Microsoft PowerPoint - Breast Cancer Management

Transcription

1 Breast cancer management Dr Peter Teo Feb 2013

2 Adjuvant vs therapeutic (metastatic) Trastuzumab Lapatinib Bevacizumab BRCA1, BRCA2 Platinols PARP PARP inhibitors (e.g. Olaparib) Pertuzumab HER 2 + (can be ER+/ -) efficacy of hormone treatment if ER+ TNBC (Triple negative Breast Cancer 1. associated with BRCA1 2. Not associated with BRCA1

3 Adjuvant vs therapeutic (metastatic) ER + (must be HER2-1. Luminal A 2. Luminal B ER+ &HER2+ Premenopausal Postmenopausal Tmx Ovarian suppression/ ablation both A1>Tmx Anti-HER2 &Anti-E2

4 Early stage of Breast Cancer

5 Risk assessment for adjuvant systemic treatments Adjuvant!Online(SEER data-breast cancer mortality rate;extrapolate recurrence rate)- clinical parameters only awaiting genomic version 21 genes(oncotype DX)-RS<18;18-31;>31 70 genes(mammoprint)-randomized study ongoing for those in whom discrepancy exists for the decision for adjuvant chemotherapy based on clinical parameters and Mammoprint result

6 The Importance of Nodes Disease Free Survival by number of involved lymph nodes San Antonio database, 51 months median follow-up Clark GM, Prognostic and predictive factors, in : Harris JR, et al eds: Diseases of the Breast, Philadelphia : J.B. Lippincott, 1996: pg 463

7 Factors affecting adjuvant treatment options 主瘤大小 癌細胞惡性程度 HER-2 病人意願 腋下淋巴受影響情度 ER, PR ( 荷爾蒙受體 ) 年齡 身體狀况 生物特性 : LVI, Ki-67%, p53

8 Treatment for Breast Cancer 診症 腫瘤偏大 (>5 厘米 ) 外科手術 化學治療 +/- 標靶治療 輔助治療 外科手術 化學治療荷爾蒙治療標靶治療放射治療

9 Adjuvant systemic treatments Chemotherapy Hormone therapy Anti-HER2(trastuzumab/lapatinib)

10 Adjuvant chemotherapy 1st generation-cmf;ac 2nd generation-fac;fec;tc;ac-t; A CMF ; FE(100)C 3rd generation-tac;fe(100)c-t;ac- T(q2w)

11 Development of Adjuvant Chemotherapy 1970s Breast Cancer Before anthracyclines CMF 1980s 1990s 2000s With anthracyclines Combinations: AC, FAC, AVCMF, FEC, CEF Dose intensity,dose density Standard treatment worldwide Taxanes (Paclitaxel/Docetaxel) Sequential: AC T Combinations: TA, TAC

12

13

14 BCIRG 001 TAC Improves DFS and OS Over FAC in Node Positive Early Breast Cancer Patients, BCIRG Months Follow-Up Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver CH, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Hugh J, Nabholtz JM, Loret C, Rupin M, Blitz S, Riva A, Vogel C. On behalf of the BCIRG 001 Investigators.

15 Design F A C 5-FU 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 R Every 3 weeks x 6 cycles Stratification Nodes Center T A C Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2

16 Conclusion (I) TAC demonstrated over FAC a significantly improved DFS (p=0.001) 28% reduction in risk of relapse OS (p=0.008) 30% reduction in mortality risk TAC significantly improves DFS irrespective of nodal, hormone receptor or HER 2 status

17 Conclusion (II) Febrile neutropenia was more frequent on TAC, but without increased incidence of infection and no septic deaths Other toxicities were predictable and manageable in both arms

18 Conclusion (III) This study establishes Taxotere in combination with doxorubicin and cyclophosphamide to have major clinical value in the adjuvant treatment of women with early stage node positive breast cancer

19 NSABP B38(ASCO 2012) Similar OS and DFS between ddac-p,ddac-pg &TAC

20 Adjuvant!Online

21

22

23

24

25 Early stage of Breast Cancer with HER2 mutation

26 Investigation for HER2 免疫組織化學測試 - Immunohistochemistry (IHC) 螢光顯影原位測試 - Fluorescence In Situ Hybridization (FISH)

27 Immunohistochemistry(IHC) - to test the extend of overexpression of HER2 receptor 沒有增生或 0+ 少量增生或 1+ 中度增生或 2+ 高度增生或 3+

28 Fluorescence In Situ Hybridization (FISH) - to test the extend of overexpression of HER2 receptor HER-2 受體沒有增生 (FISH-ve ve) HER-2 受體有增生 (FISH+ve FISH+ve)

29 HER-2 receptor proliferative index

30 Growth factor transmission route 自我復製基因啟動

31 HER-2 antibodies stop the proliferation of breast cancer cells HER-2 antibodies initiate the auto-immune response

32 Adjuvant anti-her2 FISH+ or cerbb2+++(ihc 3+) 6 prospective randomized studies(level I evidence) Adding/sequencing trastuzumab with chemotherapy:48% reduction in breast cancer recurrence rate and 30% reduction in mortality rate HER2+CAB independent poor prognosticator even for small tumours <1cm

33

34

35 Phase III Trial Comparing AC-T with AC-TH and with TCH in the Adjuvant Treatment of HER2 positive Early Breast Cancer Patients: First Interim Efficacy Analysis Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, Chan A, Smylie M, Liu M, Falkson C, Pinter T, Fornander T, Shiftan T, Valero V, Von Minckwitz G, Mackey J, Tabah-Fisch I, Buyse M, Lindsay MA, Riva A, Bee V, Pegram M, Press M, Crown J, on behalf of the BCIRG 006 Investigators. Study sponsored by Sanofi-Aventis Support from Genentech

36 BCIRG 006 AC T 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 Her2+ (Central FISH) N+ or high risk N- N=3,222 Stratified by Nodes and Hormonal Receptor Status AC TH TCH 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 1 Year Trastuzumab 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 Year Trastuzumab Slamon D., SABCS 2005

37 Disease Free Survival % Disease Free Patients Events 93% 91% 86% AC->T AC->TH TCH 86% 80% 77% 84% 80% 73% HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P< HR (TCH vs AC->T) = 0.61 [0.47;0.79] P= Year from randomization

38 Disease Free Survival AC-T n=1,073 AC-TH n=1,074 TCH n=1,075 Patients with event Observed p-values p = TCH AC-TH p = p = 0.16

39 Summary (I) - Efficacy At 23 months median follow-up, AC-TH and TCH provide over AC-T: Primary endpoint: Disease-Free Survival Statistically significant improvement: - hazard ratio of 0.49 with AC-TH (p = ) - hazard ratio of 0.61 with TCH (p = ) Secondary endpoint: Overall Survival - data not mature enough at the present time

