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上海肿瘤医院王中华_晚期乳腺癌治*部蝊图文

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Age Distribution
Data from Shanghai Cancer Institute

5-yr disease-free 5-yr recurrence Gain from adjuvant chemotherapy
70%

30%

70%

10% 20%

? Risk reduction: 30%?20%, 10/30=33% ? Absolute benefit: 10%
70% always free 20% always recurred

超过 2/3 的乳腺癌复发为远处转移

远处转移 (61%-75%)
5年生存率 41.3%
BIG = Breast International Group.
Baum et al. Lancet. 2002;359:2131. Thürlimann et al. N Engl J Med. 2005;363:2747.

对侧乳腺癌 (9%-11%)
5年生存率83.4%
局部复发 (16%-28%)
5年生存率 59.3%

晚期乳腺癌治疗目的
- 控制疾病,缓解症状 - 提高患者的生活质量,延长高质量的生存期

全面评估

内分泌

化疗

乳腺癌的分子分型与内科治疗方法

Luminar A/B
ER(+)和/或PR(+)
内分泌

Her-2 阳性 靶向

化疗
所有类型MBC
受体三阴性

全身化疗
针对所有类型的晚期乳腺癌

晚期乳腺癌的化疗发展史

Approved specifically for first-line use in MBC

Trastuzumab

2000

Docetaxel Capecitabine

Lapatinib

Methotrexate 1971

1996

Cyclophosphamide 1959
5-FU 1962

Doxorubicin Paclitaxel

1974

1994

Platinums

1998

Gemcitabine 2006 2004 Nab paclitaxel 2005
Ixabepilone 2007
Bevacizumab

2008

1955 1965 1975 1985 1995 2005 2015

Accessed on-line at fda.gov/cder/cancer/druglistframe.htm

晚期乳腺癌化疗适应证
? 病变发展迅速 ? 内脏转移,如肝、肺广泛转移 ? 无病生存期(DFS)<2年 ? ER和PR阴性 ? 既往内分泌治疗无效

化疗的应用方法
? 联合 Vs. 单药 (A+B Vs. A)
– ORR↑ – TTP ↑ – OS ↑或 —
? 联合 Vs. 序贯 (A+B Vs. A→B)
– TTP、OS未显示有明显优势

联合化疗 VS.单药
? 优先选择联合化疗
– ①有广泛转移或 – ②有临床症状,需要快速控制病情或 – ③肿瘤进展迅速或 – ④威胁生命的转移或 – ⑤患者的耐受性较好
? 优先考虑单药化疗
– ①无重要脏器转移或 – ②无临床症状或 – ③转移部位少

复发转移性乳腺癌化疗药物选择原则

辅助 未化疗 CMF 蒽环

首选

或 蒽环类
CAF、CEF

蒽环类联合 紫杉类 AT

AC、EC

多西他赛联合 卡培他滨 TX
紫杉醇吉联合 吉西他滨 GP

蒽环类及紫杉类治疗失败 卡培他滨、长春瑞滨、吉西他滨、铂类、伊沙匹隆 、ABX

单药治疗MBC有效率

? Doxorubicin ? Epirubicin ? Paclitaxel ? Docetaxel ? Capecitabine ? Gemcitabine ? Vinorelbine

First-Line 35-50%1 52-68% 29-63%1 47-65%1
25%1 23-37%1 40-44%1

1Esteva F et al, Oncologist 2001 (6): 133-146

Second-Line 25-30%1 28% 19-57% 39-58% 20-27%1 13-41%1 17-36%

白蛋白结合型紫杉醇 III 期临床试验: 试验设计

MBC
随机分组 (1:1) n = 460

注射用紫杉醇(白蛋白结合型)260 mg/m2
静脉滴注 30 分钟 每3周给药一次 无标准预处理
紫杉醇 175 mg/m2 静脉滴注3小时 每3周给药一次 标准预处理:地塞米松、抗组胺药物
和H2受体拮抗剂

