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1 列 療 M.D., Ph.D. 理

2 療 療 年 樓 樓

3 FIGURE 2. Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of Economic Development, Source: GLOBOCAN CA Cancer J Clin 2011;61: VC 2011 American Cancer Society, Inc.

4 CA Cancer J Clin 2011;61: VC 2011 American Cancer Society, Inc.

5 Age-Standardized Breast Cancer Incidence and Mortality Rates by World Area. Source: GLOBOCAN 2008.

6 2002 AJCC:TNM, stage(0,i,ii,iii,iv) Tis DSIC, LCIS, paget's disease of nipple T1 2 T1a < 0.5 T1b T1c T2 2-5 T3 > 5 T4a, 不 T4 T4b T4c T4d, 狀 T4a T4b (inflammatory carcinoma)

7 1mi 量 (0.2mm~2.0mm) N1 1a 1b 1~3 淋 淋 切 淋, 臨 理 N2 1c 2a 2b 3a 1a 1b 4~9 淋 臨 淋 淋 淋 淋 N3 3b 臨 淋 1 淋 ; 淋 切 淋 臨 > 3 淋 3c 淋

8 Metastasis status (M) MX: M0: M1:

9

10 T1 N0 M0 T1a: T 0.5 cm T1b: 0.5 cm < T 1 cm T1c: 1 cm < T 2 cm T1 T 2 cm N0 = no regional lymph node metastasis M0 = no distant metastasis

11 A T0 T1 } N1 M0 T2 N0 M0 T0 No evidence of tumor T2 2 cm < T < 5 cm N1 = metastasis to movable ipsilateral axillary lymph node(s) M0 = no distant metastasis

12 B T2 N1 M0 T3 N0 M0 T3 T > 5 cm N1 = metastasis to movable ipsilateral axillary lymph node(s) (p) N1a, N1b M0 = no distant metastasis

13 A T3 N1 M0 T0 T1 T2 T3 N2 M0 Metastasis to ipsilateral axillary lymph node(s) N1 = movable N2 = fixed to one another or to other structures M0 = no distant metastasis

14 B T4 any N M0 Any T N3 M0 Tumor of any size with direct extension to chest wall or skin T4 T4d = inflammatory carcinoma N3 = metastasis to ipsilateral internal mammary lymph node(s) M0 = no distant metastasis

15 Any T any N M1 M1 = distant metastasis (including metastases to ipsilateral supraclavicular, cervical, or contralateral internal mammary lymph nodes)

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17 療 療 療 率

18

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20 淋 度 年 理

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22 Sentinel Lymph Node (SLN) Biopsy 淋 切

23 療 療 療 療 療 復 率

24 療 見 療 (Tamoxifen) 塞 (Aromatase inhibitor) (LHRH agonist) 療 異 神 療 淋 神

25 療 療 說 不 什 練

26 類 I II 臨 (Randomized controlled trials) ( Meta-analysis) 論 臨 論 III 臨 流 行 IV V 例

27

28 什 療

29 MBC Chemotherapy Evolution Mono-chemotherapy: Alkilators (Cyclophosphamide), Antimetabolites ( 5Fu, Methotrexate). Time to progresive disease (TTP): 3-6 months Poly-chemotherapy: CMF, CMFVP TTP : 7-10 months Anthracyclines. Monotherapy: Doxorubicin, Epirubicin TTP: 7-10 months Anthracyclines. Combinations: FAC, FEC, AC, EC. TTP: 8-12 months

30 MBC Chemotherapy Evolution 1990 New drugs: Taxanes (paclitaxel, docetaxel) Antimetabolites (capecitabine, GEMZAR, ALIMTA, Raltitrexed) New anthracyclines and anthrapirazolons (Idarubicine, Doxil, Myocet, Losoxantrone) 2000s Biological treatments: Herceptin, Avastin, Sutent

31 Taxotere 葉 煉 ( Taxotere = 易 = )

32 third generation of Chemotherapy Mitotic spindle poison Catharantus roseus High anti-tumoral tumoral activity Good overall tolerance Semi-synthetic product, extracted from the leaves of the Madagascar Periwinkle.

