乳腺癌摘要和讨论课件.ppt

1、A Randomized,Phase III Clinical Trial to Compare Sentinel Node Resection to Axillary Dissection in Clinically Node-Negative Breast Cancer PatientsDefinitive Analysis of the Primary OutcomesDN Krag,SJ Anderson,TB Julian,A Brown,SP Harlow,JP Costantino,T Ashikaga,D Weaver,EP Mamounas,N WolmarkASCO Abs

2、tract LBA505.AD vs.no AD Randomized TrialsOrr RK.Ann Surg Oncol 1999;6(1):109-16 SurvivalAll trials reported higher survival in the AD group.Krag et al.Ann Surg Oncol,2003.10(10):p.1-8.1-5 nodes 15 nodesFew vs.Some vs.ManyAll nodes negativeSurvival.Clinically Negative Axillary NodesGROUP 1SN+ADSN Ne

3、g(SN only)GROUP 2SN Stratification Age Clinical Tumor Size Type of SurgeryB-32SN pos+ADSN PosSN Neg(SN+AD)Intraop cytology&postop HE FUFU1,975 patients2,011 patientsRandomization.SN Detection MethodsBlue dyeTechnetium sulfurcolloidPalpation(2%cases)B-32 Surgery.Intraop-CytologyPostop-HE Standardized

4、 Path ProtocolB-32 Pathology.Surgeon Performance Core training centers 224 surgeons audited for standard Supports accuracy and conclusions of the B-32 trial.B-32 QCSN Surgery is complex-expect variation.B-32 Analysis Plan 3,989-SN neg(71%of 5611)99.9%-follow-up information 95 months-average time on

5、study Primary endpoints OS,DFS,Regional Control Study powered to detect 2%difference OS.Evenly Balanced Entry Characteristics Age Race Tumor size Surgical treatment plan Associated Treatments Radiation Therapy 85%&84%Systemic Therapy 82%.B-32 OS*300 deaths triggered the definitive analysis*309 repor

6、ted as of 12/31/2009NSABP Protocol B-32Years After Entry%Surviving02468020406080100TrtNDeathsSNR+AD1975140SNR 2011169 HR=1.20 p=0.117Overall Survival for Sentinel Node Negative PatientsData as of December 31,2009.B-32 SN Negative Patients:Hazard Ratios of OSAccording to Stratification Variables B-32

7、 OSHazard Ratio0.20.61.01.41.82.22.6All patients with follow-upHR=1.2Patients 2 cmPlanned LumpectomyPlanned MastectomySNR+AD betterSNR better.B-32 DFSYears After Entry%Disease-Free02468020406080100NSABP Protocol B-32Disease-Free Survival for Sentinel Node Negative PatientsTrtNDeathsSNR+AD1975315SNR

8、2011336 HR=1.05 p=0.542Data as of December 31,2009.B-32 DFSB-32 SN Negative Patients:Hazard Ratios of DFSAccording to Stratification Variables Hazard Ratio0.20.40.60.81.01.21.41.61.8All patients with follow-upHR=1.05Patients 2 cmPlanned LumpectomyPlanned MastectomySNR+AD betterSNR better.B-32 Hazard

9、 Ratios Between GroupsAccording to Site of Treatment Failure B-32 DFSHazard Ratio0.20.40.60.81.01.21.41.6All eventsHR=1.05Local Regional RecurrencesDistant RecurrencesOpposite Breast Cancers2nd cancersDead,NEDSNR+AD betterSNR better.Group 1Group 2Local54 (2.7%)49 (2.4%)Axillary2(0.1%)8(0.3%)Extra-ax

10、illary5(0.25%)6(0.3%)Local and Regional Recurrencesas First EventsB-32 RR.Group 1SN+ADGroup 2SNShoulder abduction deficit19%13%Arm volume difference 5%28%17%Arm numbness31%8%Arm tingling13%7%All differences p SNIpsilateral arm and breast symptoms p0.002 allRestricted work and social activityImpaired

