1、.1A 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 A
2、bstract LBA505.2AD vs.no AD Randomized TrialsOrr RK.Ann Surg Oncol 1999;6(1):109-16 SurvivalAll trials reported higher survival in the AD group.3Krag et al.Ann Surg Oncol,2003.10(10):p.1-8.1-5 nodes 15 nodesFew vs.Some vs.ManyAll nodes negativeSurvival.4Clinically Negative Axillary NodesGROUP 1SN+AD
3、SN Neg(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.5SN Detection MethodsBlue dyeTechnetium sulfurcolloidPalpation(2%cases)B-32 Surgery.6Intraop-CytologyPostop-HE Stand
4、ardized Path ProtocolB-32 Pathology.7Surgeon 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.8B-32 Analysis Plan 3,989-SN neg(71%of 5611)99.9%-follow-up information 95 months-average
5、 time on study Primary endpoints OS,DFS,Regional Control Study powered to detect 2%difference OS.9Evenly Balanced Entry Characteristics Age Race Tumor size Surgical treatment plan Associated Treatments Radiation Therapy 85%&84%Systemic Therapy 82%.10B-32 OS*300 deaths triggered the definitive analys
6、is*309 reported 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 31,2009.11B-32 SN Negative Patients:Hazard Ratios of OSAccording to Stratification
7、Variables B-32 OSHazard Ratio0.20.61.01.41.82.22.6All patients with follow-upHR=1.2Patients 2 cmPlanned LumpectomyPlanned MastectomySNR+AD betterSNR better.12B-32 DFSYears After Entry%Disease-Free02468020406080100NSABP Protocol B-32Disease-Free Survival for Sentinel Node Negative PatientsTrtNDeathsS
8、NR+AD1975315SNR 2011336 HR=1.05 p=0.542Data as of December 31,2009.13B-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
9、better.14B-32 Hazard 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.15Group 1Group 2Local54 (2.7%)49 (2.4%)Axillary
10、2(0.1%)8(0.3%)Extra-axillary5(0.25%)6(0.3%)Local and Regional Recurrencesas First EventsB-32 RR.16Group 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
11、 social activityImpaired 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.18NSABP B-32Conclusion No significant differences were observed OS,DFS,or Regional Control Morbidity
12、 decreasedWhen the SN is negativeSN surgery aloneis appropriate,safe,effective therapy for breast cancer patientswith clinically negative lymph nodes.19ACOSOG Z0011:A Randomized Trial of Axillary Node Dissection in Women with Clinical T1-2 N0 M0 Breast Cancer who have a Positive Sentinel Node Giulia
13、no AE,McCall L,Beitsch PD,Whitworth PW,Blumencranz PW,Leitch AM,Saha S,Hunt K,Morrow M,Ballman KV.20Contemporary 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 t
14、herapy usually given for node-positive women ALND may not be necessary for everyone although it is still gold standard for SLN positive patients.21 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.
15、ALND vs.Ax RTAuthorMedian F/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.22Hypothesis:SLND alone achievessimilar locoregional controland survival as Level I and II ALND for H&E SN node-posi
16、tive women.23ACOSOG Z0011A randomized 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.24Inclusion/Exclusion Crit
17、eriaEligibility Clinical T1 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.25Z0011 S
18、tudy Design Schema.26Study Population Schema 5/9912/04.27Patient 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(+)(-).28Patient and Tumor Cha
19、racteristicsModified Bloom-Richardson22.0%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).29Adjuvant Systemic TherapyChemotherapy57.9%58.0%Hormonal therapy46.4%46.6%Either/Both96.0%97.0%P=N.S.30Median Number of Lymph Nodes Removed.31Si
20、ze of SN Metastasis.32Number of Positive Lymph Nodes.33Only 106(27.4%)patients treated with ALND had additional positive nodes removed beyond SN.34Locoregional 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 Locoreg
21、ionalRecurrence Median follow-up=6.3 yearsRegional recurrence seen in only 0.7%of the entire population P=0.11.35 It is highly improbable that the 0.9%regional or 2.8%locoregional recurrence with SLND would significantly impactsurvival.36Locoregional Recurrence-Free Survival.37Associations of Progno
22、stic Variables with Locoregional 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 Ana
23、lysisP valueMultivariable AnalysisP value.38ER/PR Status and 5-Year Locoregional Recurrence-Free Survival.39Disease-Free Survival.40Associations of Prognostic Variables with Disease-Free SurvivalPR statusTumor SizeHistologic Type0.0310.0020.016Adjuvant Systemic TherapyNSTreatment ArmNS0.005#Positive
24、 Total LNNSER status0.00030.007NSAge(50)NSNS0.006NSNSNSLVI present vs.absentNSNSModified Bloom RichardsonUnivariable AnalysisP valueMultivariable AnalysisP valueNSNSNSSN Metastasis SizeNS.41ER/PR Status and 5-Year Disease-Free Survival.42Overall Survival.43Associations of Prognostic Variables with O
25、verall SurvivalPR statusTumor 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 Metastas
26、is SizeNS.44ER/PR Status and 5-Year Overall Survival.45Summary 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
