2022
Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
Batalini F, Gulhan DC, Mao V, Tran A, Polak M, Xiong N, Tayob N, Tung NM, Winer EP, Mayer EL, Knappskog S, Lønning PE, Matulonis UA, Konstantinopoulos PA, Solit DB, Won H, Eikesdal HP, Park PJ, Wulf GM. Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers. Clinical Cancer Research 2022, 28: of1-of10. PMID: 36048535, PMCID: PMC9623231, DOI: 10.1158/1078-0432.ccr-22-0749.Peer-Reviewed Original ResearchConceptsHomologous recombination deficiencyTriple-negative breast cancerMutational signature 3Ovarian cancerImproved progression-free survivalPARP inhibitorsPanel sequencingHigh-grade serous ovarian cancerPI3K inhibitor buparlisibPhase Ib trialProgression-free survivalIdentification of patientsRoutine clinical careSignature 3Serous ovarian cancerPARP inhibitor olaparibSame patient sampleIb trialObjective responseTNBC patientsBreast cancerBRCA1/2 mutationsClinical careInstability scoreGenomic instability scorePhase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast CancerAlpelisib plus Olaparib for Triple-Negative Breast Cancer
Batalini F, Xiong N, Tayob N, Polak M, Eismann J, Cantley LC, Shapiro GI, Adalsteinsson V, Winer EP, Konstantinopoulos PA, D'Andrea A, Swisher EM, Matulonis UA, Wulf GM, Mayer EL. Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast CancerAlpelisib plus Olaparib for Triple-Negative Breast Cancer. Clinical Cancer Research 2022, 28: 1493-1499. PMID: 35149538, PMCID: PMC9066379, DOI: 10.1158/1078-0432.ccr-21-3045.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerObjective response rateCirculating-free DNABreast cancerCommon treatment-related grade 3Treatment-related grade 3Longer progression-free survivalRecurrent triple-negative breast cancerHigh-grade serous ovarian cancerPARP inhibitionPhase 1b clinical trialPhase 2 dosePhase 1b trialSecondary end pointsProgression-free survivalRecurrent breast cancerGermline BRCA mutationsImportant prognostic informationSerous ovarian cancerBreast cancer cohortBRCA-mutant tumorsNon-BRCA carriersPI3K inhibitorsEligible patientsExpansion cohort
2017
A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer
Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer. Clinical Cancer Research 2017, 23: 26-34. PMID: 27126994, PMCID: PMC5085926, DOI: 10.1158/1078-0432.ccr-16-0134.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsAromatase InhibitorsBiomarkers, TumorBreast NeoplasmsCell Line, TumorDNA Mutational AnalysisFemaleHumansIn Situ Hybridization, FluorescenceLetrozoleMaximum Tolerated DoseMiddle AgedMutationNeoplasm MetastasisNeoplasm StagingNitrilesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsReceptor, ErbB-2Receptor, Fibroblast Growth Factor, Type 1Receptors, EstrogenThiazolesTreatment OutcomeTriazolesConceptsMaximum-tolerated doseBreast cancer cellsEndocrine therapyClinical benefitCommon drug-related adverse eventsDrug-related adverse eventsMutant breast cancer cellsBreast cancer refractoryPIK3CA mutation statusPIK3CA-mutated tumorsClinical benefit ratePhase Ib studyPI3K catalytic subunit p110αDose-limiting toxicityCancer cellsSelective oral inhibitorOverexpression of FGFR1Combination of letrozoleSynergistic antitumor activityCatalytic subunit p110αCancer refractoryFGFR1/2 amplificationMetastatic ERAdverse eventsObjective response
2016
The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression–Based Meta-Analysis
Stover DG, Coloff JL, Barry WT, Brugge JS, Winer EP, Selfors LM. The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression–Based Meta-Analysis. Clinical Cancer Research 2016, 22: 6039-6050. PMID: 27330058, PMCID: PMC5161615, DOI: 10.1158/1078-0432.ccr-16-0471.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerNeoadjuvant chemotherapyPathologic complete responseBreast cancerGene expression signaturesComplete responseExpression signaturesPrimary breast cancer biopsiesImmune activation signatureBreast cancer biopsiesRole of proliferationClinicopathologic characteristicsSignature scoreImmune activityCancer biopsiesPAM50 subtypesBreast tumorsProliferation differencesCancerActivation signatureNeoadjuvant chemosensitivityChemosensitivityTumorsDNA damageScores
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 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