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 score
2020
Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases
Filho O, Leone JP, Li T, Tan-Wasielewski Z, Trippa L, Barry WT, Younger J, Lawler E, Walker L, Freedman RA, Tolaney SM, Krop I, Winer EP, Lin NU. Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. Annals Of Oncology 2020, 31: 1231-1239. PMID: 32461105, DOI: 10.1016/j.annonc.2020.05.014.Peer-Reviewed Original ResearchConceptsClinical benefit rateHER2-positive brain metastasesAlanine aminotransferase elevationCohort ABrain metastasesCohort BAminotransferase elevationBreast cancerHER2-positive breast cancer brain metastasesPhase I dose-escalation trialMedian progression-free survivalBreast cancer brain metastasesCommon dose-limiting toxicityI dose-escalation trialHER2-positive breast cancerCombination of tucatinibSecondary end pointsCancer brain metastasesDose-escalation trialProgression-free survivalDose-limiting toxicityMetastatic breast cancerBrain radiationObjective responseIntracranial activityA Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer
Barroso-Sousa R, Krop IE, Trippa L, Tan-Wasielewski Z, Li T, Osmani W, Andrews C, Dillon D, Richardson ET, Pastorello RG, Winer EP, Mittendorf EA, Bellon JR, Schoenfeld JD, Tolaney SM. A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Clinical Breast Cancer 2020, 20: 238-245. PMID: 32113750, DOI: 10.1016/j.clbc.2020.01.012.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalBiomarkers, TumorBreastBreast NeoplasmsCarcinoma, Ductal, BreastChemoradiotherapyDrug Administration ScheduleFemaleHumansInfusions, IntravenousMiddle AgedPalliative CareProgrammed Cell Death 1 ReceptorProgression-Free SurvivalReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneResponse Evaluation Criteria in Solid TumorsConceptsMetastatic breast cancerHormone receptor-positive metastatic breast cancerProgression-free survivalRadiation therapyObjective responseOverall survivalBreast cancerResponse rateMedian progression-free survivalCause adverse eventsGrade 3 eventsMedian prior linesMedian overall survivalObjective response ratePalliative radiation therapyPhase II studyTumor-infiltrating lymphocytesLymph node lesionsOverall response rateEpidermal growth factor receptorEligible patientsExploratory endpointsGrowth factor receptorPalliative radiotherapyPrimary endpoint
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 prolongationNimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer.
Barroso-Sousa R, Trippa L, Lange P, Andrews C, McArthur H, Haley B, Rugo H, Emens L, Winer E, Mittendorf E, Tolaney S. Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer. Journal Of Clinical Oncology 2019, 37: tps1115-tps1115. DOI: 10.1200/jco.2019.37.15_suppl.tps1115.Peer-Reviewed Original ResearchMetastatic breast cancerTumor mutational burdenHER2-negative breast cancerBreast cancerResponse rateObjective responseTrue response rateMetastatic HER2-negative breast cancerHER2-negative metastatic breast cancerFurther studiesCombination of nivolumabEfficacy of nivolumabPhase 2 studyPhase II studyProgression-free survivalOverall response rateMut/MbMutations/megabaseCancer gene panelRECIST 1.1II studyOverall survivalPrior linesPeripheral bloodDisease progression
2018
Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer
Stover DG, Gil Del Alcazar CR, Brock J, Guo H, Overmoyer B, Balko J, Xu Q, Bardia A, Tolaney SM, Gelman R, Lloyd M, Wang Y, Xu Y, Michor F, Wang V, Winer EP, Polyak K, Lin NU. Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. Npj Breast Cancer 2018, 4: 10. PMID: 29761158, PMCID: PMC5935675, DOI: 10.1038/s41523-018-0060-z.Peer-Reviewed Original ResearchMetastatic triple-negative breast cancerTriple-negative breast cancerPhase II studyBreast cancerII studyObjective responseNon-randomized phase II studyIL-6/JAK2/STAT3Efficacy of ruxolitinibInfrequent grade 3Refractory patient populationPrimary efficacy endpointMetastatic breast cancerInflammatory breast cancerSelective JAK1/2 inhibitorArchival tumor tissueJAK2/STAT3Central immunohistochemistryCommon toxicitiesRECIST 1.1Efficacy endpointPrimary endpointProtocol therapyJAK1/2 inhibitorPatient population
2017
A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (mBC) (HER2CLIMB).
