2023
Molecular Characterization of HER2-Low Invasive Breast Carcinoma by Quantitative RT-PCR Using Oncotype DX Assay
Lin H, Can T, Kahn A, Flannery C, Hoag J, Akkunuri A, Bailey H, Baehner R, Pusztai L, Rozenblit M. Molecular Characterization of HER2-Low Invasive Breast Carcinoma by Quantitative RT-PCR Using Oncotype DX Assay. The Oncologist 2023, 28: e973-e976. PMID: 37656608, PMCID: PMC10546821, DOI: 10.1093/oncolo/oyad249.Peer-Reviewed Original ResearchConceptsHER2 mRNA levelsIHC 0MRNA levelsOncotype DX recurrence score resultsEstrogen receptor-positive breast cancerReceptor-positive breast cancerCurrent adjuvant chemotherapyOncotype DX assayRecurrence Score resultsPositive breast cancerInvasive breast carcinomaIHC score 0Adjuvant chemotherapyQuantitative RT-PCRBreast carcinomaPositive statusScore 0Breast cancerStage IYale cohortHigher mRNA levelsCancerRT-PCRPatientsHER2HRD signature and HRD genomic landscape of tumors from 896 patients with early-stage breast cancer (BC).
Jeon J, Chen K, Madison R, Schrock A, Sokol E, Levy M, Oxnard G, Huang R, Pusztai L. HRD signature and HRD genomic landscape of tumors from 896 patients with early-stage breast cancer (BC). Journal Of Clinical Oncology 2023, 41: 539-539. DOI: 10.1200/jco.2023.41.16_suppl.539.Peer-Reviewed Original ResearchEarly-stage breast cancerPrimary breast cancerEarly breast cancerBreast cancerStage IHR-/HER2HRR deficiencyPALB2 mutationsEarly-stage primary breast cancerPARP inhibitorsStage IV diseaseHormone receptor statusMonths of diagnosisPositive breast cancerHomologous recombination repairComprehensive genomic profilingHRD signaturesClinical trial dataHigh rateSEER studySomatic BRCAAdjuvant therapyAdvanced diseaseReceptor statusBC subtypes
2020
Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)–Positive Breast Cancer
Kunst N, Wang SY, Hood A, Mougalian SS, DiGiovanna MP, Adelson K, Pusztai L. Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)–Positive Breast Cancer. JAMA Network Open 2020, 3: e2027074. PMID: 33226431, PMCID: PMC7684449, DOI: 10.1001/jamanetworkopen.2020.27074.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAdultAgedAnthracyclinesAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalAntineoplastic Agents, PhytogenicBreast NeoplasmsCase-Control StudiesCost-Benefit AnalysisCross-Linking ReagentsDrug Therapy, CombinationFemaleHumansImmunosuppressive AgentsMiddle AgedNeoadjuvant TherapyPaclitaxelQuality-Adjusted Life YearsReceptor, ErbB-2TrastuzumabTubulin ModulatorsUnited StatesConceptsErbB2-positive breast cancerAdjuvant treatment strategiesAdjuvant T-DM1Pathologic complete responseT-DM1Treatment strategiesBreast cancerKATHERINE trialResidual diseaseNeoadjuvant regimenHigher health benefitsHealth care payer perspectiveAdjuvant trastuzumab emtansineAnthracycline/cyclophosphamideDifferent adjuvant therapiesFlatiron Health databaseIncremental cost-effectiveness ratioNeoadjuvant treatment optionsHealth benefitsPositive breast cancerCare payer perspectiveCost-effectiveness ratioBase-case analysisDecision analytic modelH. PatientsAdherence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor (HR)-positive breast cancers.