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37 ( ) (FSH + LH) 卵

38 女 裡 來 來 卵, 來 (, )

39 女 裡 來 泌 (FSH + LH) 泌 (ACTH) 卵 泌

40 卵 卵 切 療 療 類

41 率 ER PR % 63% % 15% % 5% % 17% From Bland KI, et al. Surg Oncol. 1981;32:

42 理 理 狀 來 療

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44 療 例 例

45 療 Tamoxifen 女 : 卵 切 諾 雷 (Zoladex) 女 : (Arimidex 復 Femara 諾 Aromasin)

46 療 諾 雷 (FSH + LH) 卵 ( ) LHRH) ACTH ACTH, adrenocorticotrophic hormone FSH, follicle-stimulating hormone LH, luteinising hormone LHRH, LH-releasing hormone

47 Tamoxifen 率 降 益 塞 不 良 泌 尿

48 療 療 an overview of the randomized trials TABLE 3. Adjuvant drug therapy: percentage reduction in the annual al odds of either recurrence or death 年 療 復 率 降 率 率 降 率 ) (%) ) (%) < 50 Tam x 5 yrs vs. no Tx Tam x 5 yrs vs. no Tx Tam x 5 yrs vs. no Tx > 70 Tam x 5 yrs vs. no Tx Tamoxifen for 5 yrs reduce 47% of annual odds of developing contra ra-lateral breast cancer Adapted from EBCTCG Lancet 1998;351:

49 療 療 ER PR 療 數 數 / 數 % 188/ % 61/ % 8/ % 16/171 From Clark GM, McGuire WL:Breast Cancer Res Treat 3: , ,1983.

50 復 例 年 復 15% 17% 9% 18% % of patients Tamoxifen Control % 55% % of patients Tamoxifen Control 73% 64% Years Years Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, 2000.

51 復 狀 0.3 (n=2257) (n=1305) 0.2 復 率 PgR = progesterone receptor. Years Saphner et al. J Clin Oncol. 1996;14:2738.

52 年 臨 益 % of Patients 5 年 Tamoxifen + 5 年 10 年 Tamoxifen (n=593) (n=579) P Value 率 異 率 異 OS = overall survival. Fisher et al. J Natl Cancer Inst. 2001;93:684.

53 MA-17 臨 (, 狀 ) Tamoxifen 5 年 療 0 3 months Femara 2.5 mg 年 療 : 率 : 率 / / : 度 /,

54 療 降 復 不 論 淋 療 降 復 降 淋 女 降 淋 率

55 療 療 Failed Failed Failed Failed Advanced Bca or Recurrence 療 Tamoxifen 療 AI 療 療 AI 療 Fulvestrant Fulvestrant 療 Tamoxifen 療 療 AZT-FASL Mar. 2007

56 洛 洛 療 療 療 年 療 療 復 療 惡 女 AZT-FASL Mar. 2007

57 洛 (1) 女 (2) Falsodex Falsodex (3) 度 (4) 若 療 不 (1) 度 度 不 (2) 度 不 creatinine 廓 率 30ml/min

58 Tamoxifen 年 療 降 復 率 50% 降 復 率 1/3 1/ 年 不 論 淋

59 Tamoxifen Tamoxifen) 年 臨 療 復 療 年 降 復 率 降 率 療 年 降 年 年 益

60 年 療 25% 復 HR+/PM/Nodal Positive

61 療 療 降 復 復 女 療 略 降 5 年 療 25% 復 (AI)

62 (Aromatase) 復 復

63

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65 % of Patients Femara Placebo P Value / Femara 略 < 略 兩 Femara 略 兩 理 Adapted from Goss. ASCO, % of AEs grade 1 or 2.