Anders C, Murthy R, Hamilton E, Borges V, Cameron D, Carey L, Müller V, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pivot X, Pegram M, Slamon D, Hurvitz S, Tsai M, Winer E. A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (mBC) (HER2CLIMB). Journal Of Clinical Oncology 2017, 35: tps1107-tps1107. DOI: 10.1200/jco.2017.35.15_suppl.tps1107.Peer-Reviewed Original ResearchProgression-free survivalMetastatic breast carcinomaBrain metsIndependent data monitoring committeeClinical benefit ratePhase 1b studyDuration of responseIndependent central reviewPrimary study objectiveData monitoring committeeCNS progressionEGFR agentsPo bidBrain metastasesAdult patientsObjective responseOverall survivalCentral reviewStudy treatmentT-DM1CNS therapyTrastuzumab emtansineBenefit rateSelective small molecule inhibitorsBreast carcinomaA 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
2015
SU2C Phase Ib Study of Paclitaxel and MK-2206 in Advanced Solid Tumors and Metastatic Breast Cancer
Gonzalez-Angulo AM, Krop I, Akcakanat A, Chen H, Liu S, Li Y, Culotta KS, Tarco E, Piha-Paul S, Moulder-Thompson S, Velez-Bravo V, Sahin AA, Doyle LA, Do KA, Winer EP, Mills GB, Kurzrock R, Meric-Bernstam F. SU2C Phase Ib Study of Paclitaxel and MK-2206 in Advanced Solid Tumors and Metastatic Breast Cancer. Journal Of The National Cancer Institute 2015, 107: dju493. PMID: 25688104, PMCID: PMC4342675, DOI: 10.1093/jnci/dju493.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsDrug Administration ScheduleDrug EruptionsFatigueFemaleHeterocyclic Compounds, 3-RingHumansHyperglycemiaMaleMaximum Tolerated DoseMiddle AgedNeoplasmsNeutropeniaPaclitaxelSeverity of Illness IndexTreatment OutcomeConceptsDose escalationDay 1Day 2Higher adverse eventsPhase Ib studyWeeks of therapyAdvanced solid tumorsCTCAE grade 3Metastatic breast cancerPrevious phase IPreliminary antitumor activityDose expansionStable diseaseObjective responseUnacceptable toxicityAdverse eventsMedian ageWeekly dosesClinical benefitPharmacodynamic markersSystemic exposureExcessive toxicityTumor responseGrade 3Median number
2013
Phase II study of ruxolitinib in patients with pStat3+ breast cancer.
Lin N, Gelman R, Brock J, Bardia A, Mayer E, Overmoyer B, Wang V, Iannone M, Krop I, Polyak K, Winer E. Phase II study of ruxolitinib in patients with pStat3+ breast cancer. Journal Of Clinical Oncology 2013, 31: tps1134-tps1134. DOI: 10.1200/jco.2013.31.15_suppl.tps1134.Peer-Reviewed Original ResearchBreast cancerObjective responseCohort BCohort AOpen-label phase 2 trialIL-6/JAK2/STAT3Tumor tissueM.D. Anderson Symptom InventoryTriple-negative breast cancerAdequate organ functionBaseline tumor biopsiesECOG PS 0High-risk myelofibrosisPhase II studyEORTC QLQ CPhase 2 trialInflammatory breast cancerArchival tumor tissueWk 4JAK2/STAT3Further studiesAccessible diseaseMeasurable diseasePrior therapyPrimary endpointA phase II study of bevacizumab in combination with vinorelbine and trastuzumab in HER2-positive metastatic breast cancer
Lin NU, Seah DS, Gelman R, Desantis S, Mayer EL, Isakoff S, DiPiro P, Krop IE, Come SE, Weckstein D, Winer EP, Burstein HJ. A phase II study of bevacizumab in combination with vinorelbine and trastuzumab in HER2-positive metastatic breast cancer. Breast Cancer Research And Treatment 2013, 139: 403-410. PMID: 23645007, DOI: 10.1007/s10549-013-2551-9.Peer-Reviewed Original ResearchConceptsMetastatic breast cancerGrade 3/4 non-hematologic toxicitiesHER2-positive metastatic breast cancerNon-hematologic toxicitiesTreatment-related toxicityBreast cancerCommon treatment-related toxicitiesFirst-line patientsProtocol-based therapySecond-line cohortSecond-line patientsSecond-line settingPhase II studyProportion of patientsCombination of vinorelbineCo-primary endpointsEligible patientsFebrile neutropeniaMedian PFSII studyMedian durationObjective responsePrior linesUnacceptable toxicityMedian age
2012
Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors.