Foldi J, Schnabel C, Salganik M, Pusztai L, Sanft T. Adherence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor (HR)-positive breast cancers. Journal Of Clinical Oncology 2020, 38: 527-527. DOI: 10.1200/jco.2020.38.15_suppl.527.Peer-Reviewed Original ResearchLate distant recurrenceAdjuvant endocrine therapyEndocrine therapyDistant recurrenceDXA scansBreast cancerHigh riskStage IEarly-stage hormone receptorExtended endocrine therapyIntolerable side effectsOsteopenia/osteoporosisPositive breast cancerRate of adherenceSerious adverse effectsBreast cancer recurrenceMajority of ptsHigher likelihoodElectronic health recordsLocal recurrenceMedian ageLate recurrenceMetastatic recurrenceTumor characteristicsMedication adherence
2018
Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer
Dickler MN, Saura C, Richards DA, Krop IE, Cervantes A, Bedard PL, Patel MR, Pusztai L, Oliveira M, Cardenas AK, Cui N, Wilson TR, Stout TJ, Wei MC, Hsu JY, Baselga J. Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer. Clinical Cancer Research 2018, 24: 4380-4387. PMID: 29793946, PMCID: PMC6139036, DOI: 10.1158/1078-0432.ccr-18-0613.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDisease-Free SurvivalDrug-Related Side Effects and Adverse ReactionsFemaleFulvestrantHumansImidazolesMiddle AgedMutationOxazepinesReceptor, ErbB-2Receptors, EstrogenConceptsAdverse eventsClinical activityBreast cancerMutation statusOpen-label phase II studyHR-positive breast cancerHigher objective response rateConfirmatory phase III trialNCI CTCAE v4.0Median treatment durationObjective response ratePhase II studySerious adverse eventsNew safety signalsPhase III trialsPositive breast cancerClin Cancer ResIntramuscular fulvestrantMeasurable diseaseRECIST v1.1II studyIII trialsPostmenopausal womenUnacceptable toxicityTumor responseLong‐Term Survival of De Novo Stage IV Human Epidermal Growth Receptor 2 (HER2) Positive Breast Cancers Treated with HER2‐Targeted Therapy
Wong Y, Raghavendra AS, Hatzis C, Irizarry JP, Vega T, Horowitz N, Barcenas CH, Chavez‐MacGregor M, Valero V, Tripathy D, Pusztai L, Murthy RK. Long‐Term Survival of De Novo Stage IV Human Epidermal Growth Receptor 2 (HER2) Positive Breast Cancers Treated with HER2‐Targeted Therapy. The Oncologist 2018, 24: 313-318. PMID: 30139836, PMCID: PMC6519755, DOI: 10.1634/theoncologist.2018-0213.Peer-Reviewed Original ResearchConceptsDe novo stage IVProgression-free survivalMetastatic breast cancerHigher progression-free survivalPositive metastatic breast cancerExcellent long-term outcomesOverall survivalLong-term outcomesNED statusBreast cancerStage IVOS ratesLocoregional therapyRandomized studyDe novo stage IV diseaseDisease statusHER2-Targeted TherapyMedian overall survivalStage IV diseaseFirst-line therapyTrastuzumab-based therapyEstrogen receptor-positive statusPositive breast cancerImportant therapeutic goalNED patients
2017
Discussion of: “Does lymph node status influence adjuvant therapy decision-making in women 70 years of age or older with clinically node negative hormone receptor positive breast cancer?”
Chagpar AB, Horowitz N, Sanft T, Wilson LD, Silber A, Killelea B, Moran MS, DiGiovanna MP, Hofstatter E, Chung G, Pusztai L, Lannin DR. Discussion of: “Does lymph node status influence adjuvant therapy decision-making in women 70 years of age or older with clinically node negative hormone receptor positive breast cancer?”. The American Journal Of Surgery 2017, 214: 1089-1090. PMID: 28987415, DOI: 10.1016/j.amjsurg.2017.09.025.Commentaries, Editorials and LettersDoes lymph node status influence adjuvant therapy decision-making in women 70 years of age or older with clinically node negative hormone receptor positive breast cancer?
Chagpar AB, Horowitz N, Sanft T, Wilson LD, Silber A, Killelea B, Moran MS, DiGiovanna MP, Hofstatter E, Chung G, Pusztai L, Lannin DR. Does lymph node status influence adjuvant therapy decision-making in women 70 years of age or older with clinically node negative hormone receptor positive breast cancer? The American Journal Of Surgery 2017, 214: 1082-1088. PMID: 28939252, DOI: 10.1016/j.amjsurg.2017.07.036.Peer-Reviewed Original ResearchConceptsHormone receptor-positive breast cancerReceptor-positive breast cancerPositive breast cancerLymph nodesRadiation therapyBreast cancerPost-lumpectomy radiation therapyPost-mastectomy radiation therapyNational Cancer DatabaseSentinel LN biopsyBreast cancer patientsWomen 70 yearsAdjuvant chemotherapyAdjuvant therapyHormonal therapyLN biopsyLN evaluationLN statusCancer patientsCancer DatabasePatientsTherapyCancerChemotherapyHrAssociation of LN Evaluation with Survival in Women Aged 70 Years or Older With Clinically Node-Negative Hormone Receptor Positive Breast Cancer
Chagpar AB, Hatzis C, Pusztai L, DiGiovanna MP, Moran M, Mougalian S, Sanft T, Evans S, Hofstatter E, Wilson LD, Lannin DR. Association of LN Evaluation with Survival in Women Aged 70 Years or Older With Clinically Node-Negative Hormone Receptor Positive Breast Cancer. Annals Of Surgical Oncology 2017, 24: 3073-3081. PMID: 28766195, DOI: 10.1245/s10434-017-5936-x.Peer-Reviewed Original ResearchConceptsBreast cancer-specific survivalLN evaluationPositive breast cancerOverall survivalBreast cancerHormone receptor-positive breast cancerWomen Aged 70 YearsReceptor-positive breast cancerLymph node evaluationCancer-specific survivalLower hazard rateLN surgeryBetter OSPatient ageSEER databasePatient selectionTumor characteristicsSEER dataPatientsNode evaluationHormone receptorsCancerSurvivalTreatment variablesNCDBPathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer.
