1、早期乳腺癌内分泌治疗早期乳腺癌内分泌治疗的一些进展的一些进展南京医科大学第一附属医院乳腺内分泌外科南京医科大学第一附属医院乳腺内分泌外科 王王 水水 Early Breast Cancer:Endocrine Therapy 乳腺癌：一种全身性疾病乳腺癌：一种全身性疾病 治疗：综合性治疗：综合性 规范化：循证医学规范化：循证医学 个体化：个体化：target&tailorEarly Breast Cancer:Endocrine Therapy2007年年St Gallen 共识共识HER2/neu基因过表达基因过表达HER2低表达低表达HER2过表达过表达内分泌应答内分泌应答高应答高应答应答
2、不完全应答不完全无应答无应答高应答高应答应答不完全应答不完全无应答无应答绝经状况绝经状况前前后后前前后后前和后前和后前前后后前前后后前和后前和后低低危危淋巴结阴性且具有以下所有淋巴结阴性且具有以下所有特征：特征：pTpT2cm2cm,Grade 1，无血管侵袭，无血管侵袭，HER2(-)，ER和和/或或PR表达，年龄表达，年龄35岁岁EEE EE E中中危危淋巴结阴性且至少具有以下淋巴结阴性且至少具有以下一个特征：一个特征：pT 2cm,Grade 2-3，血管侵袭，血管侵袭，HER2(-)，ER和和/或或PR阴性，年龄阴性，年龄4个淋巴结阳性个淋巴结阳性CECEC CE EC CE ECCE
3、+TrCE+TrCE+TrCE+TrC+TrEarly Breast Cancer:Endocrine Therapy乳腺癌内分泌治疗的乳腺癌内分泌治疗的三三个重要标志个重要标志 双卵巢切除去势术双卵巢切除去势术 他莫昔芬标准地位的确立他莫昔芬标准地位的确立 第三代芳香化酶抑制剂第三代芳香化酶抑制剂挑战挑战他莫昔芬标准地位他莫昔芬标准地位Early Breast Cancer:Endocrine Therapy他莫昔芬治疗乳腺癌的标准地位他莫昔芬治疗乳腺癌的标准地位EBCTCG.Lancet 2005EBCTCG.Lancet 2005复发率复发率(%)(%)复发复发时间（年）时间（年）乳腺癌
4、死亡率乳腺癌死亡率60601515年受益率年受益率11.8%(SE 1.3)11.8%(SE 1.3)时序检验时序检验2p0.000012p0.00001乳腺癌死乳腺癌死亡率亡率(%)(%)505040403030202010100 0服用他莫服用他莫昔芬约昔芬约5 5年年25.6%25.6%安慰剂安慰剂34.8%34.8%0 05 510101515时间（年）时间（年）11.911.925.725.78.38.317.817.86060505040403030202010100 01515年获益年获益 11.8%(SE 1.3)11.8%(SE 1.3)时序检验时序检验 2p0.000012
5、p5mm)(5mm)的患者，改用依西美的患者，改用依西美坦治疗后，其中坦治疗后，其中5050的子宫内膜转变为正常的子宫内膜转变为正常 可显著延长骨折的出现可显著延长骨折的出现 Coombes et al.J Clin Oncol.2006;24(18S):933s.Abstract LBA527The Intergroup Exemestane Study(IES)group.Lancet.2007 Feb 17;369(9561):559-70.Early Breast Cancer:Endocrine TherapyAIsAIs Extended Extended目前结论目前结论 MA17
6、MA17、B-33B-33、ABCSG 6aABCSG 6a等研究：等研究：ExtendedExtended方案能显著降低患者复发风险方案能显著降低患者复发风险 ExtendedExtended方案显示良好的安全性方案显示良好的安全性Early Breast Cancer:Endocrine Therapy2007年年 St Gallen 共识共识绝经后患者芳香化酶抑制剂的应用策略绝经后患者芳香化酶抑制剂的应用策略 委员会倾向于委员会倾向于SwitchSwitch方案，即他莫昔芬治疗方案，即他莫昔芬治疗 2-32-3年后换用年后换用AIsAIs，少数人同时支持起始就使用少数人同时支持起始就使用
7、AIsAIs，几乎没有人倾向于他莫昔芬，几乎没有人倾向于他莫昔芬治疗治疗 5 5年后换用年后换用AIsAIs的策略的策略 对于已经完成对于已经完成 5 5年他莫昔芬治疗的病人，大部分委员支持在淋年他莫昔芬治疗的病人，大部分委员支持在淋巴结阳性的病人中再用一段时间的巴结阳性的病人中再用一段时间的AIsAIs 对于高危病人或对于高危病人或HER2HER2阳性的病人，更多接受起始使用阳性的病人，更多接受起始使用AIsAIs 有过半的委员也支持对于接受有过半的委员也支持对于接受SSRISSRI类抗抑郁药的病人起始使用类抗抑郁药的病人起始使用AIsAIs Early Breast Cancer:Endo
