2022
Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, Campone M, Petrakova K, Winer EP, Janni W, Conte P, Cameron DA, André F, Arteaga CL, Zarate JP, Chakravartty A, Taran T, Le Gac F, Serra P, O'Shaughnessy J. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. New England Journal Of Medicine 2022, 386: 942-950. PMID: 35263519, DOI: 10.1056/nejmoa2114663.Peer-Reviewed Original ResearchConceptsAdvanced breast cancerSignificant overall survival benefitMedian overall survivalOverall survival benefitProgression-free survivalOverall survivalBreast cancerSurvival benefitHER2-negative advanced breast cancerKey secondary end pointProtocol-specified final analysisLonger progression-free survivalHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Negative advanced breast cancerStratified log-rank testFirst-line ribociclibSecondary end pointsFirst-line therapyNew safety signalsPhase 3 trialGrowth factor receptor 2Kaplan-Meier methodLog-rank testFactor receptor 2
2021
Should Ki-67 be adopted to select breast cancer patients for treatment with adjuvant abemaciclib?
Tarantino P, Burstein H, Lin N, Krop I, Winer E, Schnitt S, Hamilton E, Hurvitz S, Rugo H, Curigliano G, Tolaney S. Should Ki-67 be adopted to select breast cancer patients for treatment with adjuvant abemaciclib? Annals Of Oncology 2021, 33: 234-238. PMID: 34942341, DOI: 10.1016/j.annonc.2021.12.004.Peer-Reviewed Original Research
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
Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial
Goel S, Pernas S, Tan-Wasielewski Z, Barry WT, Bardia A, Rees R, Andrews C, Tahara RK, Trippa L, Mayer EL, Winer EP, Spring LM, Tolaney SM. Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial. Clinical Breast Cancer 2019, 19: 399-404. PMID: 31235441, DOI: 10.1016/j.clbc.2019.05.010.Peer-Reviewed Original ResearchConceptsHER2-positive breast cancerAdvanced HER2-positive breast cancerProgression-free survivalBreast cancerAdverse eventsObjective responseGrade 3 adverse eventsGrade 4/5 adverse eventsHormone receptor-positive diseaseMedian progression-free survivalAnti-HER2 combinationClinical benefit rateHER2-negative diseasePhase 1b/2 studyPhase 1b/2 trialPrior therapy linesReceptor-positive diseaseAnti-HER2 therapyNew safety concernsCyclin-dependent kinase 4Stable diseaseExpansion cohortMetastatic settingPrior linesQTc prolongation
2018
Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O’Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Annals Of Oncology 2018, 29: 1541-1547. PMID: 29718092, DOI: 10.1093/annonc/mdy155.Peer-Reviewed Original ResearchMeSH KeywordsAgedAminopyridinesAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsDouble-Blind MethodFemaleFollow-Up StudiesHumansLetrozoleLiver NeoplasmsLung NeoplasmsLymphatic MetastasisNeoplasm Recurrence, LocalPrognosisPurinesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneSurvival RateConceptsProgression-free survivalFirst-line ribociclibOverall response rateMONALEESA-2 studySecondary end pointsAdvanced breast cancerBreast cancerEnd pointOverall survivalHER2-negative advanced breast cancerKey secondary end pointMedian progression-free survivalHuman epidermal growth factor receptorExploratory biomarker analysisExploratory end pointsImproved efficacy outcomesManageable toxicity profilePrimary end pointSecond interim analysisMetastatic breast cancerPhase III trialsESR1 mRNA levelsEpidermal growth factor receptorTP53 mutation statusBiomarker analysis
2017
Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer
Matulonis U, Wulf G, Barry W, Birrer M, Westin S, Farooq S, Bell-McGuinn K, Obermayer E, Whalen C, Spagnoletti T, Luo W, Liu H, Hok R, Aghajanian C, Solit D, Mills G, Taylor B, Won H, Berger M, Palakurthi S, Liu J, Cantley L, Winer E. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Annals Of Oncology 2017, 28: 512-518. PMID: 27993796, PMCID: PMC5834157, DOI: 10.1093/annonc/mdw672.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesBRCA1 ProteinBRCA2 ProteinBreast NeoplasmsDose-Response Relationship, DrugFemaleGerm-Line MutationHumansMiddle AgedMorpholinesNeoplasm GradingNeoplasm Recurrence, LocalOvarian NeoplasmsPhosphoinositide-3 Kinase InhibitorsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesConceptsGermline BRCA mutationsOvarian cancerStudy treatmentPARP inhibitorsRandomized phase II studyDose-expansion cohortsPhase II studyPhase I trialDose-escalation designWild-type patientsBiomarkers of responsePARP inhibitor combinationsCombination of BKM120Polymerase inhibitor olaparibPoly (ADP-ribose) polymerase (PARP) inhibitor olaparibPI3K inhibitorsAdditional DLTsOlaparib 300Preclinical synergyRecurrent breastEscalation studyII studyI trialClinical benefitBRCA mutations
2016
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. New England Journal Of Medicine 2016, 375: 1738-1748. PMID: 27717303, DOI: 10.1056/nejmoa1609709.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAminopyridinesAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsDisease-Free SurvivalDouble-Blind MethodDrug Administration ScheduleFemaleHumansKaplan-Meier EstimateLetrozoleMiddle AgedNeoplasm StagingNitrilesPurinesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneTriazolesConceptsAdvanced breast cancerProgression-free survivalHuman epidermal growth factor receptor 2Overall response rateRibociclib groupBreast cancerPlacebo groupAdverse eventsInvestigator-assessed progression-free survivalHER2-negative advanced breast cancerResponse rateProgression-free survival ratesEnd pointEpidermal growth factor receptor 2Hormone receptorsCDK4/6 inhibitor ribociclibCommon grade 3Initial systemic treatmentPrevious systemic therapyPrimary end pointSecondary end pointsFirst-line treatmentPhase 3 trialRate of discontinuationGrowth factor receptor 2Combination 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 inhibitionMetastasisInhibitionRemissionXenograftsMice
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