11、 QOLFrom 1 3 years15%of either group reported moderate or greater severityArm morbidity was greater with AD than SN,but lower than expected even for AD.Land et al,JCO,in press.NSABP B-32Conclusion No significant differences were observed OS,DFS,or Regional Control Morbidity decreasedWhen the SN is n

12、egativeSN surgery aloneis appropriate,safe,effective therapy for breast cancer patientswith clinically negative lymph nodes.ACOSOG Z0011:A Randomized Trial of Axillary Node Dissection in Women with Clinical T1-2 N0 M0 Breast Cancer who have a Positive Sentinel Node Giuliano AE,McCall L,Beitsch PD,Wh

13、itworth PW,Blumencranz PW,Leitch AM,Saha S,Hunt K,Morrow M,Ballman KV.19Contemporary Breast Cancer Tumors are smaller and fewer node positive than in past SLN often only node involved(40-70%)BCT common tangential field irradiation treats much of axilla Adjuvant systemic therapy usually given for nod

14、e-positive women ALND may not be necessary for everyone although it is still gold standard for SLN positive patients.20 Modern Randomized Trials of Axillary Treatment with BCTMartelli G,Ann Surg 2005,242:1;Louis-Sylvestre C,JCO 2004,22:97;Veronesi U,Ann Oncol 2005,16:383.ALND vs.Ax RTAuthorMedian F/

15、UNAxillary RecurrenceAx RT vs.ObsALND vs.ObsLouis-SylvestreVeronesiMartelli52190 vs 1.8%5.34350.5%vs 1.5%156581%vs 3%No significant differences in survival.21Hypothesis:SLND alone achievessimilar locoregional controland survival as Level I and II ALND for H&E SN node-positive women.22ACOSOG Z0011A r

16、andomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive SN165 Investigators/177 Institutions50 investigators with 5 or more patientsTarget accrual 1900 patients(non-inferiority)Closed early.23Inclusion/Exclusion CriteriaEligibility Clinical T1

17、T2 N0 breast cancer H&E-detected metastases in SN(AJCC 5th edition)Lumpectomy with whole breast irradiation Adjuvant systemic therapy by choiceIneligibility Third field(nodal irradiation)or APBI Metastases in SN detected by IHC Matted nodes 3 or more involved SN.24Z0011 Study Design Schema.25Study P

18、opulation Schema 5/9912/04.26Patient and Tumor CharacteristicsAge(median range)Clinical Stage T1T2ER(+)(-)LVI YesNo56(24-92)67.9%32.1%83.0%17.0%67.7%32.3%40.6%59.4%ALND(420 pts)54(25-90)29.4%17.0%64.8%70.6%83.0%69.9.%35.2%SLND(436 pts)30.1%PR(+)(-).27Patient and Tumor CharacteristicsModified Bloom-R

19、ichardson22.0%48.9%1.7(0.4-7.0)46.8%25.6%1.6(0.0-5.0)Clinical Tumor Size(median cm.)29.1%27.5%IIIIIIALND(420 pts)SLND(436 pts).28Adjuvant Systemic TherapyChemotherapy57.9%58.0%Hormonal therapy46.4%46.6%Either/Both96.0%97.0%P=N.S.Median Number of Lymph Nodes Removed.30Size of SN Metastasis.31Number o

20、f Positive Lymph Nodes.32Only 106(27.4%)patients treated with ALND had additional positive nodes removed beyond SN.33Locoregional RecurrencesSLND(436 pts)ALND(420 pts)2(0.5%)4(0.9%)Regional(Axilla,Supraclavicular)15(3.6%)8(1.8%)Local(Breast)17(4.1%)12(2.8%)Total LocoregionalRecurrence Median follow-

21、up=6.3 yearsRegional recurrence seen in only 0.7%of the entire population P=0.11.34 It is highly improbable that the 0.9%regional or 2.8%locoregional recurrence with SLND would significantly impactsurvival.35Locoregional Recurrence-Free Survival.36Associations of Prognostic Variables with Locoregion