Gradishar et al. J Clin Oncol. 2005;23:7794–7803

III 期临床试验:注射用紫杉醇(白蛋白结合型) 显著延长了患者的至肿瘤进展时间

1.00 0.75 0.50

注射用紫杉醇(白蛋白结合型) (n = 229) 标准紫杉醇l (n = 224)
P = 0.006 风险比 = 0.75
中位时间 = 23.0 周 (19.4–26.1)

无进展百分比

0.25
中位时间 = 16.9 wks (15.1–20.9) 0.00 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120

Gradishar et al. J Clin Oncol. 2005;23:7794–7803

III 期临床试验: 毒性

不良事件 (%)
中性粒细胞减少 血小板减少
贫血
发热性中性粒细 胞减少 脓毒性死亡

ABX n = 229

34 25 9

紫杉醇 n = 225
度 3 4 P 值? 32 22 < 0.001

3度感觉 神经病变

ABX n = 229
24 (10%)

< 1 0 < 1 0 0.290

<1 <1 0

缓解至1或2度的中位时间

< 0.279 1

22 天

< 1 < 1 < 1 0 0.491

0

0



紫杉醇 n= 225
5
(2%)

0.028

79天

Gradishar et al. J Clin Oncol. 2005;23:7794–7803

SO14999研究: 多西他赛联合希罗达 vs. 多西他赛

n=255
R
n=256

Capecitabine 1, 250mg/m2 BID days 1–14 + Docetaxel 175mg/m2 day 1

3-weekly cycles Docetaxel 100mg/m2 day 1

? 主要研究终点: TTP

Median Overall 1-year n ORR TTP survival survival

Docetaxel Docetaxel + Capecitabine P-value

255 30% 256 42%
0.006

4.2 mo 6.1 mo 0.0001

11.5 mo 14.5 mo 0.0126

47% 57% NR

O’Shaughnessy et al. J Clin Oncol. 2002;20:2812-2823

JHQG 研究设计
紫杉醇联合吉西他滨 vs. 紫杉醇

n=529
R

Gemzar 1, 250mg/m2 BID days 1,8 + Paclitaxel 175mg/m2 day 1

3-weekly cycles Paclitaxel 175mg/m2 day 1

? 主要研究终点: TTP

Paclitaxel + Gemzar Paclitaxel P-value

Median Overall

n

ORR

TTP survival

529

41

5.2

18.5

26

2.9

15.8

<0.0001 <0.0001 0.018

O’Shaughnessy et al. J Clin Oncol. 2002;20:2812-2823

蒽环类和紫杉类均耐药乳腺癌的化疗
? 希罗达 ? 伊沙匹隆 (Ixabepilone)+希罗达 (2B)
? NVB + GEM
? NVB ± 希罗达 ? NVB ± DDP/CBP ? GEM ± DDP/CBP

蒽环和紫杉类治疗失败 — GEM+NVB vs. NVB

? phase III Spanish Breast Cancer Research Group (GEICAM) trial

252 pts MBC

gemcitabine 1200 mg/m2 days 1 and 8

vinorelbine 30 mg/m2 days 1 and 8 q21d

pretreated with

PD

anthracyclines and taxanes

vinorelbine 30 mg/m2 days 1 and 8 q21d

? 疗效:

ORR (%) PFS (mos) OS (mos)

GEM+NVB 36 6.0 15.9

NVB 26 4.0 16.4

P 0.093 0.0028
0.8

? 毒副作用: GEM+NVB vs. NVB
– G3/4 ANC下降 66% vs. 44% (p = 0.0074 ) – ANC减少性发热 11% vs. 6% (p = 0.15 ) – 非*学毒性两组无显著差异

Lancet Oncology 2007; 8:219-225

Epothilone: Ixabepilone (BMS-247550)
Bristol-Myers Squibb, New York, NY

S. cellulosum

Incidence(1/100,000)

200 180 160 140 120 100
80 60 40 20
0

Age distribution of Breast Cancer,2005
500

450

No.