Balmaña J, Tung N, Isakoff S, Graña B, Ryan P, Rafi R, Tracy M, Winer E, Baselga J, Garber J. Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors. Journal Of Clinical Oncology 2012, 30: 1009-1009. DOI: 10.1200/jco.2012.30.15_suppl.1009.Peer-Reviewed Original ResearchAdvanced solid tumorsHematologic AEsEvaluable ptsMonotherapy phaseDose reductionSolid tumorsAntitumor activityOpen-label studyDose-limiting toxicityCisplatin-related toxicityDose-finding studyDrug-related deathsOral PARP inhibitorLong respondersOlaparib capsulesNeoadjuvant settingPrior regimensStable diseaseDurable responsesObjective responsePeritoneal cancerTherapy cyclesMedian numberBreast cancerTreatment cycles
2011
P2-09-07: Metabolic Response by FDG-PET in Patients (pts) Receiving Trastuzumab (T) and Lapatinib (L) for HER2+ Metastatic Breast Cancer (MBC): Correlative Analysis of TBCRC 003.
Yap J, Locascio T, Najita J, Mayer I, Hobday T, Falkson C, Dees E, Gelman R, Rimawi M, Nanda R, Berkowitz J, Franchetti Y, Wolff A, Winer E, Lin N, Van den Abbeele A. P2-09-07: Metabolic Response by FDG-PET in Patients (pts) Receiving Trastuzumab (T) and Lapatinib (L) for HER2+ Metastatic Breast Cancer (MBC): Correlative Analysis of TBCRC 003. Cancer Research 2011, 71: p2-09-07-p2-09-07. DOI: 10.1158/0008-5472.sabcs11-p2-09-07.Peer-Reviewed Original ResearchMedian progression-free survivalProgression-free survivalMetastatic breast cancerClinical benefitCohort 2Cohort 1FDG-PETWk 8Objective responsePrior linesClinical outcomesMetabolic responseTarget lesionsWk 1Longer progression-free survivalMaximum standardized uptake valuePhase II trialFDG-PET studiesStandardized uptake valueFDG-PET dataFDG-PET imagesEORTC criteriaHypermetabolic uptakeRECIST 1.0II trialRandomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases
Lin NU, Eierman W, Greil R, Campone M, Kaufman B, Steplewski K, Lane SR, Zembryki D, Rubin SD, Winer EP. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. Journal Of Neuro-Oncology 2011, 105: 613-620. PMID: 21706359, DOI: 10.1007/s11060-011-0629-y.Peer-Reviewed Original ResearchConceptsHER2-positive breast cancerProgressive brain metastasesObjective response rateBrain metastasesTopotecan armBreast cancerHER2-positive breast cancer brain metastasesCentral nervous system progressionBreast cancer brain metastasesRandomized phase II studyCombination of lapatinibPhase II studyCancer brain metastasesEfficacy of lapatinibStandard radiation therapyLack of efficacyNon-CNS lesionsExcess toxicityCapecitabine armRefractory settingCranial radiotherapyPrimary endpointSteroid requirementsII studyObjective response
2009
Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer
Lin N, Diéras V, Paul D, Lossignol D, Christodoulou C, Stemmler H, Roché H, Liu M, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum J, Rubin S, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer E. Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer. Clinical Cancer Research 2009, 15: 1452-1459. PMID: 19228746, DOI: 10.1158/1078-0432.ccr-08-1080.Peer-Reviewed Original ResearchConceptsBrain metastasesBreast cancerObjective responseVolumetric reductionCNS lesionsNeurologic signsCentral nervous system progressionMulticenter phase II studySmall phase 2 trialHER2-positive breast cancerCombination of lapatinibExtra-CNS diseaseProgressive brain metastasesPhase II studyPrimary end pointPhase 2 trialProgression-free survivalThird of patientsProgressive neurologic signsMajor clinical challengeCNS metastasesCranial radiationEligible patientsEvaluable patientsPrior trastuzumabA Comparative Study of Exemestane Versus Anastrozole in Patients with Postmenopausal Breast Cancer with Visceral Metastases
Campos SM, Guastalla JP, Subar M, Abreu P, Winer EP, Cameron DA. A Comparative Study of Exemestane Versus Anastrozole in Patients with Postmenopausal Breast Cancer with Visceral Metastases. Clinical Breast Cancer 2009, 9: 39-44. PMID: 19299239, DOI: 10.3816/cbc.2009.n.007.Peer-Reviewed Original ResearchConceptsPostmenopausal breast cancerBreast cancer metastasisBreast cancerPostmenopausal patientsVisceral metastasesAdverse eventsObjective responseVisceral sitesVisceral lesionsClinical benefitTreatment-related adverse eventsCancer metastasisAromatase inhibitor studiesAdvanced breast cancerResponse Evaluation CriteriaExemestane groupEndocrine therapyPostmenopausal womenPrimary endpointSecondary endpointsMedian survivalOverall survivalSuch patientsTreat analysisStudy closureAssays of circulating tumor cells and outcome in the triple-negative breast cancer trial TBCRC001.