8、crine TherapyAIAI的安全性特征与的安全性特征与TAMTAM不同不同 他莫昔芬：他莫昔芬：血栓栓塞血栓栓塞 子宫内膜问题、阴道出血子宫内膜问题、阴道出血/排液等妇科事件排液等妇科事件 芳香化酶抑制剂：芳香化酶抑制剂：肌肉关节症状肌肉关节症状 BMD BMD 降低，骨质疏松降低，骨质疏松 AIAI对心血管系统和血脂代谢的影响对心血管系统和血脂代谢的影响Early Breast Cancer:Endocrine Therapy目前仍然存在的问题目前仍然存在的问题 临床上如何判断真绝经？临床上如何判断真绝经？UpfrontUpfront、SwitchSwitch或或ExtendedEx
9、tended方案的合理选择？方案的合理选择？内分泌药物的合理选择？内分泌药物的合理选择？内分泌药物的安全性问题？如何介入？内分泌药物的安全性问题？如何介入？如何确定内分泌治疗的有效性？如何确定内分泌治疗的有效性？延长治疗时间、增加治疗剂量、辅助其它药物能否延长治疗时间、增加治疗剂量、辅助其它药物能否提高疗效和安全性？提高疗效和安全性？Early Breast Cancer:Endocrine TherapyATLAS:Is There Benefit to Longer Tamoxifen(5+Years)Therapy?5 years of tamoxifen therapy in pati
10、ents with ER-positive breast cancer Reduces annual recurrence rate through first decade Risk of recurrence persists,leading to questions of possible benefit to longer therapy Previous NSABP B-14 randomized extension trial showed no additional benefit beyond 5 years1 Study may have been underpowered
11、Current ATLAS trial2 Larger study of patients randomized to 5 or 10 years of tamoxifen 1.Fisher B,et al.J Natl Cancer Inst.2001;93:684-690.2.Peto R,et al.SABCS 2007.Abstract 48.Early Breast Cancer:Endocrine TherapyATLAS:Longer vs Shorter Tamoxifen in ER-Positive Breast Cancer Tamoxifen treatment for
12、 5 additional yearsPatients with breast cancer treated with adjuvant tamoxifen for 5 years(N=11,500)No additional TamoxifenYear 10Year 5Peto R,et al.SABCS 2007.Abstract 48.Annual assessments included compliance,hospital admissions,breast cancer recurrence(or new contralateral disease),other new prim
13、ary cancer,and death.Early Breast Cancer:Endocrine TherapyATLAS:Disease Recurrence and OS RatesRR significantly lower with continued tamoxifen;trend toward OS benefit(NS)CaveatsNumber of patients with ER-positive cancer probably 90%(not 100%)Some patients with untested tumors likely ER negativeTamox
14、ifen benefit probably underestimated since compliance rate 80%Peto R,et al.SABCS 2007.Abstract 48.ParameterAnnual Event Rate,%of Patients Ratio of Rates With Continued vs Stopped Tamoxifen(SE)Continued TAMStopped TAMAll recurrences/yr2.93.40.866(0.048*)Years 0-13.23.60.89(0.07)Years 2-42.83.30.87(0.