400

Rate

350

300

250

200

150

100

50

0 0~ 5~ 10~ 15~ 20~ 25~ 30~ 35~ 40~ 45~ 50~ 55~ 60~ 65~ 70~ 75~ 80~ 85~
Age(Year)

Epothilone B

Ixabepilone

? Activity in multiple tumor models ? Low susceptibility to tumor resistance mechanisms
– MRP and P-gp efflux pumps – ? (Ⅲ) tubuiln overexpression – ? tubuiln mutations ? Antitumor activity in taxane resistance models

41% 12%

35% 22%

59% 23%
36%

Study Design: International, Randomized, Phase III trial, BMS 046

Patients with metastatic or locally advanced breast
cancer to anthracyclines PRE/ RESISTANT and taxane
RESISTANT
Stratified by ? visceral metastases ? previous MBC chemotherapy ? anthracycline resistance ? study site

Ixabepilone 40 mg/m2 IV over 3 hrs Day 1, every 3 wks +
Capecitabine 1000 mg/m2 orally BID Days 1-14, every 3 wks
PD
Capecitabine 1250 mg/m2 orally BID Days 1-14 every 3 wks

Ixabepilone Plus Capecitabine vs Capecitabine Alone

蒽环类耐药

晚期
(末次给药后 进展)

3个月内

紫杉类耐药
4个月内

辅助/新辅助 (末次给药后

6个月内

进展)

12个月内

累积剂量
ADM:240 mg/m2 EPI: 360 mg/m2

Disease Characteristics
Median age, yrs Previous metastatic
regimens, % ?0 ?1 ?2 ?3 ≥ 2 disease sites
Lung and/or liver metastases

Capecitabine (n = 377)
52 (25-79)
9 49 37 6 90 84

Ixabepilone + Capecitabine (n = 375)
53 (25-76)
7 48 41 4 89
84

ER positive and/or PR positive

49

47

ER, PR, and HER2 negative

26

24

HER2 positive

14

16

Ixabepilone Plus Capecitabine vs Capecitabine Alone

? Overall response rate* – I + C vs C: 35% vs 14% (P < .0001)
? PFS benefit for combination arm* (5.8 vs 4.2 mos)
? 辅助化疗后快速复发 (5.6 vs. 2.8 mos) — 2008 SABCS

Proportion Progression Free

PFS by Independent Radiologic Review
1.0

Ixabepilone + Capecitabine

0.8

Capecitabine

0.6

0.4

HR: 0.75

(95% CI: 0.64-0.88)

P = .0003 0.2

0.0 0 4 8 12 16 20 24 28 32 36
Months

Vahdat LT, et al. ASCO 2007. Abstract 1006.

*As determined by independent radiologic review

Ixabepilone Plus Capecitabine vs Capecitabine Alone

? More hematologic toxicity observed in ixabepilone arm

Grade 3/4 Hematologic Toxicity, %
Leukopenia Neutropenia Thrombocytopenia

Capecitabine (n = 368)
6 11 4

Ixabepilone + Capecitabine
(n = 369) 57 68
8

P Value
< .0001 < .0001
.011

Febrile neutropenia

<1

Anemia

4

4

.001

10

.005

? Grade 3/4 peripheral neuropathy: 23% for ixabepilone plus capecitabine vs 0% for capecitabine alone
– 感觉神经 / 累积性 / 可逆性
– 中位恢复至 G1 or 基线: 6 weeks

October 22, 2007 FDA Approves Ixempra (ixabepilone, Bristol-Myers Squibb) for Advanced
Breast Cancer Patients
The U.S. Food and Drug Administration has approved Ixempra (ixabepilone), a new anti-cancer treatment, for use in patients with
metastatic or locally advanced breast cancer who have not responded to certain other cancer drugs.