40 Summary (II) Cardiac Safety There is a statistically significant higher incidence of cardiac events in AC-TH in comparison to AC-T but not in TCH in comparison to AC-T AC-T: 0.86% AC-TH: 2.62% (p = ) TCH: 1.04% (p = 0.82) There is also a statistically significant higher incidence of asymptomatic and persistent LVEF declines in AC-TH in comparison to AC-T and TCH

41 Summary (III) Global Safety There was no statistically significant higher incidence of hematological toxicities (febrile neutropenia and neutropenic infection) in any of the 3 treatment arms For non-hematological toxicities, all 3 regimens appear to be safe and with manageable toxicities All 3 regimens were well-tolerated (more than 90% of cycles administered)

42 Update of the HERceptin Adjuvant (HERA) trial at 4 years median follow-up Treatment for HER2 mutated early-stage breast cancer with Herpcetin

43 The HERceptin Adjuvant (HERA) trial 是迄今最大型有關乳癌的國際臨床研究 共有 5,102 名早期 HER2 型乳癌患者參與 病人跟進期的中位數達 5 年之久 觀察患者在接受化療後, 再接受標靶藥物 Herceptin 的治療成效

44 歐洲歐洲歐洲歐洲歐洲歐洲歐洲歐洲 71.5% 東歐東歐東歐東歐東歐東歐東歐東歐 : 11% 11% 中美洲中美洲中美洲中美洲中美洲中美洲中美洲中美洲及南美洲南美洲南美洲南美洲南美洲南美洲南美洲南美洲 5.5% 5.5% 共有超過共有超過共有超過共有超過 5000 名患者參加患者參加患者參加患者參加來自來自來自來自來自來自來自來自 個國家及個國家及個國家及個國家及個國家及個國家及個國家及個國家及 個中心中心中心中心中心中心中心中心 (2002 ( ) 2005) 加拿大加拿大加拿大加拿大加拿大加拿大加拿大加拿大北歐五國北歐五國北歐五國北歐五國北歐五國北歐五國北歐五國北歐五國南非地區南非地區南非地區南非地區南非地區南非地區南非地區南非地區澳洲及澳洲及澳洲及澳洲及澳洲及澳洲及澳洲及澳洲及新西蘭新西蘭新西蘭新西蘭新西蘭新西蘭新西蘭新西蘭亞太地區亞太地區亞太地區亞太地區亞太地區亞太地區亞太地區亞太地區 %

45 HERA TRIAL DESIGN Accrual (n=5102) Women with locally determined HER2- positive invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF 55% Randomization OBSERVATION n=1698 After ASCO 2005, option of switch to Trastuzumab 1 year Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n= years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n=1701 CT, chemotherapy; RT, radiotherapy

46 Patient (%) 於 2005 年發布的中期報告 : 患者復發風險降低接近一半 1-year Herceptin Observation DFS Risk ratio 1-year Herceptin 85.8 % 0.54 Observation 77.4%

47 研究結果影響國際的乳癌治療指引 研究結果反映,Herceptin 對治療早期 HER2 型乳癌, 效果非常顯著 有鑑於此, 國際間的乳癌治療指引亦採納研究的治療方案, 包括 : - 美國 NCCN 治療指引 - 英國 - NICE 治療指引 - 瑞士 - St Gallen 治療指引 治療指引表示 : Herceptin 配合化療, 成為國際間治療早期 HER2 型乳癌的一線治療方案

48 為什麼部份觀察組患者中途 接受 Herceptin 的治療? 由於在 HERA 研究的第一次中期分析中, 治療組患者在接受 1 年 Herceptin 治療後, 已見非常顯著的療效 若其他患者因為隨機抽樣後歸入觀察組, 而失去接受治療的權利, 實屬不平等及不道德 因此, 部份適合接受治療的觀察組患者, 其後可以選擇接受 曲妥株單抗 治療, 進一步控制腫瘤的惡化

49 Observation patients by status on 16 May patients originally randomised to observation 16 May 344 patients 1354 patients DFS event or lost to followup alive and disease free alive post DFS event 469 patients remained on observation 344 patients ineligible for crossover

50 HERA: DFS at 1 year of followup No. at risk Significant DFS benefit of trastuzumab vs observation Alive and disease free (%) Piccart-Gebhart MJ, et al Events Observation 2-year DFS HR 0.54 Trastuzumab 1 year 95% CI P value < Months from randomisation %

51 HERA: DFS at 4 years of followup DFS benefit of trastuzumab vs observation maintained at 4 years No. at risk Alive and disease free (%) Gianni L, et al Events year DFS HR Trastuzumab 1 year Observation Months from randomisation % CI P value < %

52 DFS and OS over time Median follow-up (% follow-up time after selective crossover) DFS benefit No. of DFS events H 1 year vs observation Median follow-up (% follow-up time after selective crossover) OS benefit No. of deaths H 1 year vs observation year (0%) vs 220 p< year (0%) 1 29 vs 37 p= years (4.3%) vs 321 p< years (4.1%) 2 59 vs 90 p= years (33.8%) 369 vs 458 p< years (30.9%) 182 vs 213 p= Favours trastuzumab HR Favours no trastuzumab Favours Favours no trastuzumab HR trastuzumab 1 Piccart-Gebhart et al NEJM 2005; 2 Smith et al Lancet 2007

53 SUMMARY: ANALYSIS OF DFS AND OS FOR 1 YEAR TRASTUZUMAB VS. OBSERVATION AT 8 YRS MFU HERA results at 8 yrs MFU show sustained and statistically significant DFS and OS benefit for 1 year trastuzumab versus observation in ITT analyses despite selective crossover. 1 year of trastuzumab remains the standard of care as part of an adjuvant therapy for patients with HER2-positive early breast cancer.

54 NOAH (MO16432): Study design An international, open-label, Phase III study of neoadjuvant adjuvant trastuzumab in patients with locally advanced or inflammatory HER2-positive breast cancer HER2-positive LABC (IHC 3+ or FISH-positive) HER2-negative LABC (IHC 0/1+) * (n = 117) (n = 118) ( n = 99) H + AT AT AT q3w x 3 cycles q3w x 3 cycles q3w x 3 cycles H + T q3w x 4 cycles H q3w or q4w x 4 cycles + CMF q4w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy H continued q3w to week crossed over to H H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); T, paclitaxel (175 mg/m 2 ); CMF, cyclophosphamide, methotrexate and fluorouracil 5-FU * A separate treatment group of HER2-negative patients received chemotherapy only; Hormone receptor-positive patients received adjuvant tamoxifen. 54 Gianni L, et al. 2010

55 NOAH: EFS (primary endpoint) in the HER2-positive; ITT population (The Lancet analysis) Significant EFS benefit with the addition of trastuzumab to chemotherapy in HER2-positive patients 1.00 With trastuzumab Without trastuzumab Probability of event-free survival With trastuzumab Without trastuzumab Patients Events HR Unadjusted p value Adjusted HR p value Number at risk With trastuzumab Without trastuzumab Gianni L, et al. 2010

