2022
A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer.
Nardone A, Qiu X, Spisak S, Nagy Z, Feiglin A, Feit A, Cohen Feit G, Xie Y, Font-Tello A, Guarducci C, Hermida-Prado F, Syamala S, Lim K, Munoz Gomez M, Pun M, Cornwell M, Liu W, Ors A, Mohammed H, Cejas P, Brock JB, Freedman ML, Winer EP, Fu X, Schiff R, Long HW, Metzger Filho O, Jeselsohn R. A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer. Cancer Research 2022, 82: 3673-3686. PMID: 35950920, PMCID: PMC9588703, DOI: 10.1158/0008-5472.can-21-3186.Peer-Reviewed Original ResearchMeSH KeywordsBreast NeoplasmsCarcinoma, Ductal, BreastCarcinoma, LobularChromatinDrug Resistance, NeoplasmFemaleHumansPrognosisReceptors, EstrogenTamoxifenConceptsInvasive lobular breast cancerInvasive ductal cancerLobular breast cancerTamoxifen resistanceBreast cancerInferior long-term outcomesTumor progressionLong-term outcomesBreast cancer subtypesPotential therapeutic avenuesDuctal cancerClinical findingsPoor outcomeReceptor axisClinical trialsDisease progressionPatient outcomesPreclinical modelsClinical investigationRelated commentaryTherapeutic avenuesCancer subtypesTherapeutic resistanceCancerClinical samples
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
Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Mao P, Cohen O, Kowalski KJ, Kusiel JG, Buendia-Buendia JE, Cuoco MS, Exman P, Wander SA, Waks AG, Nayar U, Chung J, Freeman S, Rozenblatt-Rosen O, Miller VA, Piccioni F, Root DE, Regev A, Winer EP, Lin NU, Wagle N. Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer. Clinical Cancer Research 2020, 26: 5974-5989. PMID: 32723837, DOI: 10.1158/1078-0432.ccr-19-3958.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBreast NeoplasmsCell Line, TumorDrug Resistance, NeoplasmExome SequencingFemaleFibroblast Growth Factor 3FulvestrantGene Expression Regulation, NeoplasticHumansMCF-7 CellsMiddle AgedMutationNeoplasm MetastasisPiperazinesProtein Kinase InhibitorsPyridinesReceptor, Fibroblast Growth Factor, Type 1Receptor, Fibroblast Growth Factor, Type 2Receptors, EstrogenXenograft Model Antitumor AssaysConceptsMetastatic breast cancerEstrogen receptorBreast cancerFGFR pathwaySelective estrogen receptor degraderCDK4/6 inhibitor palbociclibBreast cancer cellsMAPK pathwayWhole-exome sequencingResistant cell linesMAPK pathway inhibitorsFulvestrant resistanceInhibitor palbociclibDrug combinationsFGFR inhibitorsTherapyPathway inhibitorMEK inhibitorsConfer resistanceCancer cellsCancerInsulin receptorGenes/pathwaysBiopsyCell linesThe Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer
Wander SA, Cohen O, Gong X, Johnson GN, Buendia-Buendia JE, Lloyd MR, Kim D, Luo F, Mao P, Helvie K, Kowalski KJ, Nayar U, Waks AG, Parsons SH, Martinez R, Litchfield LM, Ye XS, Yu C, Jansen VM, Stille JR, Smith PS, Oakley GJ, Chu QS, Batist G, Hughes ME, Kremer JD, Garraway LA, Winer EP, Tolaney SM, Lin NU, Buchanan SG, Wagle N. The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer. Cancer Discovery 2020, 10: 1174-1193. PMID: 32404308, PMCID: PMC8815415, DOI: 10.1158/2159-8290.cd-19-1390.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBiopsyBreast NeoplasmsCell Cycle ProteinsCell Line, TumorCheckpoint Kinase 1Drug Resistance, NeoplasmExome SequencingFemaleGenomicsHumansProtein Kinase InhibitorsProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)Receptors, SteroidRetinoblastoma Binding ProteinsUbiquitin-Protein LigasesConceptsCyclin-dependent kinase 4/6 inhibitorsMetastatic breast cancerBreast cancerResistant tumorsHormone receptor-positive metastatic breast cancerHormone receptor-positive breast cancerReceptor-positive breast cancerEstrogen receptor expressionCandidate resistance mechanismsWhole-exome sequencingPrecision-based approachesCDK4/6i resistanceMechanisms of resistanceReceptor expressionTherapeutic strategiesCDK4/6iTherapeutic opportunitiesPatient samplesTumorsIssue featurePatientsCancerAcquired ResistanceCancer cellsAlterationsReversion 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
Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies
Nayar U, Cohen O, Kapstad C, Cuoco MS, Waks AG, Wander SA, Painter C, Freeman S, Persky NS, Marini L, Helvie K, Oliver N, Rozenblatt-Rosen O, Ma CX, Regev A, Winer EP, Lin NU, Wagle N. Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies. Nature Genetics 2018, 51: 207-216. PMID: 30531871, DOI: 10.1038/s41588-018-0287-5.Peer-Reviewed Original ResearchConceptsHER2 mutationsEstrogen receptorBreast cancerClinical resistance mechanismsMainstay of treatmentMetastatic breast cancerReceptor-directed therapyCDK6 inhibitor palbociclibPre-existing mutationsMetastatic settingEstrogen independenceInhibitor palbociclibPrimary tumorMetastatic biopsiesInhibitor neratinibTherapyPatientsER mutationsCancerTamoxifenResistance mechanismsDistinct mechanismsMutationsConfer resistanceBiopsyIntegrated 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 ResearchDrug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?
Kabraji S, Ni J, Lin NU, Xie S, Winer EP, Zhao JJ. Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain? Clinical Cancer Research 2018, 24: 1795-1804. PMID: 29437794, PMCID: PMC5899637, DOI: 10.1158/1078-0432.ccr-17-3351.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAnimalsAntineoplastic Combined Chemotherapy ProtocolsBlood-Brain BarrierBrain NeoplasmsBreast NeoplasmsClinical Studies as TopicDisease Models, AnimalDrug DevelopmentDrug Evaluation, PreclinicalDrug Resistance, NeoplasmFemaleHumansMiceModels, BiologicalReceptor, ErbB-2Translational Research, BiomedicalTreatment OutcomeXenograft Model Antitumor AssaysConceptsBreast cancer brain metastasesHER2-positive breast cancer brain metastasesTreatment of BCBMHER2-positive breast cancerHER2-targeting drugsInadequate drug penetrationBrain metastasis modelCancer brain metastasesCentral nervous systemClin Cancer ResDrug resistance mechanismsBrain metastasesFirst metastasisEffective therapyCommon siteBreast cancerMetastasis modelPharmacodynamic dataNervous systemTranslational research paradigmDrug penetrationCancer ResDrug sensitivityPatientsDrug developmentAllele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations
Jeselsohn R, Bergholz JS, Pun M, Cornwell M, Liu W, Nardone A, Xiao T, Li W, Qiu X, Buchwalter G, Feiglin A, Abell-Hart K, Fei T, Rao P, Long H, Kwiatkowski N, Zhang T, Gray N, Melchers D, Houtman R, Liu XS, Cohen O, Wagle N, Winer EP, Zhao J, Brown M. Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell 2018, 33: 173-186.e5. PMID: 29438694, PMCID: PMC5813700, DOI: 10.1016/j.ccell.2018.01.004.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAntineoplastic Agents, HormonalBreast NeoplasmsChromatinDrug Resistance, NeoplasmEstrogen Receptor alphaHumansMice, TransgenicMutationConceptsChromatin recruitmentLigand-independent functionsER mutationsPro-metastatic phenotypeGenetic screenTranscriptional networksTranscriptional programsWild-type ERTherapeutic vulnerabilitiesPotential therapeutic targetMutationsMutantsDomain mutationsLigand-binding domain mutationsActivating mutationsTherapeutic targetTherapy resistanceUnique recruitmentRecruitmentGenetic vulnerabilityCancer modelGenesBreast cancer modelERPhenotype