何时停药?治疗越长越好?
? 效不更方
– 至病情进展或不可耐受的毒性
? 选择其中一个药物
– 用至进展或不可耐受的毒性
? 更换其他一种化疗药
– 希罗达,PLD
? 更换成内分泌治疗
– 耐受性好,作用机制不同,减少耐药
? 停止用药(6-8周期后),观察
– 定期复查,进展再给予处理

三种不同剂量多西他赛治疗MBC

Docetaxel 60 mg/m2

Docetaxel 75 mg/m2

N

151

188

Median no. of cycles (range)

5 (1- 43)

6 (1- 39)

Median relative dose intensity (range) 0.99 (0.7-1.5) 0.98 (058-1.13)

Median cumulative dose (range) 303 (59-2559) 437 (72-2926)

Response rate

20%

22%

Median TTP

13 weeks

15 weeks

Median overall survival

11 months

10 months

Grade 3-4 toxicity ≥10%

Neutropenia

76%

84%

Febrile neutropenia

5%

7%

Anemia

6%

9%

Asthenia

3%

8%

Docetaxel 100 mg/m2
188 6 (1- 24) 0.97 (0.58-1.1) 533 (98-2360) 30% * 17 weeks 12 months
93% 14% * 14% 15%

* P <0.05

Paclitaxel maintenance
—— JCO, 2006

Paclitaxel (200 mg/m2 )d2 + Epirubicin (90 mg/m2) d1 or Doxorubicin (50 mg/m2) d1
?every 3 weeks 6-8cycles ?N=459

CR
/PR R
/SD
? N=215 (255)

Paclitaxel 175 mg/m2
every 3 weeks 8cycles no further
chemotherapy
*HR+ HT

? The primary end point : PFS

Gennari A, et al, JCO,2006,3912-8

—— MANTA1 study

Study Findings Number
Median PFS
Median OS

Maintenance Paclitaxel 109
8.0 months
28 months

No Maintenance
106
9.0 months
29 months

P
>0.05 >0.05

Gennari A, et al, JCO,2006,3912-8

Possible Explanation for MANTA1 study (Paclitaxel maintenance)
? Use of concurrent endocrine therapy in 60% of hormone receptor-positive patients
– Control arm patients actual received maintenance hormonal therapy
– The concurrent of chemo and hormonal may reduce the efficacy
? Toxicity of paclitaxel
– Sensory neuropathy grade 2 occurred in 26%, grade 3 in 6% and grade 4 in 2% of the patients in maintenance
– grade ? ANC↓ 24%

GEICAM 2001-01 Study — Phase III trial

288 pts MBC 一线

AT (50/75) × 6

155 pts

R
CR / PR / SD

PLD 40mg/m2 q28d × 6
78 pts

observation
77 pts

TTP ms
(From R)
TTP ms
(From Initial)
1y 生存

PLD 8.32

Obser

P

4.93 0.0008

13.18 10.06 0.0005

81% 66% 0.04

A:ADM T:TXT PLD:脂质体ADM

2008 ESMO

Randomized Studies of Chemotherapy Duration in MBC

研究

治疗方案

Coates (1987) AC/CMFP until PD vs AC x 3

Muss (1991)

FAC x 6 → CMF x 12 vs FAC x 6

Ejlertsen (1993) FEC x 18 (+TAM) vs FEC x 6 (+TAM)

Gregory (1997)

VAC/VEC x 6 → MMM x 6 vs VAC/VEC/MMM x 6

Falkson (1998) A x 6 → CMFPTH x 8 vs A x 6

FESG (2000)

FEC-75 x 11 vs FEC-100 x 4 → FEC50 x 8 vs FEC-100 x 4

Nooij (2003)

CMF until PD vs CMF x 6

Gennari (2006) AP/EP x 6-8 → P x 8 vs AP/EP x 6-8

Alba (2007)

AT x 6 →PLD vs AT x 6

*Statistically significant; ?assessed in futility analysis.