27、,nor number of lymph nodes removed was associated with locoregional recurrence.Locoregional Recurrence-Free Survival.46Summary 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
28、%)Only older age,ER-,and lack of adjuvant systemic therapy-not operation-were associated with worse OS by multivariable analysis.Disease-Free and Overall Survival.47ConclusionIn this prospective randomized study SLNDalone provided excellentlocoregional control andsurvival comparable tocompletion ALN
29、D.48This study does not support the routine use of ALND in early nodal metastaticbreast cancer.The role of this operation should be reconsidered.49ACOSOG 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
30、.Hawes,K.V.Ballman,P.W.Whitworth,P.W.Blumencranz,D.S.Reintgen,M.Morrow,A.M.Leitch,K.K.Hunt and the ACOSOG Z0010 Study Group.50Occult Metastases in Breast Cancer Recognized as holding extraordinary potential for disease management in cancer patients Assess disease progression Determine need for syste
31、mic Rx Monitor therapeutic efficacy Test molecular cancer markers Understand early events in metastasis Discover new therapeutic targets.51IHC Detected Occult Metastases to LN and BM Associated with Outcome in Patients with Operable Breast CancerCote R et al.Lancet 1999Disease-free survival 343 post
32、menopausal ptsBraun et al.NEJM 353;8:793-802,2005Disease free and overall survival in 4703 patientsIHC detected LN occult metsIHC detected BM occult mets.52 ACOSOG Z0010 SchemaALNDNo ALNDNoSpecificAxillaryTreatmentBreastRadiationTherapy,SystemicAdjuvantTherapyFOLLOWREGISTERBreastCancerClinicalT1 orT
33、2,N0,M0SLNDResult?BCT,SLND,BilateralIliac CrestBMAspiration-+NotFoundEligible&consent toZ0011?NoYesREGISTERTO Z0011ELIGIBLE&CONSENTED.53ACOSOG Z0010-Methods Bone marrow aspiration prior to SLN bx Bone marrow specimens subjected to IHC(investigators blinded to results)SLNs processed-standard patholog
34、y and H&E staining SLNs neg by H&E subjected to IHC for cytokeratin(investigators blinded to results).54Z0010 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
35、)2907(80.7)1608Tumor Size(cm),N(%)2.0 Missing1922(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)509.55Z0010 Treatment VariablesTotal SLNs Removed Median(Min,Max)Missing2(0,32)689ALND Performed,N(%)Ye
36、s No Missing925(18.0)4203(82.0)82Chemotherapy,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)932.56Overall LN and BM Results.57No concordance of SLN IHC status
37、 with BM IHCSLN status by IHCPositiveNegativeTotalBone 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).58Tumor size is associated with H&E positive SLNTumor Size(cm)SLN H&E NegativeSLNH&E Positive 2.0 cm,n
38、(%)455(12.4)268(23.1)p value0.0001.59Tumor size is associated with IHC positive SLNTumor Size(cm)SLN IHC NegativeSLNIHC Positive 2.0 cm,n(%)330(11.8)67(20.4)p value0.0001.60Tumor size is not associated with positive bone marrow IHCTumor Size(cm)Bone marrow IHC NegativeBone marrowIHC Positive 2.0 cm,
39、n(%)498(15.7)15(15.0)p value0.95.61Disease-Free Survival by SLN status.62Overall Survival by SLN status5-year OS96%for IHC+/-and H&E-vs.93%for H&E+.63Overall Survival by Bone Marrow IHC5-year OS IHC+90%vs.IHC-95%P value=0.01.64Overall Survival by Histologic SLN and BM StatusAll Patientsunivariablemu
40、ltivariableVariableHR(95%CI)p valueHR(95%CI)p valueSLN H&E negative 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)0.017.65Overall Survival by SLN IHC and BM StatusSLN H&E Negative Patientsunivariablemul
41、tivariableVariableHR(95%CI)p valueHR(95%CI)p valueSLN IHC negative 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)0.011.66Factors Predicting OS All PatientsunivariablemultivariableVariableHR(95%CI)p valueHR
42、(95%CI)p valueAge,years 501.00(ref)1.79(1.41,2.26)0.0001 1.00(ref)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)0.00
43、01 1.00(ref)1.20(0.79,1.83)0.39Tumor size 2.01.00(ref)1.27(1.02,1.58)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)0.08.67Factors Predicting OS All PatientsunivariablemultivariableVariable
44、HR(95%CI)p valueHR(95%CI)p valueAdjuvant chemotherapy No Yes1.00(ref)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 Sta
45、tus Negative Positive1.00(ref)1.90(1.13,3.20)0.0161.00(ref)1.71(0.83,3.51)0.15.68Factors 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(
46、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(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
47、)0.0030.0005 ER statusNegativepositive1.00(ref)0.55(0.4,0.682)0.0001 1.00(ref)0.69(0.38,1.25)0.22.69Factors 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
48、 No Yes1.00(ref)0.58(0.47,0.72)0.00011.00(ref)0.75(0.44,1.27)0.28Number 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)
49、0.16.70Conclusions Outcome in this population was excellent-5 year overall 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
50、examination of SLN by IHC is not supported in this patient population by this study.71State of the art in sentinel node resectionASCO 2010.72Important 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