56 Herceptin can significantly increase the DFS benefit HERA CTx H 1 year B-31 / N9831 AC PH BCIRG 006 AC TH TCarboH DFS benefit Median follow-up NOAH CTx / H H 1 year Favours trastuzumab HR Favours no trastuzumab a Based on small subgroups of patients with HER2-positive breast cancer; b DDFS; CTx, chemotherapy; AC, doxorubicin, cyclophosphamide; P, paclitaxel; T, docetaxel; Carbo, carboplatin; V, vinorelbine; CEF, cyclophosphamide, epirubicin, 5-fluorouracil Gianni et al 2008; Gianni et al 2009; Joensuu et al 2009; Slamon et al 2006; Perez et al 2007; Smith et al 2007; Spielmann et al 2007

57 1-year Herceptin treatment can reduce 1/3 of mortality rate OS benefit Median follow-up HERA CTx H 1 year 4 B-31 / N9831 AC PH 3 BCIRG 006 AC TH 3 TCarboH Favours trastuzumab HR Favours no trastuzumab Gianni et al 2009; Joensuu et al 2009; Slamon et al 2006; Perez et al 2007; Smith et al 2007

58 Treatment guidelines for HER2-positive EBC Trastuzumab recommended across international guidelines Adjuvant therapy Recommended patient groups Administration with chemotherapy St. Gallen 1 1 year of trastuzumab HER2-positive tumours 1 cm HER2-positive node-negative tumours cm (pt1b) Excludes: HER2-positive node-negative tumours cm (pt1a) Preferred: concurrent use of trastuzumab with chemotherapy Acceptable: sequential use of trastuzumab with chemotherapy ESMO 2 1 year of trastuzumab HER2-positive tumours 1 cm Use of trastuzumab should be discussed with patients with small node-negative HER2-positive breast cancers Trastuzumab may be started in parallel with a taxane Trastuzumab should not be given concurrently with an anthracycline outside the context of a clinical trial NCCN 3 1 year of trastuzumab Category 1 recommendation: patients with HER2-positive tumours 1 cm Category 2A recommendation: patients with HER2-positive node-negative tumours cm (HER2-positive node-negative pt1a or pt1b tumours: use of trastuzumab to be based on individual benefit:risk) Preferred: AC followed by concurrent administration of trastuzumab with taxane Preferred: TCH Acceptable: chemotherapy followed by trastuzumab sequentially 1. Goldhirsch A, et al. 2011; 2. Aebi S, et al. 2011; 3.

59 Side effect of Herceptin ( 赫賽汀 ) Fever Chill Tiredness Headache Abdominal pain Nausea & vomiting Abnormal cardiac function

60 ER+ Breast Cancers

61 Annual hazard rate of recurrence of breast cancer patients separated by hormone receptor status JCO 1996;14:

62 Oxford Overview 1998: ER+ Patients Yearly Risk of Recurrence Node +ve % recurrence rate/year Node -ve node (-) node (+) YEAR Early Breast Cancer Trialist s Collaborative Group. Lancet. 1998;351:1451.

63 Endocrine Therapy: 5 years of tamoxifen still the gold standard?

64 About 5 years of tamoxifen versus not in ER+ (or ER unknown) disease: 15-year probabilities of recurrence and of breast cancer mortality (10,386 women of all ages: 20% ER unknown, 30%N+) Recurrence breast cancer mortality Control 45.0% Control 34.8% 33.2% 5 years tamoxifen 25.6% 5 years tamoxifen 15-y gain 11.8% (SE1.3) Logrank 2p< y gain 9.2% (SE1.2) Logrank 2p< Lancet 2005;365: Years Years

65 Half of ER+ Recurrences and 2/3 of Breast Cancer Deaths Occur After Completing 5 Years of Tamoxifen 100 Recurrences 15% 17% Breast Cancer Deaths 9% 18% % of patients Tamoxifen Control 54.9 % of patients Tamoxifen Control Years Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, Early Breast Cancer Trialists Collaborative Group. Lancet. 2005;365: Years

66 Adjuvant hormone Premenopausal-ovarian ablation(medical/surgical/rt);tamoxifen Postmenopausal-Aromatase inhibition(ai);tamoxifen

67 ADVANCE IN ENDOCRINE TREATMENT MECHANISM OF ENDOCRINE MANIPULATION Premenopausal patient Postmenopausal patient Main site of oestrogen production Ovary Ovarian oblation Ovarian function suppression by Gn RH agonist Peripheral tissue (fat, muscle, tumour,liver) Androgen Oestrogen Aromatase enzyme Aromatase Inhibitors

68 Pre-menopausal ER+ CA breast

69 ABCSG-05: Phase III Trial for Treatment of Breast Cancer Premenopausal breast cancer patients (N = 1017) Surgery ± radiotherapy Endocrine Therapy Goserelin 3.6 mg every 28 days for 3 years Tamoxifen 20 mg daily for 5 years (n = 512) CMF Chemotherapy Cyclophosphamide 600 mg/m 2 Methotrexate 40 mg/m 2 Fluorouracil 600 mg/m 2 given IV on Days 1 and 8 for 6 cycles (n = 505) Median follow-up: 11 years Stratified based on tumor stage and grade, number of involved nodes, type of surgery, and degree of hormone receptor expression. Gnant M, et al. SABCS Abstract 17.

70 ABCSG-05: Comparison of Adjuvant Endocrine vs CMF Therapy ABCSG-05 compared adjuvant endocrine therapy vs CMF chemotherapy in premenopausal early breast cancer patients 5 years of follow-up: significantly lower relapse rate with endocrine therapy vs CMF 17.2% vs 20.8%, respectively (P =.037) Current report detailed long-term (> 10 years) survival analysis Gnant M, et al. SABCS Abstract 17.

71 ABCSG-05: Conclusions From 10 Years or More of Follow-up No differences in long-term RFS or OS rates between endocrine and CMF therapies in premenopausal women with hormone receptor positive early breast cancer RFS rate significantly longer in patients with TIA Crucial for patients administered CMF Frequency of TIA in patients receiving CMF increases with age Only in CMF treated women < 40 did TIA improve outcome Gnant M, et al. SABCS Abstract 17.

72 Premenopausal node-negative HR+ IBCSG VIII STEPP analysis Woman younger than 35 yr OFS + CMF > CMF alone or OFS alone Overall: CMF = goserelin Critisms: 1) no doxorubin to compare 2) tamoxifen not used for all three arms

73 Intergroup 0101 Premenopausal node-positive HR+ CAF + OFS + TMX > CAF + TMX > CAF alone

74 Recurrence (%) Significant Clinical Benefit of Adding LHRH Agonist to Recurrence HR: 0.88; 95% CI: ; P =.04 (n = 3307) Chemotherapy Chemotherapy ± tamoxifen LHRH addition 29.4% vs 24.0% 5.4% reduction Years Since Randomization Death After Recurrence (%) Death After Recurrence Chemotherapy ± tamoxifen LHRH addition HR: 0.85; 95% CI: ; P =.04 (n = 3307) 13.1% vs 11.3% 1.8% reduction Years Since Randomization Cuzick J, et al. SABCS Abstract 15.