TTP/ PFS

N

OS , (m)

(m)

305

6* vs 4 10.7 vs 9.4

145 9.4* vs 3.2 21.2 vs 19.6

254 14* vs 10 23 * vs 18

100 195 392 196 215? 288

10* vs 7

13 vs11

18.7* vs 7.8
10.3 * vs 8.3 * vs
6.2

32.2 vs 28.7
17.9 vs 18.9 vs 16.3

5.2* vs 3.5 14 vs 14.4

8 vs 9
8.38 * vs 5.06

28 vs 29

MBC的化疗
? 为何用? — 目的 ? 何时用? — 适应症 ? 怎么用? — 方法(联合、单药) ? 用何药? — 三级选用(蒽环,蒽环耐药,
蒽环及紫杉均耐药)
? 何时停? — 五种措施

生物靶向治疗
-与化疗联合

Targeted therapies for breast cancer

MoAb

AI Tam

mTOR

FTI
RhoB

Her-2阳性MBC -Herceptin - Lapatinib

HER2阳性定义

免疫组织化学法(IHC) 色素原位杂交法(CISH) 荧光原位杂交法(FISH)

IHC 3+



蛋白过度表达

CISH +



FISH +

基因扩赠

Hercetpin单药治疗晚期乳腺癌的疗效
——————————————————

HO649g HO551g HO650

(关键试验) (Ⅱ期) (关键试验)

_____________________________________________

N (intent-to-treat) 222

46

114

#CR

8

1

7

#PR 有效率 中位缓解期(月) 中位生存期(月)

26 15% 9.1
13

4 11%
6.6 14

23 26% 18.8 24.4

______________________________________________

Herceptin联合化疗一线治疗Her-2阳性MBC

方案

N

TTP (m) OS (m)

TH vs. T M77001 PH vs. P H0648g PCH vs. PH

188

↑ 4.5

↑8.5

10.6 vs. 6.1 31.2 vs. 22.7

145

↑4.1

↑6.9

7.1 vs. 3.0 24.8 vs. 17.9

125

↑6.3



w PCH vs. PCH 91

13.5 vs. 7.2 ↑3.3

↑14.4

TCH vs. TH BCIRG007

12.5 vs. 9.2 37.9 vs. 23.5

263

--

--

10.3 vs. 11.7 36.5 vs. 36.4

TXH vs. TH

225

↑4.4

--

CHAT

18.2 vs. 13.8 40.5 vs. 38.7

p + + + +
_
TTP + OS --

H: Herceptin, T: TXT, P: PAX, C: CBP, X: Xeloda

曲妥珠单抗联合泰索帝:同时还是序贯使用? HERTAX

曲妥珠单抗 序贯 泰索帝

每周

PD 100 mg/m?

99 例 HER2 +,

一线 M+

随机

主要目的: ?PFS

曲妥珠单抗每周 + 泰索帝 100 mg/m?

次要目的: ?RR & OS

曲妥珠单抗 ? 泰索帝 曲妥珠单抗 +泰索帝

客观反应率, %

50

73

肿瘤进展时间, 月

10.8

9.4

总生存时间, 月

20.2

30.5

曲妥珠单抗治疗时间

4.1

8.8

Bontenbal et al. ASCO 2008. Abstract 1014.

P
0.02 0.42 0.15

Lapatinib
—针对Her-2阳性MBC
FDA于2007.3.13批准上市 规格250mg/150#

Lapatinib: Targeting EGFR and HER2

? Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2
– Blocks signaling through EGFR and HER2 homodimers and heterodimers
– May also prevent signaling between ErbB1/ErbB2 and other ErbB family members

PTEN P13K pAkt

Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94. Xia W, et al. Oncogene. 2002;21:6255-6263.

