2021
The 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
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
2019
Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation
Xing Y, Lin NU, Maurer MA, Chen H, Mahvash A, Sahin A, Akcakanat A, Li Y, Abramson V, Litton J, Chavez-MacGregor M, Valero V, Piha-Paul SA, Hong D, Do KA, Tarco E, Riall D, Eterovic AK, Wulf GM, Cantley LC, Mills GB, Doyle LA, Winer E, Hortobagyi GN, Gonzalez-Angulo AM, Meric-Bernstam F. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Research 2019, 21: 78. PMID: 31277699, PMCID: PMC6612080, DOI: 10.1186/s13058-019-1154-8.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiomarkersBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDrug MonitoringFemaleHeterocyclic Compounds, 3-RingHigh-Throughput Nucleotide SequencingHumansImmunohistochemistryMiddle AgedMutationNeoplasm MetastasisNeoplasm StagingProtein Kinase InhibitorsProto-Oncogene Proteins c-aktTreatment OutcomeConceptsObjective response ratePeripheral blood mononuclear cellsPlatelet-rich plasmaAdvanced breast cancerPhase II trialPre-treatment biopsiesBreast cancerAKT inhibitor MKAKT1 mutationsPTEN lossII trialPIK3CA mutationsPIK3CA/AKT1 mutationsAdvanced breast cancer patientsInhibitor MKTriple-negative breast cancerMethodsThe primary endpointPIK3CA/AKT1Common adverse eventsPre-treated patientsProgression-free survivalResultsTwenty-seven patientsBreast cancer patientsBlood mononuclear cellsPTEN mutationsA Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB)
Mayer IA, Prat A, Egle D, Blau S, Fidalgo JAP, Gnant M, Fasching PA, Colleoni M, Wolff AC, Winer EP, Singer CF, Hurvitz S, Estévez LG, van Dam PA, Kümmel S, Mundhenke C, Holmes F, Babbar N, Charbonnier L, Diaz-Padilla I, Vogl FD, Sellami D, Arteaga CL. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Clinical Cancer Research 2019, 25: 2975-2987. PMID: 30723140, PMCID: PMC6522303, DOI: 10.1158/1078-0432.ccr-18-3160.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsCell ProliferationClass I Phosphatidylinositol 3-KinasesFemaleHigh-Throughput Nucleotide SequencingHumansLetrozoleMiddle AgedMutationNeoadjuvant TherapyReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneSignal TransductionThiazolesTreatment OutcomeConceptsObjective response rateMetastatic breast cancerBreast cancerResponse rateLetrozole treatmentPathologic complete response ratePhase II Randomized StudyHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Human epidermal growth factor receptorComplete response rateHormone receptor positiveMaculo-papular rashProgression-free survivalGrowth factor receptor 2Early breast cancerPhase I studiesWild-type cohortsFactor receptor 2Epidermal growth factor receptorCombination of alpelisibGrowth factor receptorNeoadjuvant letrozoleNeoadjuvant settingPrimary endpoint
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 ResearchMeSH KeywordsAnimalsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesCohort StudiesFemaleHumansMaleMAP Kinase Signaling SystemMiceMice, Inbred NODMice, TransgenicPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsReceptor, ErbB-2ConceptsBreast 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 activationPI3K-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 activationTBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer
Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, Rugo HS, Liu MC, Stearns V, Come SE, Timms KM, Hartman AR, Borger DR, Finkelstein DM, Garber JE, Ryan PD, Winer EP, Goss PE, Ellisen LW. TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer. Journal Of Clinical Oncology 2015, 33: 1902-1909. PMID: 25847936, PMCID: PMC4451173, DOI: 10.1200/jco.2014.57.6660.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic AgentsBiomarkers, TumorBRCA1 ProteinBRCA2 ProteinCarboplatinCisplatinClass I Phosphatidylinositol 3-KinasesDrug Administration ScheduleFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticGenomic InstabilityHeterozygoteHumansLoss of HeterozygosityMiddle AgedMutationNeoplasm StagingPhosphatidylinositol 3-KinasesTreatment OutcomeTriple Negative Breast NeoplasmsConceptsMetastatic triple-negative breast cancerGermline BRCA1/2 mutationsPhase II clinical trialTriple-negative breast cancerBRCA1/2 mutationsResponse rateClinical trialsBreast cancerMulticenter phase II clinical trialEnd pointSingle-arm phase II clinical trialCoprimary end pointsExploratory end pointsObjective response ratePIK3CA mutation statusSingle-agent platinumLong-term respondersPlatinum-based chemotherapyIdentification of patientsBRCA1/2 mutation carriersGenomic instability signatureGene expression subtypesP73 gene expressionPlatinum monotherapyMutation carriers
2014
Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer
Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, Sanders ME, Yap JT, Van den Abbeele AD, Li Y, Cantley LC, Winer E, Arteaga CL. Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. Journal Of Clinical Oncology 2014, 32: 1202-1209. PMID: 24663045, PMCID: PMC3986383, DOI: 10.1200/jco.2013.54.0518.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCell Line, TumorClass I Phosphatidylinositol 3-KinasesDose-Response Relationship, DrugDrug Administration ScheduleFemaleFluorodeoxyglucose F18HumansLetrozoleMiddle AgedMorpholinesMultimodal ImagingNitrilesPhosphoinositide-3 Kinase InhibitorsPositron-Emission TomographyProtein Kinase InhibitorsRadiopharmaceuticalsReceptor, ErbB-2Receptors, EstrogenTomography, X-Ray ComputedTriazolesConceptsMaximum-tolerated dosePhase Ib studyPET/CTEndocrine therapyDisease progressionBreast cancerIb studyCommon drug-related adverse eventsDrug-related adverse eventsPIK3CA hot spot mutationsPositive breast cancer cell linesER-positive breast cancerPositron emission tomography/Human epidermal growth factor receptorBreast cancer refractoryClinical benefit rateOral reversible inhibitorPIK3CA mutation statusPhase III trialsMetastatic breast cancerRapid disease progressionEmission tomography/Different administration schedulesBreast cancer cell linesMetabolic disease progression