15、08)Years 5+2.43.00.77(0.12)Deaths1.41.50.895(0.070)Years 0-11.01.01.00(0.14)Years 2-41.61.80.90(0.10)Years 5+1.92.40.79(0.13)P=.005Early Breast Cancer:Endocrine TherapyATAC:A vs T in Postmenopausal Women With Localized Breast Cancer1.Howell A,et al.Lancet.2005;365:60-62.2.Forbes JF M,et al.SABCS 200
16、7.Abstract 41.Postmenopausal women with early-stage invasive breast cancer(N=6241)Anastrozole(n=3125)Tamoxifen(n=3116)Long-termfollow-upYear 5Previous ATAC results showed less disease recurrence in postmenopausal women with localized disease on anastrozole vs tamoxifen1Anastrozole well tolerated but
17、 higher risk of fracturesCurrent study assessed long-term efficacy and toxicity of anastrozole2Early Breast Cancer:Endocrine TherapyATAC:Efficacy ResultsOutcome(Hormone ReceptorPositive Patients)HR(95%CI)P ValueDFS0.85(0.76-0.94).003TTR0.76(0.67-0.87).0001TTDR0.84(0.72-0.97).022CLBC0.60(0.42-0.85).0
18、04OS0.97(0.86-1.11).70Death after recurrence0.90(0.75-1.07).20Forbes JF,et al.SABCS 2007.Abstract 41.Long-term results showed that anastrozole superior to tamoxifen for DFS,TTR,TTDR,and CLBC,but not for OS and deaths after recurrence Similar findings observed when analyses restricted to hormone rece
19、ptorpositive populationEarly Breast Cancer:Endocrine TherapyATAC:Adverse Events for Anastrozole vs TamoxifenForbes JF,et al.SABCS 2007.Abstract 41.Serious Adverse Events,n(%)On TreatmentOff TreatmentAnastrozole(n=3092)Tamoxifen(n=3094)Anastrozole(n=3092)Tamoxifen(n=3094)Fracture episodes*375(12.13)2
20、34(7.56)146(4.72)143(4.62)Treatment-related events153(4.95)284(9.18)49(1.58)57(1.84)Myocardial infarction34(1.10)33(1.07)26(0.84)28(0.90)Cerebrovascular accident20(0.65)34(1.10)22(0.71)20(0.65)Endometrial cancer4(0.13)12(0.39)1(0.03)12(0.34)Excess in fractures diminished after cessation of therapy R
21、R of fracture for anastrozole vs tamoxifen for Years 0-5:1.55(P 1 fracture episode allowedEarly Breast Cancer:Endocrine TherapyAIs and Bone Loss AI-induced estrogen ablation accelerates bone loss and augments fracture risk in postmenopausal women AI-induced bone loss more rapid than bone loss associ
22、ated with postmenopausal status alone IV bisphosphonates may decrease AI-associated bone loss 1-year follow-up of Z-FAST trial using the bisphosphonate ZA previously reported1 Current Z-FAST study evaluated 36-month safety and efficacy of upfront vs delayed IV ZA in decreasing AI-associated bone los
23、s in postmenopausal women with early breast cancer2 1.Brufsky A,et al.J Clin Oncol.2007;25:829-836.2.Brufsky A,et al.SABCS 2007.Abstract 27.Early Breast Cancer:Endocrine TherapyZ-FAST:Upfront vs Delayed ZABrufsky A,et al.SABCS 2007.Abstract 27.Postmenopausal women with ER-positive or PgR-positive br
24、east cancer(N=602)*All patients treated with calcium and vitamin D.ZA initiated when T-score decreased to -2 or clinical fracture occurs.Delayed ZA*+Letrozole 2.5 mg/day(n=301)Upfront ZA*4 mg IV every 6 months+Letrozole 2.5 mg/day(n=301)Early Breast Cancer:Endocrine TherapyZ-FAST:Change in BMD for D
25、elayed vs Upfront ZALumbar spine and total hip BMD increased for patients on upfront ZA but decreased for patients on delayed ZABy 36 months,62(21%)patients in the delayed arm initiated ZA36-month fracture rates:5.7%for upfront arm vs 6.3%on delayed ZA arm Trend toward less disease recurrence in upf
26、ront arm vs delayed arm9(3.5%)vs 16(6.9%),respectively(P=.13)Brufsky A,et al.SABCS 2007.Abstract 27.-4-3-2-101234Lumbar Spine BMDTotal Hip BMDChange in BMD at 36 Mos(%)P .0001P .0001Upfront ZADelayed ZAEarly Breast Cancer:Endocrine TherapyIBIS-II Substudy:Risedronate vs Placebo for Bone LossSingh S,