Phospholipid cell membrane

Lapatinib Ras

Shc

Grb2

Raf

So8

pErk

EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer

Refractory, progressive metastatic or locally advanced
HER2+ breast cancer previously treated with
anthracycline, taxane, or trastuzumab
(N = 528 planned*)

Lapatinib 1250 mg daily + Capecitabine 2000 mg/m2 daily
for Days 1-14, 3-week cycles (n = 160)
Capecitabine 2500 mg/m2 daily for Days 1-14, 3-week cycles (n = 161)

Follow-up: until progression or unacceptable toxicity

*Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint.
Geyer CE, et al. ASCO 2006. Clinical Science Symposium.

EGF100151

到疾病进展时间(ITT Population)

Lap + Cap Cap

100

病例数, n

160

161

Median TTP, wk

36.9

19.7

80

HR (95% CI)

0.51 (0.35–0.74)

P value (log-rank)

0.00016

60

Patients Progression Free* (%)

40

20

Lap + Cap

Cap

0

0

10

20

30

40

50

60

70

Time (weeks)

Geyer CE, et al. N Engl J Med 2006 ;355(26):2733-2743.

含曲妥珠单抗一线治疗Her-2阳性MBC进展后
? GBG-26:曲妥珠单抗加希罗达 vs. 希罗达,延 长TTP*3个月(8.2m vs. 5.6m P<0.05)
? EGF104900:曲妥珠单抗加拉帕替尼 vs. 拉帕 替尼,显著延长TTP(2.8m vs. 1.9m P=0.008)
von Minckwitz G et al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1025. O’Shaughnessy J et al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1015.

PCH 或wPCH

贝伐单抗

Paclitaxel ± Bevacizumab in MBC (E2100)

N=715

Locally

recurrent

R

or 1st-line

MBC

Paclitaxel 90 mg/m2 d 1, 8, 15 q4w
Paclitaxel 90 mg/m2 d 1, 8, 15 q4w + bevacizumab 10 mg/kg d1, 15

ORR, % PFS, mo OS, mo

Results

Paclitaxel

Paclitaxel + Bevacizumab

21.2

36.9

5.9

11.8

25.2

26.7

Hazard Ratio
0.60 0.88

? 值得关注的是贝伐单抗组有更多感染、 3/4 级的高血压、蛋白尿、头痛、

心脑血管局部缺血

Yellow text indicates statistically significant values.

Miller et al. N Engl J Med. 2007;357:2666-2676

Docetaxel ± Bevacizumab in MBC (AVADO)

N=705

Locally recurrent

or 1st-line MBC

Stratification:

R

? Region

? Prior taxane/time to

relapse since

adjuvant chemo

? Measurable disease

? HR status

Docetaxel 100mg/m2 + Placebo q3w Docetaxel + Bevacizumab 7.5mg/kg q3w Docetaxel + Bevacizumab 15mg/kg q3w

Bevacizumab continued to disease progression; all pts given option to receive bevacizumab with 2nd-line chemo; docetaxel administered for maximum of 9 cycles
Miles et al. ASCO 2008. Late-Breaking Abstract 1011.

Phase III Studies: E2100 and AVADO

E2100*

ORR (measurable), %
PFS, months

Paclitaxel 25.2 5.9

P + Bev 49.2 11.8

Hazard ratio

0.60

p OS, months

<0.0001

25.2

26.7

AVADO**

Taxotere

T + Bev 7.5/15

49

55/63

8.0

8.7/8.8

0.79 (vs 7.5 mg/kg)

0.72 (vs 15 mg/kg)

vs. 低剂量 vs. 低剂量

0.0318 0.0099

NR

NR

Yellow text indicates statistically significant values. *Miller et al. N Eng J Med. 2007; **Miles et al. ASCO 2008 (LBA#1011).