66 洛 Number of patients (%) Fulvestrant (n=428) Anastrozole (n=423) (CR) (PR) (CR+PR) 20 (4.7) 11 (2.6) 62 (14.5) 59 (13.9) 82 (19.2) 70 (16.5)* ³24 weeks 臨 益 (CR + PR + SD ³24 weeks) 104 (24.3) 103 (24.3) 186 (43.5) 173 (40.9) *Odds ratio (95.14% CI): 1.21; ( ); p=0.31 AZT-FASL Mar Robertson JFR et al. Cancer 2003; 98:

67 洛 Number of adverse events (%) Faslodex (n=428) Anastrozole (n=423) p value 不 206 (48.7) 192 (45.4) (21.7) 94 (22.2) (8.3) 54 (12.8) (3.5) 19 (4.5) 泌 尿 37 (8.7) 25 (5.9) (2.6) 8 (1.9) (1.4) 9 (2.1) a GI disturbances include: anorexia, constipation, diarrhoea, nausea and emesis b Joint disorders include: arthralgia, arthrosis and arthritis Extended median follow-up of 27.0 months AZT-FASL Mar Howell A et al. Cancer 2005; 104:

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69 療 度 療 臨

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71 度

72 療 療 臨

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76 Figure 1. Lapatinib binds to the tyrosine kinase (TK) domain, competitively blocking ATP binding, thus inhibiting the downstream cascade of events Tykerb Moy, B. et al. Oncologist 2007;12: Copyright 2007 AlphaMed Press

77 Tykerb is an oral, small-molecule, molecule, dual-targeted agent

78 酪 酪 路 來 刺

79 Erb Erb-b2 b2 HER2 / HER2 /neu neu Erb Erb-b3 b3 HER3 HER3 Erb Erb-b4 b4 HER4 HER4 TGF TGFα EGF EGF HRG HRG (NRG1) (NRG1) Epi Epi β-cel cel HB HB-EGF EGF Amp Amp Epi Epi HB HB-GF GF NRG1 NRG1 NRG2 NRG2 NRG3 NRG3 NRG4 NRG4 Tyrosine Tyrosine kinase kinase domain domain Ligand Ligand binding binding domain domain Transmembrane Transmembrane Erb Erb-b1 b1 HER1 HER1

80 ErbB-1 ErbB-1 ErbB-1 ErbB-3 ErbB-2 ErbB-2 ErbB-1 ErbB-4 ErbB-1 ErbB-2 ErbB-3 ErbB-3 ErbB-4 ErbB-4 ErbB-3 ErbB-4 ErbB-2 ErbB-4 ErbB-2 ErbB-3 Weakest Strongest 1. Holbro T, and Hynes N. Annu Rev Pharmacol Toxicol. 2004;44: Harari D, and Yarden Y. Oncogene. 2000;19: Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.

81 Lapatinib 兩 ErbB1 ErbB2 lapatinib Erb 1 Erb 2

82 Targeting growth factor signalling pathways may delay the onset of endocrine-resistant disease Gefitinib EGFR TGFα HER2 Trastuzumab ER X AKT MAPK P p XAF1 T T p AIB1 XX KK p RNA POLY X Accelerated tumour growth

83 若 若 度 度 不

84 療 類 度 度 酪 類 療 裡 療 量 療 力 冷

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86 療 路 Anti-HER2 MAbs Herceptin, Omnitarg TM Farnesyl-transferase inhibitors R115777, SCH66336, BMS Tumour-activated chemotherapy Xeloda TP Ras signalling Apoptosis VEGF signalling HER signalling HER tyrosinekinase inhibitors Tarceva TM, gefitinib Anti-VEGF MAbs Avastin TM Apoptotic agents

87 Multidrug resistance-related proteins (MRP) Taxane Extracellular P-glycoprotein (P-gp) Tumor cell membrane ATP Intracellular Tumor cells that have been exposed to one antineoplastic agent may develop cross-resistance to that agent as well as other structurally unrelated drugs. IXEMPRA (ixabepilone) Package Insert Taiwan Thomas ES, et al. J Clin Oncol. 2007;25:

88 β-tubulin mutations β b-tubulin mutations: Normal b-tubulin Taxane ß Microtubule with normal b-tubulin Mutated b-tubulin Microtubule with mutated b-tubulin ß ß Taxane resistance can arise due to mutations of b-tubulin at paclitaxel binding sites in cancer cells. IXEMPRA (ixabepilone) Package Insert Taiwan Thomas ES, et al. J Clin Oncol. 2007;25:

89 Ixabepilone 易 S cellulosum Epothilone B Ixabepilone Isolated from the soil-dwelling myxobacterium Sorangium cellulosum S. cellulosum is a unique bacterial species Largest known bacterial genome Rich source of secondary metabolites Lee JJ, Swain SM. Semin Oncol. 2005;32(suppl 7):S22-S26; Kamath K et al. J Biol Chem. 2005;280: ; Mozzetti S et al. Clin Cancer Res. 2005;11:

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91 療 年 切

92 療 年 年

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94 Cross-Talk Between Signal Transduction and Endocrine Pathways Growth factor Estrogen Plasma membrane P IGFR P P P Lapatinib EGFR / HER2 Letrozole ER Cell survival Akt PI3-K P p90 RSK P P P SOS RAS RAF MAPK MEK P P Cytoplasm P P P ER P ER p160 CBP Basal transcription machinery Cell growth Nucleus ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S.

95 Bisphosphonates combined with Endocrine Therapy 泌 療

96 ZO-FAST Immediate v Delayed Zoledronate against AI bone loss in postmen women receiving letrozole IMMEDIATE Eligibility: ER+/PgR+ early breast cancer Postmenopausal T score 2 Stratification: Adjuvant CT T score Established vs recent postmenopausal 1060 women R A N D O M I Z E Letrozole 2.5 mg/d Zoledronic acid 4 mg IV q6mo DELAYED Letrozole 2.5 mg/d Add zoledronic acid if: BMD T score below 2 or clinical or asymptomatic fracture at 36 months 5 years 1065 pts in 128 centers in Asia Pacific, Central and South America, Egypt, and Europe

97 ZO-FAST Primary Endpoint Mean Change in BMD from Baseline 6 4 BMD change (%) Immediate Delayed -4-6 Lumbar Spine P< Hip P< Mean Percent Change in BMD from Baseline to 36 Months

98 Kaplan Meier Plot of Disease-Free Survival by Treatment Group (All Randomized Patients) 100 Disease-Free Survival, % Immediate zoledronic acid significantly decreased the risk of DFS events. HR % CI (0.361, 0.959). p-value = Study Month

99 復 Immediate N=532 No. of Patients (%) Delayed N=532 No. of Patients (%) Month (2.8) 17 (3.2) Month (3.9) 32 (6.0) Month (4.9) 43 (8.1)

100 立 北 金 劉

101 行 2008 年 Stage 0&I : 55% vs 37% OS 5yr% I II III IV Taiwan US Total OS: 89% vs 83% 料 來 年 2002 年 10 2,174 5 年 料 料. Survival Report, 2008 年 年 299,900 5 年 料

102 聆

103 類

104 年 諸 論 牢 不 不 若 狀 連 領 類

105 女 療 不 年

106 若 狀

107 良 年 若 不 不 洞 怒

108

109 若 療 捻 爛 見 療

110 療 聯 理

111 療 行 益 類

112 療 論 論 留 益

113 行 復 降 丹 參 靈 不 留 行

114 參 猪 蘭 刺 金 葉 蓮 龍 連 漏 蘆

115 鶴 益 參 參 參 刺 靈

116 / / 療 療 療 臨 療

117 便 便 見 狀 類 不 療 行 便

118 療 便 療 葉 來 來 利 便 便 便 便 便 數 便 參 便 便

119 療 療 不 數 不 不 不 留 便 留 療 不 益 參 益 神 金

120 療 六 滑 滑 數 蓮 葉 不 滑 滑 參 益 降 益

121