Foldi J, Mougalian S, Silber A, Lannin D, Killelea B, Chagpar A, Horowitz N, Frederick C, Rispoli L, Abu-Khalaf M, Sabbath K, Sanft T, Fischbach N, Brandt D, Hofstatter E, DiGiovanna M, Pusztai L. Pathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer. Journal Of Clinical Oncology 2017, 35: 577-577. DOI: 10.1200/jco.2017.35.15_suppl.577.Peer-Reviewed Original ResearchPathologic complete response rateHER2-positive breast cancerDual HER2 blockadeComplete response ratePCR rateEstrogen receptorHER2 blockadeBreast cancerStage IResponse rateGrade 3/4 adverse eventsSymptomatic congestive heart failureClinical stage ICompletion of chemotherapyPhase II studyTaxane-based chemotherapyCongestive heart failureEfficacy of anthracyclinesPositive breast cancerNormal cardiac functionEntire treatment durationER- cancersER cohortNeoadjuvant pertuzumabWeekly paclitaxelLong-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy.
Wong Y, Raghavendra A, Hatzis C, Irizarry J, Vega T, Barcenas C, Chavez-Mac Gregor M, Valero V, Tripathy D, Pusztai L, Murthy R. Long-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy. Journal Of Clinical Oncology 2017, 35: 1021-1021. DOI: 10.1200/jco.2017.35.15_suppl.1021.Peer-Reviewed Original ResearchProgression-free survivalLonger progression-free survivalPositive breast cancerHER2-positive cancersMedian OSNED patientsOS ratesFree survivalOverall survivalPositive cancersBreast cancerDe novo stage IV diseaseHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2MD Anderson Cancer CenterStage IV diseaseAggressive multimodality therapyEvidence of diseaseFirst-line therapyGrowth factor receptor 2Year of diagnosisEarly-stage patientsAnderson Cancer CenterLong-term survivalDuration of neoadjuvant endocrine therapy and breast cancer outcomes.
Mougalian S, Soulos P, Lannin D, Pusztai L, Gross C, Killelea B. Duration of neoadjuvant endocrine therapy and breast cancer outcomes. Journal Of Clinical Oncology 2017, 35: e12129-e12129. DOI: 10.1200/jco.2017.35.15_suppl.e12129.Peer-Reviewed Original ResearchNeoadjuvant endocrine therapyEndocrine therapyClinical stagePathologic stageNational Cancer Data BasePR-positive breast cancerHigher nodal stageNetwork cancer programsAdjuvant endocrine therapyMultiple comorbid conditionsBreast cancer outcomesPopulation of patientsType of surgeryPositive breast cancerSimilar response ratesNeoadjuvant chemotherapyUnderwent surgeryNodal stageComorbid conditionsCancer outcomesLarge tumorsCancer programsBreast cancerOlder womenPatientsHealth economic impact of breast cancer index (BCI) in patients with hormone responsive breast cancer (HRBC) considering extended adjuvant endocrine therapy (EET).