22、al RecurrenceER statusPR statusTumor SizeHistologic Type0.0002NSNSNS0.0012NS0.00020.0421NSLVI present vs.absentSN Metastasis Size#Positive Total LNModified Bloom-RichardsonTreatment ArmAdjuvant Systemic TherapyAge(50)0.0207NSNSNSNSNSNSNS0.02580.0260NSNSNSUnivariable AnalysisP valueMultivariable Anal

23、ysisP value.37ER/PR Status and 5-Year Locoregional Recurrence-Free Survival.38Disease-Free Survival.39Associations of Prognostic Variables with Disease-Free SurvivalPR statusTumor SizeHistologic Type0.0310.0020.016Adjuvant Systemic TherapyNSTreatment ArmNS0.005#Positive Total LNNSER status0.00030.00

24、7NSAge(50)NSNS0.006NSNSNSLVI present vs.absentNSNSModified Bloom RichardsonUnivariable AnalysisP valueMultivariable AnalysisP valueNSNSNSSN Metastasis SizeNS.40ER/PR Status and 5-Year Disease-Free Survival.41Overall Survival.42Associations of Prognostic Variables with Overall SurvivalPR statusTumor

25、SizeHistologic TypeNS0.0420.020Univariable AnalysisP valueMultivariable AnalysisP valueAdjuvant Systemic TherapyNSTreatment ArmNS0.044#Positive Total LNNSER status0.0120.013NSAge(50)0.0020.0060.025NSNSNSLVI present vs.absentNSNSModified Bloom RichardsonNSNSNSSN Metastasis SizeNS.43ER/PR Status and 5

26、-Year Overall Survival.44Summary Locoregional recurrence in only 2.8%of SLND and 4.1%of ALND patients.Only age(50)and higher Bloom-Richardson score were associated with locoregional recurrence by multivariable analysis.Neither number of positive SN,size of SN metastasis,nor number of lymph nodes rem

27、oved was associated with locoregional recurrence.Locoregional Recurrence-Free Survival.45Summary No significant difference in DFS between patients treated with SLND(83.9%)or ALND(82.2%)No significant difference in OS between patients treated with SLND(92.5%)or ALND(91.8%)Only older age,ER-,and lack

28、of adjuvant systemic therapy-not operation-were associated with worse OS by multivariable analysis.Disease-Free and Overall Survival.46ConclusionIn this prospective randomized study SLNDalone provided excellentlocoregional control andsurvival comparable tocompletion ALND.47This study does not suppor

29、t the routine use of ALND in early nodal metastaticbreast cancer.The role of this operation should be reconsidered.48ACOSOG Z0010:A multicenter prognostic study of sentinel node and bone marrow micrometastases in clinical T1,T2 N0 M0 breast cancerR.J.Cote,A.E.Giuliano,D.Hawes,K.V.Ballman,P.W.Whitwor

30、th,P.W.Blumencranz,D.S.Reintgen,M.Morrow,A.M.Leitch,K.K.Hunt and the ACOSOG Z0010 Study Group.Occult Metastases in Breast Cancer Recognized as holding extraordinary potential for disease management in cancer patients Assess disease progression Determine need for systemic Rx Monitor therapeutic effic

31、acy Test molecular cancer markers Understand early events in metastasis Discover new therapeutic targets.IHC Detected Occult Metastases to LN and BM Associated with Outcome in Patients with Operable Breast CancerCote R et al.Lancet 1999Disease-free survival 343 postmenopausal ptsBraun et al.NEJM 353

32、;8:793-802,2005Disease free and overall survival in 4703 patientsIHC detected LN occult metsIHC detected BM occult mets.ACOSOG Z0010 SchemaALNDNo ALNDNoSpecificAxillaryTreatmentBreastRadiationTherapy,SystemicAdjuvantTherapyFOLLOWREGISTERBreastCancerClinicalT1 orT2,N0,M0SLNDResult?BCT,SLND,BilateralI