27、et al.SABCS 2007.Abstract 28.*Preliminary results for patients who completed first year of treatment;final N will be 1000.T-scores at lumbar spine or femoral neck.Observation(n=227 112 anastrozole)Postmenopausal women at high risk for breast cancer(N=350*)Stratum I(Normal)T-score -1(n=227)Stratum II
28、(Osteopenic)-2.5 T-score -1(n=80)Stratum III(Osteoporotic)-4 T-score 6 monthsPhase III,randomized,double-blind,placebo controlled trialPrimary endpoint:%change in lumbar spine BMD from baseline to Month 12Measured using DEXAEarly Breast Cancer:Endocrine TherapyDenosumab:Effect on Lumbar Spine Bone M
29、ineral DensityMore serious adverse events(reportedly not related to treatment)in denosumab arm(15%)vs placebo(9%)Ellis G,et al.SABCS 2007.Abstract 47.Early Breast Cancer:Endocrine TherapyOvarian Suppression+TAM or ANA ZA:ABCSG-12 Trial DesignGnant M,et al.ASCO 2008.Abstract LBA4.Accrual 1999-2006180
30、3 premenopausal breast cancer patientsEndocrine-responsive(ER and/or PgR positive)Stage I and II,250 mgEarly Breast Cancer:Endocrine TherapyNEWEST:Impact of High-and Low-Dose Fulvestrant on Ki67 LabelingGreater reduction in Ki67 labeling index with high-dose fulvestrant corresponds with significantl
31、y greater reduction in ER expression at 4 weeks(P .0003)At Week 16,reductions in Ki67 labeling index(P .0001),ER expression,and PgR expression greater with high-dose fulvestrant compared with standard-dose fulvestrantReduction in Ki67 Labeling Index at 4 WeeksHigh-DoseFulvestrant(n=60)Standard-DoseF
32、ulvestrant(n=63)P ValueMean%reduction from baseline,%(95%CI)78.8(70.8 to 84.6)47.3(47.3 to 61.2).0001Absolute reduction from baseline(95%CI)-17.5(-15.7 to-18.8)-10.5(-6.3 to-13.6).0001Kuter I,et al.SABCS 2007.Abstract 23.Early Breast Cancer:Endocrine TherapyNEWEST:Tumor Response Rates in Evaluable P
33、atientsKuter I,et al.SABCS 2007.Abstract 23.Fulvestrant 250 mg(n=69)Fulvestrant 500 mg(n=69)020406080100Response to Treatment(%)30.48836.258.011.6ORR(CR+PR*)SDOR:1.30(0.64-2.64)53.610.1PD*PR defined as 65%reduction in tumor volume.Early Breast Cancer:Endocrine TherapyNeoadjuvant Everolimus+Letrozole
34、 in ER-Positive Postmenopausal WomenEverolimus 10 mg/day+Letrozole 2.5 mg/day(n=138)Placebo+Letrozole 2.5 mg/day(n=132)Postmenopausal women with ER-positive invasive breast cancer2(N=270)SurgeryWeek 161.Awaada A,et al.Eur J Cancer.Nov 24;Epub ahead of print.2.Baselga J,et al.SABCS 2007.Abstract 2066
35、.Everolimus:kinase inhibitor of mTORTargets the mTOR-phosphoinositide 3 kinase-Akt axis,which is activated in breast cancer oncogenesisSuppresses cell growth and proliferationCombination therapy with letrozole and everolimus has additive effects in vitro and has shown antitumor effects and no drug-d
36、rug interactions in a phase Ib study1Early Breast Cancer:Endocrine TherapyUnavailableEverolimus+Letrozole:Overall Clinical ResponseBaselga J,et al.SABCS 2007.Abstract 2066.Everolimus(n=138)Placebo(n=69)020406080100Response to Treatment(%)1388CRPRNo ChangePDORR955502530410326859Early Breast Cancer:En
37、docrine TherapyEverolimus+Letrozole:Safety ProfileBaselga J,et al.SABCS 2007.Abstract 2066.Most Common Adverse Events,n(%)Everolimus Arm(n=137)Placebo Arm(n=132)Stomatitis50(36.5)8(6.1)Rash28(20.4)10(7.6)Thrombocytopenia25(18.2)1(0.8)Asthenia24(17.5)13(9.8)Hypercholesterolemia22(16.1)8(6.1)Hyperglyc
38、emia18(13.1)4(3.0)Pruritus18(13.1)0Fatigue17(12.4)6(4.5)Anorexia17(12.4)5(3.8)ALT increase16(11.7)5(3.8)Grade 3 adverse events in everolimus arms:hyperglycemia(5.1%),stomatitis(2.2%),infections(2.2%),interstitial lung disease(2.2%),fatigue(1.5%),thrombocytopenia(1.5%),hypokalemia(1.5%),ALT increase(1.5%)1 grade 4 infection in everolimus arm Early Breast Cancer:Endocrine Therapy