Sanft T, Berkowitz A, Schroeder B, Hatzis C, Schnabel C, Aktas B, Brufsky A, Pusztai L, Gustavsen G, Van Londen G. Health economic impact of breast cancer index (BCI) in patients with hormone responsive breast cancer (HRBC) considering extended adjuvant endocrine therapy (EET). Journal Of Clinical Oncology 2017, 35: 25-25. DOI: 10.1200/jco.2017.35.8_suppl.25.Peer-Reviewed Original ResearchHormone-responsive breast cancerBreast Cancer IndexAdjuvant endocrine therapyEndocrine therapyCancer indexBreast cancerEarly-stage hormone receptor-positive breast cancerHormone receptor-positive breast cancerReceptor-positive breast cancerYale Cancer CenterReal-world cohortResponsive breast cancerPopulation of patientsGene expression-based testsPositive breast cancerHealth economic impactHealth economic analysisLikelihood of benefitPittsburgh Medical CenterNet cost savingsYr of treatmentGross cost savingsAdverse eventsExtended therapyLate recurrenceRNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial
Fumagalli D, Venet D, Ignatiadis M, Azim HA, Maetens M, Rothé F, Salgado R, Bradbury I, Pusztai L, Harbeck N, Gomez H, Chang TW, Coccia-Portugal MA, Di Cosimo S, de Azambuja E, de la Peña L, Nuciforo P, Brase JC, Huober J, Baselga J, Piccart M, Loi S, Sotiriou C. RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial. JAMA Oncology 2017, 3: 227-234. PMID: 27684533, PMCID: PMC5374044, DOI: 10.1001/jamaoncol.2016.3824.Peer-Reviewed Original ResearchEvent-free survivalAnti-HER2 therapyAnti-HER2 agentsErbB2/HER2Genomic grade indexCombination armTreatment armsGene signatureBreast cancerHER2-positive early-stage breast cancerNeoadjuvant anti-HER2 therapyPathologic complete response rateHuman epidermal growth factor receptor 2Early-stage breast cancerEpidermal growth factor receptor 2Candidate predictive markersCycles of fluorouracilDual HER2 blockadeImmune gene signaturesComplete response rateGrowth factor receptor 2Positive breast cancerLong-term outcomesRandomized clinical trialsHigh PCR
2015
Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer
Sanft T, Aktas B, Schroeder B, Bossuyt V, DiGiovanna M, Abu-Khalaf M, Chung G, Silber A, Hofstatter E, Mougalian S, Epstein L, Hatzis C, Schnabel C, Pusztai L. Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer. Breast Cancer Research And Treatment 2015, 154: 533-541. PMID: 26578401, PMCID: PMC4661200, DOI: 10.1007/s10549-015-3631-9.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAntineoplastic Agents, HormonalAnxietyBreast NeoplasmsChemotherapy, AdjuvantDecision MakingFemaleGene Expression Regulation, NeoplasticGenetic TestingHumansMiddle AgedNeoplasm Recurrence, LocalPrognosisProspective StudiesReceptors, EstrogenSurveys and QuestionnairesTamoxifenConceptsBreast Cancer IndexExtended endocrine therapyER-positive breast cancerAdjuvant endocrine therapyEndocrine therapyDecisional Conflict ScaleBreast cancerCancer indexPhysician recommendationRisk/benefit discussionEarly-stage estrogen receptorEndocrine therapy trialsYale Cancer CenterPositive breast cancerState-Trait Anxiety Inventory FormMean STAIExtended therapyLate recurrenceAbsolute benefitCancer CenterPatient satisfactionPrognostic informationTreatment recommendationsPatient anxietyImproved outcomesGenomic predictor of residual risk of recurrence after adjuvant chemotherapy and endocrine therapy in high risk estrogen receptor-positive breast cancers
Khan SS, Karn T, Symmans WF, Rody A, Müller V, Holtrich U, Becker S, Pusztai L, Hatzis C. Genomic predictor of residual risk of recurrence after adjuvant chemotherapy and endocrine therapy in high risk estrogen receptor-positive breast cancers. Breast Cancer Research And Treatment 2015, 149: 789-797. PMID: 25651779, DOI: 10.1007/s10549-015-3277-7.Peer-Reviewed Original ResearchConceptsRecurrence-free survivalAdjuvant chemotherapyEndocrine therapyHigh riskOncotype DXBreast cancerEstrogen receptor-positive breast cancerReceptor-positive breast cancerRisk categoriesEarly-stage estrogen receptorEndocrine therapy sensitivityGood prognosis patientsER-positive patientsHigh-risk patientsPoor prognosis groupPositive breast cancerLow-risk groupAdjuvant endocrineMultimodality therapyPrognosis patientsRisk patientsEndocrine sensitivityIndependent predictorsPrognosis groupT stageThe Influence of Host Factors on the Prognosis of Breast Cancer: Stroma and Immune Cell Components as Cancer Biomarkers.