Rugo H, Carey L, Mayer E, Marcom P, Liu M, Ma C, Storniolo A, Forero A, Esteva F, Wolff A, Hobday T, Ferraro M, Davidson N, Winer E, Moore D, Scott J, Park J. Assays of circulating tumor cells and outcome in the triple-negative breast cancer trial TBCRC001. Cancer Research 2009, 69: 6048. DOI: 10.1158/0008-5472.sabcs-6048.Peer-Reviewed Original ResearchBasal-like breast cancerArm 1Study treatmentCTC levelsTumor cellsPhase II studyPhase II trialTime pointsBreast cancer trialsMarkers of activityRank correlation coefficientCc bloodMetastatic BrCaShorter TSTPrimary endpointII studyII trialObjective responseFirst infusionCancer trialsEfficacy dataArm 2Breast cancerCTC measurementCTC enumeration
2008
Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, Harris GJ, Bullitt E, Van den Abbeele AD, Henson JW, Li X, Gelman R, Burstein HJ, Kasparian E, Kirsch DG, Crawford A, Hochberg F, Winer EP. Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer. Journal Of Clinical Oncology 2008, 26: 1993-1999. PMID: 18421051, PMCID: PMC4524351, DOI: 10.1200/jco.2007.12.3588.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorNon-CNS sitesPrimary end pointBrain metastasesBreast cancerGrowth factor receptorEnd pointAdverse eventsObjective responseAdvanced human epidermal growth factor receptor 2Human epidermal growth factor receptor 2Epidermal growth factor receptor 2Human epidermal growth factor receptorBrain tumor burdenProgressive brain metastasesRefractory brain metastasesCommon adverse eventsSecondary end pointsPhase II trialResponse Evaluation CriteriaEfficacy of lapatinibFactor receptorGrowth factor receptor 2Metastatic brain lesionsPositive breast cancer
2007
Phase II study of CT-2103 as first- or second-line chemotherapy in patients with metastatic breast cancer: unexpected incidence of hypersensitivity reactions
Lin NU, Parker LM, Come SE, Burstein HJ, Haldoupis M, Ryabin N, Gelman R, Winer EP, Shulman LN. Phase II study of CT-2103 as first- or second-line chemotherapy in patients with metastatic breast cancer: unexpected incidence of hypersensitivity reactions. Investigational New Drugs 2007, 25: 369-375. PMID: 17345004, DOI: 10.1007/s10637-007-9034-y.Peer-Reviewed Original ResearchConceptsMetastatic breast cancerHypersensitivity reactionsEfficacy of CTBreast cancerPrior linesPatient populationGrade 3HER2-negative metastatic breast cancerSmall studyHER2-negative breast cancerTrue drug allergyPhase II studySecond-line chemotherapyPercent of womenNovel conjugatesAdjuvant settingConjugated paclitaxelEighteen womenIntravenous CTMetastatic treatmentPrior chemotherapyRoutine premedicationDrug allergyII studyObjective response
2006
Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer
Lin N, Carey L, Liu M, Younger J, Come S, Bullitt E, Van Den Abbeele A, Li X, Hochberg F, Winer E. Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer. Journal Of Clinical Oncology 2006, 24: 503-503. DOI: 10.1200/jco.2006.24.18_suppl.503.Peer-Reviewed Original ResearchBrain metastasesBreast cancerObjective responsePrimary endpointCNS lesionsCNS diseaseCentral nervous system metastasesVolumetric declinesCentral radiology reviewProgressive brain metastasesNervous system metastasesPhase II trialEfficacy of lapatinibMetastatic breast cancerFDG-PET scansMean age 52Analysis of QOLCommon AEsEligible patientsMeasurable diseasePo bidII trialPrior radiationRECIST criteriaSecondary endpoints