早期乳腺癌内分泌治疗的一些进展.ppt

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 王 水,乳腺癌：一种全身性疾病 治疗：综合性 规范化：循证医学 个体化：target & tailor,2007年St Gallen 共识,乳腺癌内分泌治疗的三个重要标志,双卵巢切除去势术 他莫昔芬标准地位的确立 第三代芳香化酶抑制剂挑战他莫昔芬标准地位,他莫昔芬治疗乳腺癌的标准地位,EBCTCG. Lancet 2005,SE, 为标准误差,芳香化酶抑制剂,他莫昔芬先治疗23年,初始辅助治疗试验,换药治疗试验,延续辅助治疗试验,他莫昔芬,芳香化酶抑制剂,他莫昔芬,芳香化酶抑制剂,他莫昔芬,初始和序贯治疗试验,他莫昔芬,他莫昔芬,芳香化酶抑制剂,芳香化酶抑制剂,0,5,时间（年）,芳香化酶抑制剂,随机分组,安慰剂,他莫昔芬先治疗5年,随机分组,随机分组,随机分组,AIs挑战他莫昔芬标准地位,AIs Upfront目前结论,ATAC100和BIG1-98：阿那曲唑和来曲唑有效性（在DFS、TTR、TTDR及CLBC等方面）优于他莫昔芬，但在OS方面尚无显著统计学意义 毒副反应各有不同。应根据病人个体情况进行选择 对于低危至中危患者，绝对收益偏小。有些病人如存在骨代谢、妇科等问题，可考虑应用他莫昔芬,Smith IE. SABCS, 2007,AIs Switch目前结论,IES031：依西美坦Switch方案显著提高DFS和OS；荟萃分析显示阿那曲唑Switch方案能提高DFS和OS Switch方案具有良好的安全性 对低危至中危患者，Switch方案是较好的选择,Switch方案显示良好的安全性,IES研究：依西美坦Switch方案能显著降低血栓栓塞事件的风险，其他心血管不良事件的发生率无显著差异 严重妇科事件发生率显著降低 逆转他莫昔芬引起的子宫内膜增厚 原用他莫昔芬治疗子宫内膜增厚(5mm)的患者，改用依西美坦治疗后，其中50的子宫内膜转变为正常 可显著延长骨折的出现,Coombes et al. J Clin Oncol. 2006;24(18S):933s. Abstract LBA527 The Intergroup Exemestane Study (IES) group. Lancet. 2007 Feb 17;369(9561):559-70.,AIs Extended目前结论,MA17、B-33、 ABCSG 6a等研究：Extended方案能显著降低患者复发风险 Extended方案显示良好的安全性,2007年 St Gallen 共识,绝经后患者芳香化酶抑制剂的应用策略 委员会倾向于Switch方案，即他莫昔芬治疗 2-3年后换用AIs，少数人同时支持起始就使用AIs，几乎没有人倾向于他莫昔芬治疗 5年后换用AIs的策略 对于已经完成 5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AIs 对于高危病人或HER2阳性的病人，更多接受起始使用AIs 有过半的委员也支持对于接受SSRI类抗抑郁药的病人起始使用AIs,AI的安全性特征与TAM不同,他莫昔芬： 血栓栓塞 子宫内膜问题、阴道出血/排液等妇科事件 芳香化酶抑制剂： 肌肉关节症状 BMD 降低，骨质疏松 AI对心血管系统和血脂代谢的影响,目前仍然存在的问题,临床上如何判断真绝经？ Upfront、Switch或Extended方案的合理选择？ 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？ 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、辅助其它药物能否提高疗效和安全性？,ATLAS: Is There Benefit to Longer Tamoxifen (5+ Years) Therapy?,5 years of tamoxifen therapy in patients 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 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.,ATLAS: Longer vs Shorter Tamoxifen in ER-Positive Breast Cancer,Tamoxifen treatment for 5 additional years,Patients with breast cancer treated with adjuvant tamoxifen for 5 years (N = 11,500),No additional Tamoxifen,Year 10,Year 5,Peto R, et al. SABCS 2007. Abstract 48.,Annual assessments included compliance, hospital admissions, breast cancer recurrence (or new contralateral disease), other new primary cancer, and death.,ATLAS: Disease Recurrence and OS Rates,RR significantly lower with continued tamoxifen; trend toward OS benefit (NS) Caveats Number of patients with ER-positive cancer probably 90% (not 100%) Some patients with untested tumors likely ER negative Tamoxifen benefit probably underestimated since compliance rate 80%,Peto R, et al. SABCS 2007. Abstract 48.,P = .005,ATAC: A vs T in Postmenopausal Women With Localized Breast Cancer,1. Howell A, et al. 