75 Small, Nonsignificant Clinical Benefit of Adding LHRH Agonist to Tamoxifen Recurrence Death After Recurrence Tamoxifen LHRH + tamoxifen Tamoxifen LHRH + tamoxifen Recurrence (%) HR: 0.85; 95% CI: ; P =.20 (n = 1013) 22.8% vs 18.2% 4.6% reduction Years Since Randomization Death After Recurrence (%) HR: 0.86; 95% CI: ; P =.33 (n = 1013) 8.8% vs 7.3% 1.5% reduction Years Since Randomization Cuzick J, et al. SABCS Abstract 15.

76 Post-menopausal ER+ CA breast

77 The Breast International Group (BIG) 1-98 clinical trial

78 BIG 1-98 study compared Letrozole ( 芬香酵素抑制劑 ) with Tamoxifen ( 三苯氧胺 ) as adjuvant treatment for steroid-hormonereceptor positive breast cancer in postmenopausal women with clear surgical margins and adequate haematologic, renal, and hepatic function. Patients are randomized into 2 groups: 1. On Tamoxifen 2. On Letrozole * 此項研究尚在進行當中 Coates A S et al. J Clin Oncol 2007;25(5):1-12.

79 BIG 1-98 study results (51 months follow-up) Letrozole is more effective in reducing the overall disease recurrent rate by 18% than Tamoxifen. (HR=0.82, 95% CI: ; p=0.007) 18% (HR=0.77, 95% CI: ; p=0.004) 23% 復發數目 (HR=0.74, 95% CI: ; p=0.03) 26% Tamoxifen Letrozole (n=4007) (n=4003) 整體個案 Tamoxifen Letrozole (n=1651)) (n=1660) 淋巴結呈陽性的女性 Tam1009en Letrozole (n=1651) (n=1005) 曾接受化療之女性 Coates A S et al. J Clin Oncol 2007;25(5):1-12.

80 BIG 1-98 輔助治療研究結果 (51 個月跟進 ) the greatest benefit of Letrozole was in patients who had received chemotherapy (26%) and in those with node-positive disease (23%). (HR=0.82, 95% CI: ; p=0.007) 18% (HR=0.77, 95% CI: ; p=0.004) 23% 復發數目 (HR=0.74, 95% CI: ; p=0.03) 26% Tamoxifen Letrozole (n=4007) (n=4003) 整體個案 Tamoxifen Letrozole (n=1651)) (n=1660) 淋巴結呈陽性的女性 Tam1009en Letrozole (n=1651) (n=1005) 曾接受化療之女性 Coates A S et al. J Clin Oncol 2007;25(5):1-12.

81 The most recent update of BIG I-98 After a median follow-up of 76 months increased disease-free survival by 12% increased overall survival by 13% prolonged time-to-recurrence by 15% 76 個月跟進 1. SABCS 2008

82 ATAC study design 9366 postmenopausal women with localized breast cancer were enrolled Mean age=64; 84% had hormone receptor-positive disease 61% node-negative disease; 64% tumor size 2 cm Anastrozole n=3125 Surgery ± Radiotherapy ± Chemotherapy Randomization 1:1:1 5 years Tamoxifen Discontinued 合併療法 following n=3116 initial n=3125 analysis as no efficacy or tolerability benefit compared with Regular follow-up tamoxifen arm Primary endpoints: disease-free survival (DFS), safety & tolerability Secondary endpoints: incidence of new contralateral breast cancer (CLBC), time to distant recurrence (TTDR), overall survival (OS) death after recurrence

83 ATAC100 analysis Results from median follow-up of 100 months: Anastrozole significantly prolongs disease-free survival and time to recurrence compared with tamoxifen Anastrozole was better tolerated than Tamoxifen and resulted in fewer serious complications Anastrozole had a more favorable overall risk benefit profile than Tamoxifen

84 ITT & Hormone-receptor-positive subpopulation Intention to Treat (ITT) Hormone-receptor-positive population Anastrozole 較佳 Tamoxifen 較佳 危機率 所有病人 危機率 荷爾蒙受體呈陽性病人 DFS TTR TTDR CLBC Death-all causes Death after recurrence Death without recurrence 危機率 (A / T) and 95% CI

85 Anastrozole is more effective in prolonging disease-free survival (DFS) by 15% than tamoxifen Patient (%) HR+ HR % CI (0.76, 0.94) p-value % Tamoxifen (T) Anastrozole (A) 16.4% 25.8% % 10 At risk: A T HR, hazard ratio; CI, confidence interval Absolute difference: 2.5% 4.1% Follow-up time (year)

86 Anastrozole is more effective in minimizing risk of recurrence by 24% than Tamoxifen Patient (%) HR+ HR % CI (0.67, 0.87) p-value % Tamoxifen (T) Anastrozole (A) 12.5% 17.0% % 5 At risk: A T Absolute difference: Follow-up (year) % 4.8%

87 Anastrozole is more effective in reducing the risk of time to distant recurrence (TTDR) by 16% than Tamoxifen 病人 (%) HR+ HR % CI (0.72, 0.97) p-value Tamoxifen (T) Anastrozole (A) 15.6% % 13.2% 10 At risk: A T % Absolute difference : 1.3% 2.4% 追蹤期 ( 年 )

88 Anastrozole is more effective in reducing risk of CLBC by 40% than Tamoxifen Patient (%) 5 4 HR+ HR % CI (0.42, 0.85) p-value % Tamoxifen (T) Anastrozole (A) 2.5% % 1.0% 2 1 At risk: A T 0 Absolute difference : 0.8% 1.7% Follow-up time (year)

89 Overall survival total death (Hormone-receptor-positive) Patient (%) HR+ HR % CI (0.86, 1.11) p-value Tamoxifen (T) Anastrozole (A) At risk: A T Follow-up time (year)

90 Time-to-recurrence (Hormone-receptor-positive) Favour Anastrozole Favour Tamoxifen Hazard ratio (95% CI) Node +ve -ve unknown 0.84 ( ) 0.68 ( ) 0.48 ( ) Tumor size 2 cm Receptor >2 cm ER+ / PgR+ ER+ / PgR ( ) 0.74 ( ) 0.87 ( ) 0.42 ( ) Chemotherapy Age ITT 是 否 <65 歲 65 歲 是 否 危機率 (A / T) and 95% CI 0.89 ( ) 0.71 ( ) 0.76 ( ) 0.77 ( ) 0.76 ( ) A, anastrozole; T, tamoxifen