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 inhibitionMetastasisInhibitionRemissionXenograftsMicePictilisib 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
Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets
Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K, Ligon KL, Tabernero J, Seoane J, Martinez-Saez E, Curry WT, Dunn IF, Paek SH, Park SH, McKenna A, Chevalier A, Rosenberg M, Barker FG, Gill CM, Van Hummelen P, Thorner AR, Johnson BE, Hoang MP, Choueiri TK, Signoretti S, Sougnez C, Rabin MS, Lin NU, Winer EP, Stemmer-Rachamimov A, Meyerson M, Garraway L, Gabriel S, Lander ES, Beroukhim R, Batchelor TT, Baselga J, Louis DN, Getz G, Hahn WC. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discovery 2015, 5: 1164-1177. PMID: 26410082, PMCID: PMC4916970, DOI: 10.1158/2159-8290.cd-15-0369.Peer-Reviewed Original ResearchConceptsBrain metastasesPrimary tumorPrimary biopsiesRegional lymph node metastasisLymph node metastasisPI3K/Akt/mTORRegional lymph nodesPotential therapeutic targetPrimary tumor biopsiesPrimary tumor samplesAkt/mTORDistinct genetic alterationsWhole-exome sequencingExtracranial metastasesLymph nodesNode metastasisDismal prognosisActionable alterationsMetastasis sitesInformative alterationsIndividualized therapyTherapeutic targetMetastasisPrimary siteEGFR inhibitorsPI3K-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
Trastuzumab 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
2010
Triple-negative breast cancer: disease entity or title of convenience?
Carey L, Winer E, Viale G, Cameron D, Gianni L. Triple-negative breast cancer: disease entity or title of convenience? Nature Reviews Clinical Oncology 2010, 7: 683-692. PMID: 20877296, DOI: 10.1038/nrclinonc.2010.154.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBRCA1 ProteinBreast NeoplasmsCarcinoma, Ductal, BreastCase ManagementCombined Modality TherapyDrug Resistance, NeoplasmFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, BRCA1Genes, erbB-2HumansMitotic IndexNeoplasm InvasivenessNeoplasm MetastasisNeoplasm ProteinsNeoplasm Recurrence, LocalPrognosisReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneConceptsTriple negative breast cancer tumorsNew systemic therapiesGood initial responseGroup of tumorsPoly (ADP-ribose) polymerase (PARP) inhibitorsBreast cancer tumorsHormonal therapySystemic therapyLuminal subtypeWorse prognosisClinical trialsDisease entityMTOR inhibitorsAngiogenesis inhibitorsPolymerase inhibitorsTherapeutic agentsCancer tumorsInitial responseTherapyTumorsInhibitorsSrc kinaseAgentsChemotherapyPatients
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-2TrastuzumabAdvances in Adjuvant Endocrine Therapy for Postmenopausal Women
Lin NU, Winer EP. Advances in Adjuvant Endocrine Therapy for Postmenopausal Women. Journal Of Clinical Oncology 2008, 26: 798-805. PMID: 18258989, DOI: 10.1200/jco.2007.15.0946.Peer-Reviewed Original ResearchConceptsPostmenopausal womenAromatase inhibitorsEndocrine therapyBreast cancerHormone receptor-positive breast cancerHormone receptor-positive cancersInitial breast cancer diagnosisReceptor-positive breast cancerMost postmenopausal womenUpfront aromatase inhibitorsYears of tamoxifenAdjuvant endocrine therapyDisease-free survivalReceptor-positive cancersCommon tumor subtypeBreast cancer diagnosisPostmenopausal settingEndocrine treatmentOverall survivalDisease recurrenceRandomized trialsAvailable trialsIndividual patientsHigh riskTumor subtypes