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-term follow-up,Year 5,Previous ATAC results showed less disease recurrence in postmenopausal women with localized disease on anastrozole vs tamoxifen1 Anastrozole well tolerated but higher risk of fractures Current study assessed long-term efficacy and toxicity of anastrozole2,ATAC: Efficacy Results,Forbes 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 receptorpositive population,ATAC: Adverse Events for Anastrozole vs Tamoxifen,Forbes JF, et al. SABCS 2007. Abstract 41.,Excess in fractures diminished after cessation of therapy RR of fracture for anastrozole vs tamoxifen for Years 0-5: 1.55 (P .0001) RR of fracture for anastrozole vs tamoxifen for Years 5-9: 1.03 (P = .79),* 1 fracture episode allowed,AIs 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 associated 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 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.,Z-FAST: Upfront vs Delayed ZA,Brufsky 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 = 301),Upfront ZA* 4 mg IV every 6 months + Letrozole 2.5 mg/day (n = 301),Z-FAST: Change in BMD for Delayed vs Upfront ZA,Lumbar spine and total hip BMD increased for patients on upfront ZA but decreased for patients on delayed ZA By 36 months, 62 (21%) patients in the delayed arm initiated ZA 36-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 arm 9 (3.5%) vs 16 (6.9%), respectively (P = .13),Brufsky A, et al. SABCS 2007. Abstract 27.,-4,-3,-2,-1,0,1,2,3,4,Lumbar Spine BMD,Total Hip BMD,Change in BMD at 36 Mos (%),P .0001,P .0001,Upfront ZA,Delayed ZA,IBIS-II Substudy: Risedronate vs Placebo for Bone Loss,Singh 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 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 (Osteopenic) -2.5 T-score -1 (n = 80),Stratum III (Osteoporotic) -4 T-score -2.5 (n = 43),Risedronate PO 35 mg weekly (n = 43 25 anastrozole),Placebo (n = 37 13 anastrozole),Risedronate PO 35 mg weekly (n = 45 22 anastrozole),Anastrozole 1 mg/day (n = 175),Placebo (n = 175),IBIS-II bone substudy,IBIS II Substudy: Decreased BMD With Risedronate vs Placebo at 1 Year,Singh S, et al. SABCS 2007. Abstract 28.,Mean Change in BMD for lumbar spine at 1 Year (%),-6,-4,-2,0,2,4,6,STRATUM-I Normal BMD No Risedronate,STRATUM-II Osteopenic Risedronate or Placebo,STRATUM-III Osteoporotic All Risedronate,P,A,P,P,P,A,P,R,R,A,R,R,A,P,-0.8%,-2.3%,-0.08%,-1.0%,0.6%,0.5%,3.4%,2.1%,n = 115,112,24,13,18,25,23,22,P = .006,O,O,Results similar when hip BMD measured,Denosumab: Bone Resorption Inhibitor,Adjuvant AIs more commonly used than tamoxifen for postmenopausal hormone receptorpositive breast cancer Associated with accelerated bone loss and increased fracture risk RANKL stimulates osteoclasts and bone resorption Denosumab Novel fully human monoclonal antibody to RANKL Does not bind TNF-, TNF-, TRAIL, or CD40L Possible agent to reverse AI-induced bone loss,Ellis G, et al. SABCS 2007. Abstract 47.,Bone,Cancer Cells in Bone,Cytokines and Growth Factors (IL-6, IL-8, IL-1b, PGE-2, TNF-a, CSF-1, PTHrP),Osteoclast,Growth Factors (TGF-b, IGFs, FGFs, PDGFs, BMPs),Osteoblast Lineage,Direct effects on tumor?,Bone