91 Efficacy summary In hormone-receptor-positive cases, Anastrozole is more effective than Tamoxifen in reducing risk of: DFS : 15% (p=0.003) Recurrence: 24% (p=0.0001) Distant recurrence: 16% (p=0.022) Contralateral recurrence: 40% (p=0.004)

92 Conclusions At 100-month median follow-up, data show anastrozole is significantly superior to tamoxifen at preventing all forms of recurrence: Locoregional Contralateral Distant The absolute difference in recurrence rates continues to increase after treatment completion: HR+ population: 2.8% at 5 years increased to 4.8% after 9 years HR = 0.75; p=0.01 Anastrozole is well-tolerated long term: No excess fracture rate seen after treatment completion Risk of fracture on treatment needs to be taken into consideration and can be managed according to established guidelines No new morbidity or mortality increases seen after treatment completion

93 Fracture episode rate 每年骨折 骨折率 (%) 4 3 Tamoxifen (T) Anastrozole (A) 時間由隨機分配隨機分配開始 ( 年 ) At risk: A T

94 Switching and Sequential Therapy Trials Surgery Analysis 5 years TAMOXIFEN ANASTROZOLE LETROZOLE EXEMESTANE BIG 1-98 TEAM 2 years 2 years 2-3 years 5 years 5 years 3 years 3 years 2-3 years IES ABCSG-8/ARNO ITA 2-3 years 2 years 2-3 years 2-3 years 2-3 years 3 years 3 years 2-3 years 2-3 years Sequential trials include all events from start of adjuvant therapy Switching trials only include events from point of switch (after 2-3 years tamoxifen)

95 Kaplan-Meier curve of DFS of metaanalysis of ARNO 95, ABCSG 8 and ITA Lancet 2006;7:

96 Death rate of meta-analysis of ARNO 95, ABCSG 8 and ITA Lancet 2006;7:

97 Lancet 2007;369: IES trial: DFS

98 Extended Adjuvant Trials MA 17 Tamoxifen Tamoxifen Letrozole Placebo NSABP B-33 Tamoxifen Tamoxifen Exemestane Placebo ABCSG 6a Tamoxifen Tamoxifen Anastrozole Placebo Years

99 Letrozole MA-17 was conducted by National Cancer Institute of Canada The trial enrolled 5,187 post-menopausal women with early-stage breast cancer in whom 5 years of Tamoxifen (range years) therapy had been completed less than 3 months before enrollment. Eligible women were randomly assigned to receive treatment with letrozole (2.5 mg) or placebo orally daily for 60 months Goss et al. J Natl cancer Inst. 2005;97:1262.

100 MA.17: research design 隨機分組 ( 所有病人 disease-free) Tamoxifen 0-3 mo n=2575 Letrozole (Femara ) 2.5 mg qd* Placebo qd n=2582 Approx. 5 y adjuvant 5 y extended adjuvant Primary end point: DFS Secondary end points: OS/safety/QOL Substudies: : BMD/bone markers, lipid profile *n=2575 (efficacy), 2154 (safety); n=2582 (efficacy), 2145 (safety). Goss et al. N Engl J Med. 2003;349:1793; Goss et al. J Natl Cancer Inst. 2005;97:1262.

101 MA.17: Survival Benefit Associated With Letrozole Following Tamoxifen Postmenopausal women with HR+ breast cancer and with 5 years of prior tamoxifen therapy; median age: 62 years (N = 5158) Letrozole (n = 2576) Age-based stratification* Placebo (n = 2582) Median follow-up: 30 months In preliminary analyses, letrozole therapy significantly improved DFS and decreased risk of recurrence by 42% compared with placebo Current analysis assessed age-dependent differences in DFS, OS, safety, and quality of life * 60 yrs < 60 years; years; 70 years. Muss HB, et al. SABCS Abstract 102.

102 MA.17: Trial Design and Rationale (1998) Tamoxifen Approx. 5 years adjuvant 0-3 months Randomization (PMW, HR+, disease-free) Letrozole 2.5 mg qd (n=2582) Placebo qd (n=2586) 5 years extended adjuvant Rationale Lack of benefit with adjuvant tamoxifen extended beyond 5 y Need to extend DFS/OS beyond adjuvant tamoxifen Increasing risk for long-term adverse effects with tamoxifen Letrozole effective in MBC following adjuvant tamoxifen

103 Goal: 2.4 % reduction in 4 yr DFS was considered Estimated 4-y DFS (total population) Practice Changing Letrozole (n=2582) Placebo (n=2586) Abs. Difference % (p = ) 4-y DFS/N % Year 5 10: 3% per annum node ve 2%; node +ve 4% (p = 0.005) 4-y DFS/N % (p = 0.003) Goss et al. N Engl J Med. 2003;349:1793. Goss et al. J Natl Cancer Inst. 2005;97:1262.

104 MA.17: Letrozole Reduced All Tamoxifen 5 yrs Events(N+/N-) R Placebo Letrozole 5 yrs Node+ Node No. of events Placebo Letrozole Placebo Letrozole Placebo Distant Locoregional New primary only Letrozole Goss et al. J Natl Cancer Inst. 2005;97:1262.

105 MA17 Node +ve patients HR 0.61* (95% CI, ) HR 0.53* (95% CI, ) HR 0.61* (95% CI, ) All patients DFS* HR 0.58; p<0.001 Distant DFS* HR 0.60; p<0.002 OS HR 0.82; p=0.3 Node ve patients HR 0.45* (95% CI, ) HR 0.63 (95% CI, ) HR 1.52 (95% CI, ) Significant 39% reduction in the risk of death in node+ patients *Statistically significant benefit of letrozole. HR = hazard ratio; CI = confidence interval. Goss et al. J Natl Cancer Inst. 2005;97:1262.

106 MA.17: Summary of Efficacy LETROZOLE Results Significantly and clinically meaningfully improves 4-year DFS rate and distant metastases by 4.6% vs placebo (94.4 vs 89.8%; p = ) Lowers the risk of recurrence by 43% vs placebo Improves 4-year overall OS rate by 2% vs placebo (96% vs 94%) and significantly in node +ve patients (n = ~2500; p = 0.04) Decreases incidence of contralateral new primary breast cancer by 46% in addition to the carrry-over tamoxifen reduction of ~ 40% (prevention) Goss et al. N Engl J Med. 2003;349:1793.

107 MA.17 Safety and Quality of Life

108 MA.17: Safety Profile - Summary % of Patients Letrozole Placebo (n=2154) (n=2145) P Value Hot flashes < Arthralgia < Myalgia Edema Hypercholesterolemia Cardiovascular events Fractures Osteoporosis Vaginal bleeding Patients in the letrozole arm did not discontinue treatment due to side effects significantly more often than placebo patients (4.5% vs 3.6%, respectively; P=0.11). Goss et al. N Engl J Med. 2003;349:1793.