E2100 and AVADO Safety data

E2100*

AE (%)

Paclitaxel weekly

P + Bev

血栓形成***

0

3.0

高血压

1.4

16.0

出血症

0.3

2.3

蛋白尿

0

2.4

疲劳

5.2

10.7

感染 + 中性粒细胞减少 1.4

2.8

LV dysfn/CHF

0

2.2

Sensory neuropathy

17.6

24.3

AVADO*

Taxotere q3w

T+ Bev
7.5 mg 15mg

0.4

0

0

1.3

0.4

3.2

0.9

1.2

1.2

0

0

0.4

5.2

8.4

6.5

12.0

15.2 16.6

0

0

0

1.7

3.2

4.5

*Miller et al. N Eng J Med. 2007; **Miles et al. ASCO 2008 (LBA#1011). ***VTE: no increase in bevacizmab arm in either study.

Ongoing Phase III Trials Evaluating Bevacizumab in First-Line MBC

Single-agent taxane therapy

Anthracycline-based chemotherapy

BeIvmaNcaizogumeab

Capecitabine

HER2+ Disease Trastuzumab-containing
regimens

Hormonal therapy

晚期乳腺癌的内分泌治疗
—针对Luminal A/B 的 MBC
ER(+)PR(+) ER(+)或 PR(+)

内分泌治疗与化学治疗

内分泌
? 改变肿瘤的内环境来抑制 其生长
? 对正常细胞影响小,副作 用小
? 2~8周起效,缓解期长 ? 不需要升白、止吐等支持
治疗 ? 治疗费用较低

化疗
? 阻断肿瘤复制来杀死肿瘤 细胞
? 对正常细胞有杀伤,副作 用大
? 1~2周起效,缓解期短 ? 常需要升白、止吐等支持
治疗 ? 治疗费用一般较高

晚期乳腺癌内分泌治疗适应证
? 患者年龄>35岁 ? 无病生存期(DFS) >2年 ? 骨和软组织转移;无症状的内脏转移 ? ER和/或PR阳性

晚期乳腺癌的内分泌治疗

月经状况
绝经前

治疗药物
戈舍瑞林 (Goserelin, zoladex) 亮丙瑞林 (Leuprolide acetate)

绝经后

瑞宁得(Anastrozole ) 来曲唑( Letrozole) 依西美坦

各种年龄 他莫昔芬,孕激素

‘Arimidex’ (anastrozole) versus Tamoxifen for the Firstline Treatment of Advanced Breast Cancer in Postmenopausal Women
from Trials 0030 and 0027 Known to be Receptor-positive

Percentage not progressed

100 90 80 70 60 50 40 30 20 10 0 0

‘Arimidex’ (n=305) Tamoxifen (n=306)
Median TTP: ‘Arimidex’ 10.7 months tamoxifen 6.4 months p=0.022 (2-sided)*

6

12

18

24

30

36

42

Time to progression (months)

阿那曲唑的一线疗效优于TAM

025试验设计 : 来曲唑 vs. 他莫昔芬 作为晚期一线治疗

试验人群: 绝经后; 局部晚期或局部复发或转移的乳腺癌; ER 和/或 PgR阳性或未知

来曲唑

他莫昔芬

比值比

P

n=453

n=454

(95% CI)

客观有效率 CR + PR
临床获益率
CBR 至进展时间
TTP

32% 50% 9.4 mo

21% 38% 6.0 mo

1.78 (1.32–2.40)
1.62 (1.24–2.11)
0.72 (0.62–0.83)

0.0002 0.0004 <0.0001

来曲唑的一线疗效优于TAM
Mouridsen et al. J Clin Oncol. 2001;19: 2596.

非甾体类 AI 失败后的内分泌治疗MBC

芳香化酶抑制剂作用机理: 非甾体 VS 甾体

雄激素

芳香化酶

非甾体类(抑制剂) (eg, anastrozole, letrozole)
Geisler et al. Clin Cancer Res. 1998;4:2089-93.

甾体类(灭活剂) (eg, exemestane)

EFECT: Evaluation of Treatment Options Following AI Failure

Postmenopausal women with hormone receptor–positive,
progressing/recurring advanced breast cancer
after nonsteroidal AI
(N = 693)

Fulvestrant IM injection loading-dose regimen*
(n = 351)
Exemestane 25 mg/day orally
(n = 342)

Progression, death, or withdrawal

*Fulvestrant loading-dose regimen comprised 500 mg on Day 0, 250 mg on Days 14 and 28, and 250 mg monthly thereafter.