33、liac CrestBMAspiration-+NotFoundEligible&consent toZ0011?NoYesREGISTERTO Z0011ELIGIBLE&CONSENTED.ACOSOG Z0010-Methods Bone marrow aspiration prior to SLN bx Bone marrow specimens subjected to IHC(investigators blinded to results)SLNs processed-standard pathology and H&E staining SLNs neg by H&E subj

34、ected to IHC for cytokeratin(investigators blinded to results).Z0010 Patient CharacteristicsAge(Years)Median(Min,Max)Missing56(23,95)15Tumor Type,N(%)Ductal Lobular Both Other Missing 4154(80.1)431(8.3)138(2.7)463(8.9)24LVI,N(%)Present Absent Missing2695(19.3)2907(80.7)1608Tumor Size(cm),N(%)2.0 Mis

35、sing1922(39.1)2250(45.8)742(15.1)296ER Status,N(%)Positive Negative Missing3916(81.2)907(18.8)387PR Status,N(%)Positive Negative Missing3171(67.5)1530(32.6)509.Z0010 Treatment VariablesTotal SLNs Removed Median(Min,Max)Missing2(0,32)689ALND Performed,N(%)Yes No Missing925(18.0)4203(82.0)82Chemothera

36、py,N(%)Yes No Missing2297(53)2035(47)878Hormonal Rx,N(%)Yes No Missing2943(67.9)1389(32.1)878Radiation Rx,N(%)Yes No Missing3884(90.8)394(9.2)932Any Adj Rx,N(%)Yes No Missing4210(98.4)68(1.6)932.Overall LN and BM Results.No concordance of SLN IHC status with BM IHCSLN status by IHCPositiveNegativeTo

37、talBone marrow IHCPositive6(0.3)62(2.8)68(3.1)Negative238(10.8)1899(86.1)2137(96.9)Total244(11.1)1961(88.9)Kappa statistic(95%CI):-0.01(-0.07 to 0.05).Tumor size is associated with H&E positive SLNTumor Size(cm)SLN H&E NegativeSLNH&E Positive 2.0 cm,n(%)455(12.4)268(23.1)p value0.0001.Tumor size is

38、associated with IHC positive SLNTumor Size(cm)SLN IHC NegativeSLNIHC Positive 2.0 cm,n(%)330(11.8)67(20.4)p value0.0001.Tumor size is not associated with positive bone marrow IHCTumor Size(cm)Bone marrow IHC NegativeBone marrowIHC Positive 2.0 cm,n(%)498(15.7)15(15.0)p value0.95.Disease-Free Surviva

39、l by SLN status.Overall Survival by SLN status5-year OS96%for IHC+/-and H&E-vs.93%for H&E+.Overall Survival by Bone Marrow IHC5-year OS IHC+90%vs.IHC-95%P value=0.01.Overall Survival by Histologic SLN and BM StatusAll PatientsunivariablemultivariableVariableHR(95%CI)p valueHR(95%CI)p valueSLN H&E ne

40、gative positive1.00(ref)1.47(1.19,1.80)0.00031.00(ref)1.44(1.11,1.88)0.007BM IHC negative positive1.00(ref)1.90(1.13,3.20)0.0161.00(ref)1.88(1.12,3.17)0.017.Overall Survival by SLN IHC and BM StatusSLN H&E Negative PatientsunivariablemultivariableVariableHR(95%CI)p valueHR(95%CI)p valueSLN IHC negat

41、ive positive1.00(ref)0.92(0.63,1.33)0.651.00(ref)0.98(0.62,1.54)0.93BM IHC negative positive1.00(ref)1.90(1.13,3.20)0.0161.00(ref)2.22(1.21,4.10)0.011.Factors Predicting OS All PatientsunivariablemultivariableVariableHR(95%CI)p valueHR(95%CI)p valueAge,years 501.00(ref)1.79(1.41,2.26)0.0001 1.00(ref