109 Bone Management Strategies for Pts Taking AI s History and Physical BMD and Annual Height Measurements Lifestyle Modifications Lifestyle Modifications Lifestyle Modifications Lifestyle Modifications T Score > -1 T Score Between -1.0 and -1.5 T Score Between -1.5 and -2.0 T Score < -2.0 Re-screen in 2 Year. If BMD > Screen Every 2 years* Annual Screening* Check Vitamin D Level (25[OH]D) Check Vitamin D Level (25[OH]D) Consider Bisphosphonate Therapy Depending on Risk Factors+ Treat with Bisphosphonate Therapy+ In addition to monitoring changes in BMD, any changes in height or complaints of back pain should prompt the oncologist to obtain a lateral thoracic and lumbar x-ray of the spine to determine if vertebral fracutres are present. If so, the patient should be referred to a bone health specialist. Chien & Goss Journal of Clinical Oncology 2006 Nov 20;24(33): Goss et al. American Journal of Oncology Review March 2006; 5(3);Suppl 1; 35-43

110 ABCSG-12: background cases 1,803 premenopausal women (aged 19-59) with endocrine-responsive (ER+ and/or PR+) early breast cancer. Stage I/II, <10 nodal metastases Preoperative chemotherapy was allowed, but none of the patients received adjuvant chemotherapy Median follow-up: 60 months Treatment time: 3 years Tamoxifen 20 mg QD Surgery (+RT) Goserelin 3.6 mg (Q28D) Randomly assigned into 4 groups 1 : 1 : 1: 1 Anastrozole1 mg QD Tamoxifen 20 mg QD + Zoledronic acid 4 mg Q6M Anastrozole 1 mg QD + Zoledronic acid 4 mg Q6M

111 The addition of zoledronic acid significantly improved disease-free survival, as compared with the use of endocrine therapy alone Disease-free survuval(%) Zoledronic acid 54 No Zoledronic acid Median follow-up = 60 months. Gnant M, 主編 : 2008 年,ASCO 會, 芝加哥, IL. LBA4 節錄彙報 Hazard ratio (95% CI) no. of events for disease progression Months since randomization P-value ( ) 0.91) % improvement

112 The addition of zoledronic acid significantly improved recurrence-free survival, as compared with the use of endocrine therapy alone Disease-free survival(%) Zoledronic acid 54 No Zoledronic acid 82 Hazard ratio (95% CI) no. of events for disease progression Months since randomization P-value ( ) 0.91) % improvement Median follow-up up= 60 months. Gnant M, 主編 : 2008 年,ASCO 會, 芝加哥, IL. LBA4 節錄彙報

113 The addition of zoledronic acid reduces risk of bone metastases 100 survival free of bone metastasis(%) Zoledronic acid 16 No Zoledronic acid 24 Hazard ratio (95% CI) no. of events for disease progression P-value ( ) Months since randomization Median follow-up up=60 months Gnant M, 主編 : 2008 年,ASCO 會, 芝加哥, IL. LBA4 節錄彙報

114 Adverse events, no. of people(%) Adverse effect TAM (n = 435) TAM + ZOL (n = 434) ANA (n = 436) ANA + ZOL (n = 439) P value Arthralgia 52 (11.5) 65 (14.5) 112 (24.7) 150 (33.3) <.0001 Bone pain 94 (20.8) 132 (29.4) 128 (28.3) 185 (41.1) <.0001 Fever 9 (2.0) 34 (7.6) 11 (2.4) 46 (10.2) <.0001 Periodontal disease * 5 (1.1) 3 (0.7) 0 (0.0) 6 (1.3).054 Depression,sleep sleep disturbance 70 (15.5) 74 (16.5) 97 (21.4) 80 (17.8).110 Severe adverse events, no. of people(%) Arthralgia 0 (0.0) 1 (0.2) 0 (0.0) 1 (0.2).374 Bone pain 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.2).499 Fever 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.4).882 Depression, sleep disturbance 1 (0.2) 3 (0.7) 0 (0.0) 1 (0.2).198 Fracture 6 (1.3) 4 (0.9) 4 (0.9) 7 (1.6).747 Thrombosis 3 (0.7) 5 (1.1) 0 (0.0) 0 (0.0).012 Uterine polyp 40 (8.9) 51 (11.4) 7 (1.6) 5 (1.1) <.0001 Periodontal disease* 0 (0.0) 1 (0.2) 0 (0.0) 1 (0.2).374 TAM = 三苯氧胺 ; ZOL = 唑來磷酸 ; ANA = 阿那曲唑. * 沒有確實的頜骨壞死病例. P 值爲四組的比較 (Fisher 的測試節錄 ) Gnant M, 主編 : 2008 年,ASCO 會, 芝加哥, IL. LBA4 節錄彙報

115 Conclusion At a median follow-up of 5 years, in the cohort of patients who received zoledronic acid, 845 of 899 patients (94.0%) were disease-free and 883 of 899 (98.2%) were alive. In conclusion, in premenopausal women with endocrineresponsive early breast cancer, the addition of zoledronic acid to endocrine therapy significantly improved disease-free survival. The addition of zoledronic acid (4mg, every 6 months) to adjuvant endocrine therapy increased the rate of disease-free survival and recurrence-free survival, as compared with endocrine therapy alone a reduction in the risk of disease progression by 36% (Hazard ratio= 0.64; P =.01) reduced the risk of recurrence by 35% (Hazard ratio = 0.65; P =.015 The addition of zoledronic acid reduces risk of bone metastases Gnant M, 主編 : 2008 年,ASCO 會, 芝加哥, IL. LBA4 節錄彙報

116 Metastatic Breast Cancer

117 Metastatic Breast Cancer Local recurrence Lymph node Bone Liver Lung Brain

118 Treatment objectives Decrease tumor bulk relieve symptoms Extend patient s life span and increase overall survival (median survival ~2-3 years) In some low tumor burden cases, the tumor may enter resting state, or can be cured

119 Investigations for metastatic breast cancer Biopsy ER, PR, HER-2 To examine the extend of metastases: Lung, liver, bone, brain (X-ray, U/S, CT, PET-scan) Tumor markers(ca 15.3, CA 27.29) Body health check: LRFT, lung & cardiac funtions, CBC, calcium, Hep.B status

120 Treatment for metastatic breast cancer Treatment options : Chemotherapy Hormonal therapy Targeted therapy Radiotherapy Surgery Other adjuntive treatments: bisphosphonates,or,denosumab, pain killers

121 Treatment of metastatic breast cancer Metastatic breast cancer ER+, low grade with bone & soft tissue involvement ER+ / ER-, high grade with lung & liver involvement Hormonal therapy For HER-2 mutation test If +ve Herceptin and/or lapatinib chemotherapy