Karn T, Pusztai L, Rody A, Holtrich U, Becker S. The Influence of Host Factors on the Prognosis of Breast Cancer: Stroma and Immune Cell Components as Cancer Biomarkers. Current Cancer Drug Targets 2015, 15: 652-64. PMID: 26452382, DOI: 10.2174/156800961508151001101209.Peer-Reviewed Original ResearchConceptsBreast cancerPredictive markerImmune cellsStromal componentsHER2-positive breast cancerHigh lymphocytic infiltrationPositive breast cancerHER2-positive cancersImmune cell componentsNovel therapeutic optionsType breast cancerBreast cancer subtypesHost immunological responseImmunotherapeutic regimensClinical courseImmune markersLymphocytic infiltrationPositive cancersTherapeutic optionsInflammatory cellsClinical subtypingImmunological parametersClinical trialsImmune parametersImmunological responseMultigene prognostic tests in breast cancer: past, present, future
Győrffy B, Hatzis C, Sanft T, Hofstatter E, Aktas B, Pusztai L. Multigene prognostic tests in breast cancer: past, present, future. Breast Cancer Research 2015, 17: 11. PMID: 25848861, PMCID: PMC4307898, DOI: 10.1186/s13058-015-0514-2.BooksConceptsER-negative cancersPrognostic valuePredictive markerBreast cancerPrognostic signatureExtended adjuvant endocrine therapyPrognostic testAdjuvant endocrine therapyCandidate predictive markersImmune gene signaturesPositive breast cancerGood prognostic valueSignificant prognostic valueTreatment response predictorsNew predictive markers
2013
Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers
Bianchini G, Pusztai L, Karn T, Iwamoto T, Rody A, Kelly C, Müller V, Schmidt M, Qi Y, Holtrich U, Becker S, Santarpia L, Fasolo A, Del Conte G, Zambetti M, Sotiriou C, Haibe-Kains B, Symmans WF, Gianni L. Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers. Breast Cancer Research 2013, 15: r86. PMID: 24060333, PMCID: PMC3978752, DOI: 10.1186/bcr3481.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Agents, HormonalBiomarkers, TumorBreast NeoplasmsCell ProliferationChemoradiotherapy, AdjuvantEstrogensFemaleFollow-Up StudiesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansMiddle AgedMitosisNeoplasm GradingNeoplasm MetastasisNeoplasm Recurrence, LocalNeoplasm StagingPrognosisReceptors, EstrogenRiskSignal TransductionTamoxifenConceptsNode-negative tumorsLate relapseNeoadjuvant letrozoleEndocrine therapyEarly relapseNegative tumorsBreast cancerEstrogen receptor-positive breast cancerProliferation markersReceptor-positive breast cancerER-positive breast cancerAdjuvant endocrine therapyAffymetrix gene expression profilesExtended endocrine therapyTamoxifen-treated patientsER-positive patientsGenomic grade indexPositive breast cancerRisk of recurrenceRisk of relapseEstrogen receptor activitySmall independent cohortEstrogen-related genesAdjuvant tamoxifenSystemic therapyA 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories
Szekely B, Iwamoto T, Szasz AM, Qi Y, Matsuoka J, Symmans WF, Tokes AM, Kulka J, Swanton C, Pusztai L. A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories. Breast Cancer Research And Treatment 2013, 138: 691-698. PMID: 23504136, DOI: 10.1007/s10549-013-2475-4.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, NeoplasmBreast NeoplasmsCell ProliferationChemotherapy, AdjuvantCohort StudiesDatabases, GeneticDNA Topoisomerases, Type IIDNA-Binding ProteinsFemaleForkhead Box Protein M1Forkhead Transcription FactorsGene Expression Regulation, NeoplasticGenome, HumanHumansKi-67 AntigenPoly-ADP-Ribose Binding ProteinsPredictive Value of TestsPrognosisReceptors, EstrogenSurvival RateTamoxifenConceptsGenomic grade indexGrade 2 cancersPrognostic valueProliferation scoreBreast cancerDistant metastasis-free survival curvesGrade 2Metastasis-free survival curvesER-positive breast cancerSystemic adjuvant therapyHigh expressionCohort of patientsHistological grade 2Intermediate-risk cancerPositive breast cancerSimilar prognostic valueGrade 2 tumorsHigh-risk groupGrade 1 cancersHistological grade groupsNon-significant trendWorse DMFSAdjuvant tamoxifenAdjuvant therapyWorse survival