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1、早期乳腺癌内分泌治疗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不完全应答不完全无应答无应
2、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：pT2cmpT2cm, 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+TrCE+TrCE+
3、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）乳腺癌死亡率乳腺癌死亡率6
4、0601515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服用他莫昔服用他莫昔芬约芬约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 2p0.000012p5mm)(
5、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 TherapyAIs ExtendedAIs 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方方案能显著降低患者复发风险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
7、用AIsAIs，几乎没有人倾向于他莫昔，几乎没有人倾向于他莫昔芬治疗芬治疗 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: Endoc
8、rine 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ExtendedExte
9、nded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 p
10、atients with ER-positive breast cancer Reduces annual recurrence rate through first decadeRisk of recurrence persists, leading to questions of possible benefit to longer therapyPrevious NSABP B-14 randomized extension trial showed no additional benefit beyond 5 years1Study may have been underpowered
11、Current ATLAS trial2Larger 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 tre
12、atment for 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 disea
13、se), other new primary 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 tumor
14、s likely ER negativeTamoxifen 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.
15、60.89 (0.07) Years 2-42.83.30.87 (0.08) 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.
16、 Lancet. 2005;365:60-62.2. Forbes JF M, et al. SABCS 2007. 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 dis
17、ease on anastrozole vs tamoxifen1Anastrozole well tolerated but 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).0
18、03TTR0.76 (0.67-0.87).0001TTDR0.84 (0.72-0.97).022CLBC0.60 (0.42-0.85).004OS0.97 (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 af
19、ter recurrenceSimilar findings observed when analyses restricted to hormone receptorpositive 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
20、= 3092)Tamoxifen(n = 3094)Anastrozole(n = 3092)Tamoxifen(n = 3094)Fracture episodes*375 (12.13)234 (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
21、.65)Endometrial cancer4 (0.13)12 (0.39)1 (0.03)12 (0.34)Excess in fractures diminished after cessation of therapyRR of fracture for anastrozole vs tamoxifen for Years 0-5: 1.55 (P 1 fracture episode allowedEarly Breast Cancer: Endocrine TherapyAIs and Bone LossAI-induced estrogen ablation accelerate
22、s bone loss and augments fracture risk in postmenopausal womenAI-induced bone loss more rapid than bone loss associated with postmenopausal status aloneIV bisphosphonates may decrease AI-associated bone loss1-year follow-up of Z-FAST trial using the bisphosphonate ZA previously reported1 Current Z-F
23、AST study evaluated 36-month safety and efficacy of upfront vs delayed IV ZA in decreasing AI-associated bone loss 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
24、-FAST: Upfront vs Delayed ZABrufsky A, et al. SABCS 2007. Abstract 27.Postmenopausal women with ER-positive or PgR-positive breast 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
25、= 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 Delayed 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
26、 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 upfront 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 i
27、n BMD at 36 Mos (%)P .0001P .0001Upfront ZADelayed ZAEarly Breast Cancer: Endocrine TherapyIBIS-II Substudy: Risedronate vs Placebo for Bone LossSingh S, 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 sp
28、ine 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(Osteopenic) -2.5 T-score -1(n = 80)Stratum III(Osteoporotic)-4 T-score 6 monthsPhase III, randomized, double-blind, placebo controlled
29、 trialPrimary endpoint: % change in lumbar spine BMD from baseline to Month 12Measured using DEXAEarly Breast Cancer: Endocrine TherapyDenosumab: Effect on Lumbar Spine Bone Mineral DensityMore serious adverse events (reportedly not related to treatment) in denosumab arm (15%) vs placebo (9%)Ellis G
30、, 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 1999-20061803 premenopausal breast cancer patientsEndocrine-responsive (ER and/or PgR positive)Stage I and II, 250 mgEarly
31、 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 significantly greater reduction in ER expression at 4 weeks (P .0003) At Week 16, reductions in Ki67 labeling index (
32、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-DoseFulvestrant (n = 63)P ValueMean % reduction from baseline, % (95% CI)78.8 (70.8 to 84.6)47.3 (47.
33、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 PatientsKuter I, et al. SABCS 2007. Abstract 23.Fulvestrant 250 mg (n = 69
34、)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 in ER-Positive Postmenopausal WomenEverolimus 10 mg/
35、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.Everolimus: kinase inhibitor of m
36、TORTargets 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-drug interactions in a phase Ib s
37、tudy1Early 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: Endocrine TherapyE
38、verolimus + 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)Hyp
39、erglycemia18 (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 Therapy46