122 METASTATIC BREAST CANCER CRITERIA FOR SELECTION OF A CHEMOTHERAPY Activity Prior therapies Performance Status, Age Co morbidities: Cardiac disease, peripheral vascular disease, diabetes Patient Considerations: Convenience, route of administration Risk of febrile neutropenia Other toxicity profile: Peripheral neuropathy, Mucositis, Hand-Foot Foot-Syndrome, Diarrhea Physical appearance: Alopecia, i.v.. Port

123 Metastatic CA breast(mbc) Chemotherapy-combination of drugs-aim for high RR within short time-for visceral metastases;rapid disease tempo; avoid previously used drugs in the adjuvant setting or previous lines of treatment for the MBC Role of bevacizumab(avastin) Role of anti-her2 (trastuzumab/lapatinib/tdm1/pertuzumab)

124 EFFICACY OF CURRENT CHEMOTHERAPIES IN MBC: 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% NAVELBINE NAVELBINE NVB* DCT PCT DOX EPI NVB** 5-FU CAP (* first line / **subsequent) ORR in 1 st LINE Review by G. Hortobagyi, ASCO 2003 Educational Session

125 PROLONGATION MAINTENANCE TREATMENT in MBC More versus fewer cycles of chemotherapy for MBC: longer TTP and survival advantage for patients randomised to longer duration of CT (MS 23% longer). «The combined evidence from these metanalysis supports a policy of continuing chemotherapy in the absence of disease progression or unacceptable toxicity.» Coates, ASCO 03 Gennari, ASCO 08

126 PROLONGATION OF TREATMENT Cardiac toxicity risk: anthracycline cumulative dose: Doxorubicin Epirubicin 550 mg/m mg/m 2 Toxicity risk linked to the prolonged use of taxanes: Docetaxel Paclitaxel risk of cumulative fluid retention risk of cumulative neurotoxicity De Vita, 6th ed 2000; Sikov, ASCO 2002; Gauzina, Tumon 85; Von Hoff, Ann. Intern. Med 79

127 NAVELBINE MAINTENANCE TREATMENT NAVELBINE: a major drug for breast cancer treatment (high ORR, long duration of response). NAVELBINE: 30 mg/m²/week. /week. No cumulative toxicity with NAVELBINE. Only one weekly administration, outpatient treatment. Hortobagyi, ASCO 2003; Fumoleau, JCO 1993; De Vita, 6 th edition 2001

128 NAVELBINE IV + CAPECITABINE (NAVCAP) IN FIRST LINE : R Ph II + SEQUENTIAL TAXOTERE Toxicity G3-4 (% pts) NAVCAP NAVCAP TXT Evaluable pts Neutropenia 10 6 Anemia 5 9 Diarrhea 0 0 Nausea / Vomiting 0 0 Ghosn, SABCS 2008, abst. 6116

129 Targeted therapy Targeted therapy has minimal effect on normal cells of the body only act against the molecules of cancer cells or interfere the growth process of cancer cells HER 2 positive (HER2+): Herceptin/lapatinib It acts on the EGFR HER2 protein and inhibit the proliferation of breast cancer caused by the overexpression of HER2 HER 2-negative (HER2-) : Avastin angiogenesis inhibitor

130 TRASTUZUMAB AND CHEMOTHERAPY In n vitro activity against HER2+ breast cancer cell lines Synergistic Vinorelbine Docetaxel Endoxan Peg-Doxorubicin Additive Doxorubicin Epirubicin Paclitaxel Antagonistic Methotrexate Gemcitabine Fluorouracil Pietras et al., Oncogene 1998 ; Pegram et al., Oncogene 1999 ; Konecny et al., Breast Cancer Research Treatment 1999

131 HER2-positive metastatic breast cancer

132 Herceptin ( 赫賽汀 ) 單一 使用對轉移性 HER-2 型乳癌 療效臨床研究結果 單一使用 Herceptin 在 HER-2 型的乳癌病人 Herceptin 乳癌病人 35% 的 HER2 型病人有療效癌細胞有 50% 或以上的萎縮或被控制

133 Herceptin ( 赫賽汀 ) 對轉移性 HER-2 型乳癌療效對比臨床研究結 果 混合使用 Herceptin +paclitaxel ( 紫杉醇 ) 的乳癌病人比單一使用 paclitaxel ( 紫杉醇 ) 多 2 倍以上的病人癌細胞有 50% 或以上的萎縮或被控制 Herceptin +paclitaxel paclitaxel 49% 乳癌病人 17%

134 Herceptin ( 赫賽汀 ) 對轉移性 HER-2 型乳癌臨床研究結果 混合使用 Herceptin +paclitaxel ( 紫杉醇 ) 持續有效時間中位數為 7.1 個月對比單一使用 paclitaxel 為 3 個月

135 Herceptin ( 赫賽汀 ) 對轉移性 HER-2 型乳癌臨床研究存活率對比 結果 單一使用 paclitaxel ( 紫杉醇 ) 和混合使用 paclitaxel ( 紫杉醇 ) + Herceptin 存活率對比 無惡化存活率 (%) 紫杉醇 Herceptin + 紫杉醇 時間 ( 月 )

136 Herceptin ( 赫賽汀 ) 對轉移性 HER-2 型乳癌療效對比臨床研究結 果 混合使用 Herceptin +docetaxel 的乳癌病人比單一使用 docetaxel 多 2 倍的病人癌細胞有 50% 或以上的萎縮或被控制 Herceptin +docetaxel 61% docetaxel 乳癌病人 34%

137 Herceptin ( 赫賽汀 ) 對轉移性 HER-2 型乳癌臨床研究結果 混合使用 Herceptin +docetaxel 持續有效時間中位數為 11.7 個月對比單一使用 docetaxel 為 6.1 個月

138 最新研究顯示曾經接受 Herceptin HER2 型病人在復發後繼續使用 Herceptin 仍然有效

139 GBG-26 Herceptin 顯著地增加離疾病惡化時間 (31%) 機會率 % a a 時間 ( 月 ) Herceptin + Xeloda (n=78) Xeloda (n=78) HR=0.69 (2-sided p=0.034; 1-sided p=0.015) a Median TTP in months TTP, time to progression; HR, hazard ratio von Minckwitz et al. J Clin Oncol 27:2000-6,

140 荷爾蒙受體 (ER+) 呈陽性的晚期乳癌病人 聯合針對生長受體因子聯合針對生長受體因子 的臨床證據 研究名稱 TAnDEM Obsborne et al Cristofanilli et al 療法 Anastrozole +/- Herceptin Tamoxifen +/- gefitinib Anastrozole +/- gefitinib 病人數病人類別目 無惡化存活期 PFS ( 月 ) 內分泌治療內分泌治療 + 抗 ErbB 治療 陽性 HER * 4.8* 治療意向分析陽性 HER2 組 治療意向分析 * 確定 ER 狀態後, 增加了無惡化存活期 3.8 vs 5.6 月