Resorption,RANKL,RANKL,Denosumab vs Placebo in ER-Positive Breast Cancer,Ellis G, et al. SABCS 2007. Abstract 47.,Denosumab* 60 mg SC every 6 months (n = 127),Women with hormone receptorpositive breast cancer on adjuvant AI therapy (N = 252),Placebo* SC every 6 months (n = 125),Year 2,*Both arms given calcium 1000 mg daily and vitamin D 400 IU daily.,Stratified by AI use: 6 months vs 6 months,Phase III, randomized, double-blind, placebo controlled trial Primary endpoint: % change in lumbar spine BMD from baseline to Month 12 Measured using DEXA,Denosumab: Effect on Lumbar Spine Bone Mineral Density,More serious adverse events (reportedly not related to treatment) in denosumab arm (15%) vs placebo (9%),Ellis G, et al. SABCS 2007. Abstract 47.,Ovarian Suppression + TAM or ANA ZA: ABCSG-12 Trial Design,Gnant M, et al. ASCO 2008. Abstract LBA4.,Accrual 1999-2006 1803 premenopausal breast cancer patients Endocrine-responsive (ER and/or PgR positive) Stage I and II, 10 positive nodes No chemotherapy except neoadjuvant Treatment duration: 3 yrs,Tamoxifen 20 mg/day,Anastrozole 1 mg/day,Tamoxifen 20 mg/day + Zoledronic acid 4 mg Q6Mos,Anastrozole 1 mg/day + Zoledronic acid 4 mg Q6Mos,Surgery (+RT),Goserelin 3.6 mg Q28D,Inhibition of Multiple Steps in Tumor Cell Metastasis,Gnant M, et al. ASCO 2008. Abstract LBA4.,Synergy with anticancer drugs,Induces tumor cell apoptosis,Stimulates immune surveillance,Inhibits angiogenesis,Decreases matrix invasion,Primary tumor,Angiogenesis,Invasion,Arrest in distant capillary,Metastases,Adhesion and extravasation,Micrometastases,Decreases adhesion to bone,DFS: ZA vs No ZA,Gnant M, et al. ASCO 2008. Abstract LBA4.,Time Since Randomization (Mos),No. at Risk,No ZA,ZA,899,904,838,851,744,735,565,573,441,434,270,265,161,131,60,59,DFS (%),0,20,40,60,80,100,90,70,50,30,10,ZA,No ZA,54,83,No. of Events HR (95% CI) Events vs No ZA,0.643 (0.46-0.91); P = .011,0,20,40,60,80,100,90,70,50,30,10,0,12,24,36,48,60,72,84,Secondary Endpoints: ZA Vs No ZA,Gnant M, et al. ASCO 2008. Abstract LBA4.,Time Since Randomization (Mos),Overall survival, %,899,904,838,851,744,735,565,573,441,434,270,265,161,131,60,59,OS,No. at risk,No ZA,ZA,0,20,40,60,80,100,90,70,50,30,10,Time Since Randomization (Mos),Recurrence-Free Survival (%),0,12,24,36,48,60,72,84,RFS,ZA-Mediated Mechanisms Contributing to Improved DFS,Gnant M, et al. ASCO 2008. Abstract LBA4.,Direct antitumor activity,Immune activation,Bone mets recurrence,Nonbone mets recurrence,Contralateral recurrence,Locoregional mets recurrence,DFS,Polymorphisms in Drug Metabolizer CYP2D6 Affect Tamoxifen Metabolism,Single nucleotide polymorphism in CYP2D6 can affect efficacy and safety,Active metabolite,Italian Tamoxifen Chemoprevention Trial: Activity of CYP2D6 Variants,CYP450 test used to identify CYP2D6 polymorphisms 33 alleles examined Based on known allele activities, patients given score and classified into 4 cohorts Poor metabolizers: no CYP2D6 activity