Gradishar W, et al. SABCS 2006. Abstract 12.

EFECT: Similar TTP in Patients Treated With Fulvestrant or Exemestane

1.0

Exemestane

Fulvestrant

Proportion of Patients Progression Free

0.8

Exemestane: 3.7 months

0.6

Fulvestrant:3.7 months

P=.65 0.4

0.2

0.0

0

3

6

9

12

15

18

21

24

27

No. at Risk

Months

Fulvestrant 351 195 96

50

25

12

4

2

0

0

Exemestane 342 190 98 41 21 12

8

6

1

0

Gradishar W, et al. SABCS 2006. Abstract 12.

绝经后MBC的内分泌治疗

辅助 一线 二线 三线

TAM 孕激素 雄激素

1985~ TAM
AI 孕激素

2002~
AI
氟维司群 ? TAM ? 孕激素 ?

新方向 靶向联合内分泌

2008 SABCS

EGF30008:拉帕替尼联合来曲唑
随机Ⅲ期临床
绝经后 ER/PR阳性 MBC一线
PFS

P:拉帕替尼,L:来曲唑 T:TAM

2008 SABCS

受体三阴性乳腺癌

Triple-Negative BC and PARP Inhibition

1. DNA damage via platinum adducts and DNA crosslinking
PARP1
2. PARP1 up-regulation Base-excision repair

3. PARP1 inhibition
PARP1
BSI-201
PARP1

4. Replication fork collapse
Double strand DNA break

CELL SURVIVAL
PARP: 聚腺苷二磷酸核糖聚合酶

BRCA1 BRCA2
CELL DEATH

Phase II Trial of BSI-201: Schema

Metastatic TNBC
N = 120

RANDOMIZE

Gemcitabine
(1000 mg/m2, IV, d 1, 8)
Carboplatin
(AUC 2, IV, d 1, 8)
N=62

21-Day Cycle

BSI-201
(5.6 mg/kg, IV, d 1, 4, 8, 11)
Gemcitabine
(1000 mg/m2, IV, d 1, 8)
Carboplatin
(AUC 2, IV, d 1, 8) N=61

Patients receiving gemcitabine/carboplatin could cross-over to the other treatment arm upon documented disease progression.

RESTAGING
Post-Cycle 2 & every 6-8 wks

Phase II Trial of BSI-201 Results: Efficacy

ORR, % CBR, % Median PFS, mo Median OS, mo

GC GC + BSI-201

P-Value

16

48

.002

21

62

.0002

3.3

6.9

<0.0001 (HR=0.342)

5.7

9.2

0.0005 (HR=0.348)

O’Shaughnessy et al. ASCO 2009;Abstract 3.

Phase II Trial of BSI-201 Results: Safety

? No differences in hematologic or non-hematologic toxicities
? No differences in GC dose reductions between arms

Grade 3-4 Toxicities, % of pts Anemia Thrombocytopenia Neutropenia Febrile neutropenia Nausea Fatigue Neuropathy Diarrhea

GC (n=59) BSI-201 + GC (n=57)

12

12

20

23

52

44

7

0

3

0

10

2

0

0

2

2

转移性乳腺癌内科治疗共识
? 晚期乳腺癌的主要治疗目的是提高患者的生活 质量,延长高质量的生存期
? 由于新药的不断问世以及合理使用,晚期乳腺 癌治疗的疗效不断提高
? 化疗与内分泌治疗是治疗晚期乳腺癌的两种同 用有效地治疗方法,但分别有各自的适应证
? 对Her-2/neu阳性的患者,化疗联合生物治疗 能显著提高疗效
? 通过合理的内科治疗,能显著延长患者的生存 期,部分患者甚至能够长期生存

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