42、)1.77(1.18,2.66)0.0059Tumor typeDuctalLobularBothother1.00(ref)0.86(0.60,1,22)1.31(0.78,2.20)0.61(0.41,0.91)-0.390.310.017 1.00(ref)0.91(0.47,1.75)1.45(0.59,3.60)0.74(0.34,1.59)-0.830.400.46 LVIAbsentpresent1.00(ref)1.68(1.32,2.15)0.0001 1.00(ref)1.20(0.79,1.83)0.39Tumor size 2.01.00(ref)1.27(1.02,1

43、.58)2.36(1.83,3.03)0.030.0001 1.00(ref)2.19(1.42,3.37)2.96(1.76,4.96)0.00040.0001 ER statusNegativepositive1.00(ref)0.55(0.4,0.682)0.0001 1.00(ref)0.66(0.41,1.05)0.08.Factors Predicting OS All PatientsunivariablemultivariableVariableHR(95%CI)p valueHR(95%CI)p valueAdjuvant chemotherapy No Yes1.00(re

44、f)1.03(0.83,1.27)0.831.00(ref)0.83(0.56,124)0.36Adjuvant hormonal rx No Yes1.00(ref)0.58(0.47,0.72)0.00011.00(ref)0.75(0.49,1.15)0.19SLN H&E status Negative Positive1.00(ref)1.47(1.19,1.80)0.00031.00(ref)0.75(0.43,1.29)0.30BM IHC Status Negative Positive1.00(ref)1.90(1.13,3.20)0.0161.00(ref)1.71(0.8

45、3,3.51)0.15.Factors Predicting OS SLN H&E Neg PtsunivariablemultivariableVariableHR(95%CI)p valueHR(95%CI)p valueAge,years 501.00(ref)1.79(1.41,2.26)0.0001 1.00(ref)2.34(1.33,4.12)0.003Tumor typeDuctalLobularBothother1.00(ref)0.86(0.60,1,22)1.31(0.78,2.20)0.61(0.41,0.91)-0.390.310.017 1.00(ref)0.86(

46、0.37,2.02)1.92(0.69,5.36)1.22(0.53,2,84)-0.730.210.64 LVIAbsentpresent1.00(ref)1.68(1.32,2.15)0.0001 1.00(ref)1.00(0.52,1.93)0.99Tumor size 2.01.00(ref)1.27(1.02,1.58)2.36(1.83,3.03)0.030.0001 1.00(ref)2.14(1.29,3.54)3.14(1.64,5.99)0.0030.0005 ER statusNegativepositive1.00(ref)0.55(0.4,0.682)0.0001

47、1.00(ref)0.69(0.38,1.25)0.22.Factors Predicting OS SLN H&E Neg PtsunivariablemultivariableVariableHR(95%CI)p valueHR(95%CI)p valueAdjuvant chemotherapy No Yes1.00(ref)1.03(0.83,1.27)0.831.00(ref)0.79(0.50,1.26)0.32Adj hormonal rx No Yes1.00(ref)0.58(0.47,0.72)0.00011.00(ref)0.75(0.44,1.27)0.28Number

48、 of nodes removed1.03(1.02,1.04)0.00011.08(0.97,1.19)0.16SLN IHC status Negative Positive1.00(ref)1.92(0.63,1.33)0.651.00(ref)0.86(0.44,1.68)0.66BM IHC Status Negative Positive1.00(ref)1.90(1.13,3.20)0.0161.00(ref)1.82(0.78,4.23)0.16.Conclusions Outcome in this population was excellent-5 year overal

49、l survival of 93%in pts with H&E+SLNs.Detection of BM occult mets by IHC identifies clinical T1,2 N0 M0 pts at significantly increased risk for death.IHC detected SLN metastases do not appear to impact overall survival.Routine examination of SLN by IHC is not supported in this patient population by

50、this study.State of the art in sentinel node resectionASCO 2010.Important areas covered ASCO 2010 Is SLNB enough for SLNB negative patients Is there a group of patients with positive SLNB who can avoid ALND Significance of micrometastasis in SLNB and BM micrometastasis.BACKGROUND of SLNB Routine ALN