Intermediate metabolizers: reduced CYP2D6 activity Extensive metabolizers: normal CYP2D6 activity Ultrarapid metabolizers: hyperactive CYP2D6 Current study aim: investigate association between CYP450 polymorphisms and tamoxifen benefit in 5408 hysterectomized women with breast cancer randomized to placebo or tamoxifen for 5 years,Bonanni B, et al. SABCS 2007. Abstract 29.,Italian Tamoxifen Chemoprevention Trial: CYP2D6 Polymorphism Results,Bonanni B, et al. SABCS 2007. Abstract 29.,PMs less likely than other phenotypes to benefit from tamoxifen Patients with CYP2D6 *2A allele (EM) more likely to benefit from tamoxifen treatment CYP2C19*17 polymorphisms did not impact tamoxifens effect on breast cancer,COBRA Tamoxifen Trial: Effect of CYP2D6 Polymorphisms on Adherence,Women with ER-positive breast cancer (N = 297) genotyped for polymorphisms in drug-metabolizing enzymes by CYP450 test CYP2D6 CYP2C19 CYP3A5 Patient data collected on concurrent use of medications that stimulate or inhibit CYP2D6 activity Study investigated hypothesis that an association exists between CYP2D6 activity and compliance to tamoxifen May explain discrepancies in outcomes observed in previous tamoxifen trials,Rae JM, et al. SABCS 2007. Abstract 77.,COBRA Tamoxifen Trial: CYP2D6 Activity Inversely Related to Adherence,Presence of active CYP2D6 alleles and higher scores associated with higher likelihood of treatment discontinuation Those most likely to benefit from tamoxifen also most likely to discontinue treatment,Rae JM, et al. SABCS 2007. Abstract 77.,0,20,40,60,80,100,Patients Remaining on Treatment (%),100,93.3,90.3,89.2,PM,86.0,IM,IM/EM,EM/UM,EM,n =,10,15,72,50,120,Preoperative Hormonal Therapy,Preoperative hormonal therapy a relatively nontoxic alternative to chemotherapy Reduces tumor burden Reduces chemotherapy-prohibiting comorbidities Allows for determination of tumors susceptibility to surgery Makes breast conservation surgery feasible Optimal regimens unknown,NEWEST: High-Dose vs Low-Dose Fulvestrant for ER+ Breast Cancer,Postmenopausal women with locally advanced (T2,3,4b, N0, M0), ER-positive breast cancer (N = 211),High-Dose Fulvestrant 500 mg/month + 500 mg on Day 14 of Month 1 (n = 109),Week 4,Week 16 (surgery),Standard-Dose Fulvestrant 250 mg/month (n = 102),Kuter I, et al. SABCS 2007. Abstract 23.,Phase II, randomized neoadjuvant trial Dose-dependent downregulation of ER and Ki67 biomarkers with fulvestrant noted in 2 presurgical studies No data on clinical/biological activity of fulvestrant at doses 250 mg,NEWEST: Impact of High- and Low-Dose Fulvestrant on Ki67 Labeling,Greater 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 (P .0001), ER expression, and PgR expression greater with high-dose fulvestrant compared with standard-dose fulvestrant,Kuter I, et al. SABCS 2007. Abstract 23.,NEWEST: Tumor Response Rates in Evaluable Patients,Kuter I, et al. SABCS 2007. Abstract 23.,Fulvestrant 250 mg (n