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 王 水 Early Breast Cancer: Endocrine Therapy 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 24(18S):933s. Abstract LBA527 The Intergroup Exemestane Study (IES) group. Lancet. 2007 Feb 17;369(9561):559-70. Early Breast Cancer: Endocrine Therapy AIs Extended目前结论 MA17、 B-33、
2、 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 Early Breast Cancer: Endocrine Therapy 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
3、员也支持对于接受 SSRI类抗抑郁药的病人起始使用 AIs Early Breast Cancer: Endocrine Therapy 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 Early Breast Cancer: Endocrine Therapy 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
4、？ 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？ Early Breast Cancer: Endocrine Therapy 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 t
5、o 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
6、. 2001;93:684-690. 2. Peto R, et al. SABCS 2007. Abstract 48. Early Breast Cancer: Endocrine Therapy ATLAS: Longer vs Shorter Tamoxifen in ER-Positive Breast Cancer Tamoxifen treatment for 5 additional yearsPatients with breast cancer treated with adjuvant tamoxifen for 5 years (N = 11,500) No addit
7、ional Tamoxifen Year 10Year 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. Early Breast Cancer: Endocrine Therapy ATLAS: Disease Recurrence and OS Rat
8、es 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 2
9、007. Abstract 48. Parameter Annual Event Rate, % of Patients Ratio of Rates With Continued vs Stopped Tamoxifen (SE) Continued TAM Stopped TAM All recurrences/yr 2.9 3.4 0.866 (0.048*) Years 0-1 3.2 3.6 0.89 (0.07) Years 2-4 2.8 3.3 0.87 (0.08) Years 5+ 2.4 3.0 0.77 (0.12) Deaths 1.4 1.5 0.895 (0.07
10、0) Years 0-1 1.0 1.0 1.00 (0.14) Years 2-4 1.6 1.8 0.90 (0.10) Years 5+ 1.9 2.4 0.79 (0.13) P = .005 Early Breast Cancer: Endocrine Therapy 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. Po
11、stmenopausal 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
12、 higher risk of fractures Current study assessed long-term efficacy and toxicity of anastrozole2 Early Breast Cancer: Endocrine Therapy ATAC: Efficacy Results Outcome (Hormone ReceptorPositive Patients) HR (95% CI) P Value DFS 0.85 (0.76-0.94) .003 TTR 0.76 (0.67-0.87) .0001 TTDR 0.84 (0.72-0.97) .0
13、22 CLBC 0.60 (0.42-0.85) .004 OS 0.97 (0.86-1.11) .70 Death after recurrence 0.90 (0.75-1.07) .20 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 obser
14、ved when analyses restricted to hormone receptorpositive population Early Breast Cancer: Endocrine Therapy ATAC: Adverse Events for Anastrozole vs Tamoxifen Forbes JF, et al. SABCS 2007. Abstract 41. Serious Adverse Events, n (%) On Treatment Off Treatment Anastrozole (n = 3092) Tamoxifen (n = 3094)
15、 Anastrozole (n = 3092) Tamoxifen (n = 3094) Fracture episodes* 375 (12.13) 234 (7.56) 146 (4.72) 143 (4.62) Treatment-related events 153 (4.95) 284 (9.18) 49 (1.58) 57 (1.84) Myocardial infarction 34 (1.10) 33 (1.07) 26 (0.84) 28 (0.90) Cerebrovascular accident 20 (0.65) 34 (1.10) 22 (0.71) 20 (0.6
16、5) Endometrial cancer 4 (0.13) 12 (0.39) 1 (0.03) 12 (0.34) Excess in fractures diminished after cessation of therapy RR of fracture for anastrozole vs tamoxifen for Years 0-5: 1.55 (P 1 fracture episode allowed Early Breast Cancer: Endocrine Therapy AIs and Bone Loss AI-induced estrogen ablation ac
17、celerates 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
18、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. Early Breast Cancer: Endoc
19、rine Therapy 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* + L
20、etrozole 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 Therapy 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
21、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
22、1 2 3 4 Lumbar Spine BMD Total Hip BMD Change in BMD at 36 Mos (%) P .0001 P .0001 Upfront ZA Delayed ZA Early Breast Cancer: Endocrine Therapy 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 o
23、f 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-s
24、core 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 Early Breast Cancer: Endocrine Therapy Denosumab: Effect on Lumbar Spine Bone Mineral Density More serious adverse events (reported
25、ly not related to treatment) in denosumab arm (15%) vs placebo (9%) Ellis G, et al. SABCS 2007. Abstract 47. Early Breast Cancer: Endocrine Therapy 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
26、patients Endocrine-responsive (ER and/or PgR positive) Stage I and II, 250 mg Early Breast Cancer: Endocrine Therapy 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
27、 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 Reduction in Ki67 Labeling Index at 4 Weeks High-Dose Fulvestrant (n = 60) Standard-Dose Fulves
28、trant (n = 63) P Value Mean % reduction from baseline, % (95% CI) 78.8 (70.8 to 84.6) 47.3 (47.3 to 61.2) .0001 Absolute reduction from baseline (95% CI) -17.5 (-15.7 to -18.8) -10.5 (-6.3 to -13.6) .0001 Kuter I, et al. SABCS 2007. Abstract 23. Early Breast Cancer: Endocrine Therapy NEWEST: Tumor R
29、esponse Rates in Evaluable Patients Kuter I, et al. SABCS 2007. Abstract 23. Fulvestrant 250 mg (n = 69) Fulvestrant 500 mg (n = 69) 0 20 40 60 80 100 Response to Treatment (%) 30.4 88 36.2 58.0 11.6 ORR (CR + PR*) SD OR: 1.30 (0.64-2.64) 53.6 10.1 PD *PR defined as 65% reduction in tumor volume. Ea
30、rly Breast Cancer: Endocrine Therapy Neoadjuvant Everolimus + Letrozole in ER-Positive Postmenopausal Women Everolimus 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) Surgery Week 16 1. Awaada
31、 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 mTOR Targets the mTOR-phosphoinositide 3 kinase-Akt axis, which is activated in breast cancer oncogenesis Suppresses cell growth and proliferation Combination therapy
32、with letrozole and everolimus has additive effects in vitro and has shown antitumor effects and no drug-drug interactions in a phase Ib study1 Early Breast Cancer: Endocrine Therapy Unavailable Everolimus + Letrozole: Overall Clinical Response Baselga J, et al. SABCS 2007. Abstract 2066. Everolimus
33、(n = 138) Placebo (n = 69) 0 20 40 60 80 100 Response to Treatment (%) 13 88 CR PR No Change PD ORR 9 55 50 25 30 4 10 3 2 68 59 Early Breast Cancer: Endocrine Therapy Everolimus + Letrozole: Safety Profile Baselga J, et al. SABCS 2007. Abstract 2066. Most Common Adverse Events, n (%) Everolimus Arm
34、(n = 137) Placebo Arm(n = 132) Stomatitis 50 (36.5) 8 (6.1) Rash 28 (20.4) 10 (7.6)Thrombocytopenia 25 (18.2) 1 (0.8) Asthenia 24 (17.5) 13 (9.8) Hypercholesterolemia 22 (16.1) 8 (6.1)Hyperglycemia 18 (13.1) 4 (3.0) Pruritus 18 (13.1) 0Fatigue 17 (12.4) 6 (4.5) Anorexia 17 (12.4) 5 (3.8) ALT increas
35、e 16 (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
