandomized phase 2 trialReceptor-positive breast cancerMinimal therapeutic effectPhase 2 trialMetastatic breast cancerOverall survival resultsPre-treatment tumorsCheckpoint inhibitorsCytokine changesICI responseCombination therapyImmune infiltrationImmunoregulatory cytokinesSurvival resultsAntigen presentationTherapeutic effectTherapeutic validationCancerMolecular correlatesTumor heterogeneityThe impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2-positive breast cancer
Janiszewska M, Stein S, Filho O, Eng J, Kingston NL, Harper NW, Rye IH, Alečković M, Trinh A, Murphy KC, Marangoni E, Cristea S, Oakes B, Winer EP, Krop I, Russnes HG, Spellman PT, Bucher E, Hu Z, Chin K, Gray JW, Michor F, Polyak K. The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2-positive breast cancer. JCI Insight 2021, 6: e147617. PMID: 33886505, PMCID: PMC8262355, DOI: 10.1172/jci.insight.147617.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDNA Copy Number VariationsDrug Resistance, NeoplasmEpithelial CellsFemaleFibroblastsHumansMacrophagesMiddle AgedMutationNeoplasm TransplantationReceptor, ErbB-2TrastuzumabTumor MicroenvironmentVesicular Transport ProteinsConceptsBreast cancerTherapeutic resistanceHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2Patient-derived xenograft modelsLymphatic vessel endothelial hyaluronan receptorHER2-targeted therapiesGrowth factor receptor 2Impact of tumorFibroblastic reticular cellsFactor receptor 2Tumor epithelial cellsIntratumor heterogeneityDivergent cellular phenotypesResistance-conferring mutationsClinical outcomesPIK3CA mutationsTreatment responseClinical challengeDifferent therapiesFrequency of cellsXenograft modelReceptor 2Stromal determinants
2020
Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer
Waks AG, Cohen O, Kochupurakkal B, Kim D, Dunn CE, Buendia J, Wander S, Helvie K, Lloyd MR, Marini L, Hughes ME, Freeman SS, Ivy SP, Geradts J, Isakoff S, LoRusso P, Adalsteinsson VA, Tolaney SM, Matulonis U, Krop IE, D’Andrea A, Winer EP, Lin NU, Shapiro GI, Wagle N. Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer. Annals Of Oncology 2020, 31: 590-598. PMID: 32245699, PMCID: PMC7946408, DOI: 10.1016/j.annonc.2020.02.008.Peer-Reviewed Original ResearchMeSH KeywordsBRCA1 ProteinBRCA2 ProteinBreast NeoplasmsDrug Resistance, NeoplasmFemaleHumansOvarian NeoplasmsPlatinumPoly(ADP-ribose) Polymerase InhibitorsConceptsMetastatic breast cancerPlatinum chemotherapyDNA-damaging therapyMechanisms of resistanceBreast cancerMetastatic breast cancer patientsBreast cancer patientsTumor DNA sequencingNovel sequence alterationsWhole-exome sequencingDNA-damaging therapiesTreatment failureCancer patientsFunctional statusDisease progressionTumor biopsiesClinical cohortImmunohistochemical stainingSubsequent linesBRCA1/2 mutationsTherapeutic benefitPatientsUseful biomarkerFunctional assessmentTumor sections
2018
Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer
Tanioka M, Fan C, Parker JS, Hoadley KA, Hu Z, Li Y, Hyslop TM, Pitcher BN, Soloway MG, Spears PA, Henry LN, Tolaney S, Dang CT, Krop IE, Harris LN, Berry DA, Mardis ER, Winer EP, Hudis CA, Carey LA, Perou CM. Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer. Clinical Cancer Research 2018, 24: 5292-5304. PMID: 30037817, PMCID: PMC6214737, DOI: 10.1158/1078-0432.ccr-17-3431.Peer-Reviewed Original Research
2016
Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nature Medicine 2016, 22: 723-726. PMID: 27270588, PMCID: PMC4938731, DOI: 10.1038/nm.4120.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAminopyridinesAnimalsAntineoplastic AgentsApoptosisBrain NeoplasmsBreast NeoplasmsCarrier ProteinsCaspase 3Cell Cycle ProteinsDNA RepairDrug Resistance, NeoplasmDrug Therapy, CombinationEukaryotic Initiation FactorsEverolimusFemaleGene Expression ProfilingGenomic InstabilityHumansImmunohistochemistryKi-67 AntigenMagnetic Resonance ImagingMechanistic Target of Rapamycin Complex 1MiceMice, SCIDMolecular Targeted TherapyMorpholinesMultiprotein ComplexesNeoplasm TransplantationPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationReceptor, ErbB-2Remission InductionTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsBreast cancer brain metastasesCancer brain metastasesBrain metastasesHER2-positive breast cancer brain metastasesOrthotopic patient-derived xenograftsPI3KPatient-derived xenograftsDurable remissionsTherapeutic responseMouse modelCombined inhibitionCombination inhibitionMetastasisInhibitionRemissionXenograftsMiceHeterogeneity 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 clonesPictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial
Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, de Boer R, Petrakova K, Vallentin S, Perez EA, Piccart M, Ellis M, Winer E, Gendreau S, Derynck M, Lackner M, Levy G, Qiu J, He J, Schmid P. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Oncology 2016, 17: 811-821. PMID: 27155741, PMCID: PMC5524539, DOI: 10.1016/s1470-2045(16)00106-6.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBreast NeoplasmsDouble-Blind MethodDrug Resistance, NeoplasmEstradiolEstrogen Receptor AntagonistsFemaleFollow-Up StudiesFulvestrantHumansMiddle AgedNeoplasm Recurrence, LocalNeoplasm StagingPrognosisReceptor, ErbB-2Receptors, EstrogenSalvage TherapySurvival RateConceptsProgression-free survivalSerious adverse eventsTreatment-related serious adverse eventsWorse adverse eventsPlacebo groupAdverse eventsNon-measurable diseaseAromatase inhibitor treatmentPIK3CA mutationsBreast cancerDay 1Grade 3Inhibitor treatmentDay 15Cycle 1Median progression-free survivalHER2-negative breast cancerEndocrine-resistant breast cancerPIK3CA-mutated tumorsPhase 2 studyPhase 2 trialMetastatic breast cancerWeeks of treatmentAromatase inhibitor resistanceF Hoffmann-La RocheOvercoming 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 phosphorylationTumorsCDK4/6Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
Shu S, Lin CY, He HH, Witwicki RM, Tabassum DP, Roberts JM, Janiszewska M, Jin Huh S, Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Peluffo G, Brown J, D’Santos C, Krop I, Dillon D, McKeown M, Ott C, Qi J, Ni M, Rao P, Duarte M, Wu S, Chiang C, Anders L, Young R, Winer E, Letai A, Barry W, Carroll J, Long H, Brown M, Shirley Liu X, Meyer C, Bradner J, Polyak K. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 2016, 529: 413-417. PMID: 26735014, PMCID: PMC4854653, DOI: 10.1038/nature16508.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAzepinesBinding, CompetitiveCasein Kinase IICell Cycle ProteinsCell Line, TumorCell ProliferationChromatinDrug Resistance, NeoplasmEpigenesis, GeneticFemaleGene Expression Regulation, NeoplasticGenome, HumanHumansMediator Complex Subunit 1MiceNuclear ProteinsPhosphorylationPhosphoserineProtein BindingProtein Phosphatase 2Protein Structure, TertiaryProteomicsTranscription FactorsTranscription, GeneticTriazolesTriple Negative Breast NeoplasmsXenograft Model Antitumor Assays
2015
PI3K-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
2014
New research on the treatment of small HER2-positive breast cancers.
Krop IE. New research on the treatment of small HER2-positive breast cancers. Clinical Advances In Hematology And Oncology 2014, 12: 124-7. PMID: 24892258.Peer-Reviewed Original ResearchTrastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer
Krop I, Winer EP. Trastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer. Clinical Cancer Research 2014, 20: 15-20. PMID: 24135146, DOI: 10.1158/1078-0432.ccr-13-0541.Peer-Reviewed Original ResearchConceptsMetastatic breast cancerT-DM1Breast cancerAntibody-drug conjugatesAntibody-dependent cell-mediated cytotoxicityRecent phase III trialsHER2-positive breast cancerNovel antibody-drug conjugateCapecitabine/lapatinibFirst-line settingHepatic transaminase elevationsCombination of trastuzumabPhase II studyProgression-free survivalPhase III trialsInhibition of HER2Cell-mediated cytotoxicityFavorable toxicity profileHER2-positive tumor cellsMonoclonal antibody trastuzumabTransaminase elevationII studyIII trialsOverall survivalAdverse events
2013
Beyond 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
2009
Mechanisms of trastuzumab resistance in breast cancer.
Tolaney SM, Krop IE. Mechanisms of trastuzumab resistance in breast cancer. Anti-Cancer Agents In Medicinal Chemistry 2009, 9: 348-55. PMID: 19275526, DOI: 10.2174/1871520610909030348.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBreast NeoplasmsDrug Resistance, NeoplasmFemaleHumansTrastuzumabConceptsBreast cancerTrastuzumab resistanceHER2-positive metastatic breast cancerHER2-positive breast cancerDevelopment of trastuzumabOutcomes of patientsTrastuzumab-based therapyMetastatic breast cancerInvasive breast cancerHER2/neu geneHumanized monoclonal antibodyPoor patient outcomesNovel therapeutic agentsPatient outcomesTherapeutic agentsPatientsTrastuzumabCancerMonoclonal antibodiesAntitumor activityNeu genePotential mechanismsOutcomesSignificant improvementExtracellular domainManaging 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-2Trastuzumab