141 Lapatinib ( 拉帕替尼 ) Target agent oral Bind to the EGFR (epidermal growth factor receptor)and HER-2(human epidermal growth factor receptor 2), inhibiting the action of tyrosine kinase and hinder the message transmission, so as to inhibit the growth of tumor cells Can only be used in HER2+ve end-stage or metastatic breast cancer. Lapatinib can be used together with Capecitabine, or in patients previously treated with Anthracycline, Taxane or Trastuzumab. Side effects include diarrhoea, nausea, vomiting, mucositis, HFS, skin itchiness, tiredness

142 Vascular Endothelial Growth Factor (VEGF) (VEGF) stimulates vasculogenesis and angiogenesis Vasculogenesis and angiogenesis of tumor VEGF Adapted from Bergers, et al. Nature 2002

143 VEGF is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. VEGF receptor Signal transmission

144 Angiogenesis leads to the growth of tumor cells and metastases New vessel Tumor cells

145 Blocking VEGF may lead to apoptosis of vascular endothelial cells VEGF the endothelial cells bleb VEGF receptor

146 Avastin 抑制血管生成的過程 A C B D A. Normal vessel B. Effective inhibition of early and metastatic tumor growth through prevention of cancerous angiogenesis C. 減低血管滲透性及癌腫瘤內的壓力, 能有助改善其他抗癌藥物進入腫瘤內發揮效用 D. 令癌腫瘤的血管萎縮, 使腫瘤有機會進入靜止狀態 Jain RK. Nat Med. 2001;7:

147 多項第三期乳癌研究的結果 證實 Avastin 用於擴散性乳癌一線治療的療效

148 第三期研究結果證實 Avastin 用於擴散性乳癌一線治療的療效 E2100 研究 1,2 第三期 開放性 隨機抽樣的研究 (Avastin + 紫杉醇類化療 Vs 單獨接受紫杉醇化療 ) AVADO 研究 3 第三期 多中心試驗 隨機抽樣 雙盲對照的研究 (Avastin + 多西紫杉醇類化療 Vs 安慰劑 + 多西紫杉醇 ) RIBBON-1 研究 4 第三期 隨機抽樣 雙盲對照 針對化療的研究 ( 紫杉醇 / 小紅莓類化療及 Xeloda + Avastin) 1. Miller, et al. NEJM 2007 ; 2. Klencke, et al. JCO 2008; Miles, et al. ASCO 2008; N. Robert, et al. ASCO 2009

149 E2100 研究 : 決定性研究批准 Avastin 用於擴散性乳癌一線治療 ( 紫杉醇化療 paclitaxel ± Avastin) 局部復發或擴散性乳癌的一線治療 (N=722) * 紫杉醇化療 : 90mg/m 2 /w for 3 weeks of a 4-week cycle 紫杉醇化療 * (n=354) 紫杉醇化療 * + Avastin (n=368) 10mg/kg q2w 治療直至疾病 / 腫瘤惡化 沒有交叉試驗 治療直至疾病 / 腫瘤惡化 主要研究目的 : 無病變存活期 (PFS) 次要研究目的 : 整體反應率 (ORR) 整體存活期 (OS) 生活質素 (QoL) 安全性 (safety) Miller, et al. NEJM 2007

150 60 50 整體反應率 (%) E2100 研究 :Avastin 能有效增 加腫瘤的整體反應率 22% 50% p< 紫杉醇化療病人 = 243* Avastin + 紫杉醇化療病人 = 229* IRF = 獨立審閱評核 Independent Review Facility * 病人的病情在某一階段會被評估 Klencke, et al. ASCO 2008

151 1.0 E2100 研究 :Avastin 有效提升無病變存活期 (PFS) (Avastin 加紫杉醇化療 ) 無病變存活期 (PFS) 個月 11.3 個月 無病變存活期 紫杉醇化療 (n=354) Avastin 加紫杉醇化療 (n=368) 風險值 (HR)=0.48 p< 時期 ( 個月 ) Klencke, et al. ASCO 2008

152 AVADO 研究 : 進一步肯定 Avastin 加化療藥物的治癌療效 局部復發或擴散性乳癌的一線治療 (N=736) 安慰劑 + 多西紫杉醇類化療 * q3w x 9 (n=241) Avastin ( 劑量 7.5mg/kg)+ 多西紫杉醇類化療 * q3w x 9 (n=248) 安慰劑 (3 個星期一次 ) Avastin ( 劑量 7.5mg/kg) (3 個星期一次 ) 治療直至疾病 / 腫瘤 惡化 * 多西紫杉醇類化療 : 100mg/m 2 q3w Avastin ( 劑量 15mg/kg)+ 多西紫杉醇類化療 * q3w x 9 (n=247) Avastin ( 劑量 15mg/kg) (3 個星期一次 ) 腫瘤惡化後, 所有病人可選擇接受 Avastin 於第二線的化療 主要研究目的 : 無病變存活期 (PFS) 次要研究目的 : 反應率 (RR) 反應時期 (duration of response) 整體存活期 (OS) 生活質素 (QoL) 安全性 (safety) Miles, et al. ASCO 2008

153 100 AVADO 研究 : Avastin 能有效增加腫瘤整體反應率 整體反應率 (%) 40 44% 55% (p=0.0295) 63% (p=0.0001) 20 0 安慰劑 + 多西紫杉醇 Avastin ( 劑量 7.5) + (n=207*) 多西紫杉醇 (n=201*) * 病人的病情在某一階段會被評估 ; mg/kg q3w Avastin ( 劑量 15) + 多西紫杉醇 (n=206*) Miles, et al. ASCO 2008

154 AVADO 研究 : Avastin 有效提升無病變存活期 (PFS) 1.0 Avastin 15mg/kg q3w + docetaxel (n=247) 0.8 Placebo + docetaxel (n=241) Stratified HR*=0.67 ( ), p= 無病變存活期 (PFS) 時期 ( 個月 ) *Censored for non-protocol therapy prior to progressive disease p values are of exploratory nature; HR = hazard ratio Pivot, et al. ASCO 2009

155 整體反應率 (%) 多項第三期研究測試不同化療方案的整體反應率 ( 擴散性乳癌一線治療 ) 單一化療兩藥化療 ( 紫杉醇類 ) ( 紫杉醇類 ) 單一紫杉醇類化療單一多西紫杉醇類化療 * * * * 多西紫杉醇 + 卡培他濱紫杉醇 + 吉西他濱多西紫杉醇 + 吉西他濱 * Avastin + 紫杉醇類化療 Avastin + 紫杉醇 Avastin + 多西紫杉醇 * * * 0 Albain, et al E2100 (Klencke, et al. 2008) O Shaughnessy, et al (31% first-line) AVADO (Miles, et al. 2008) O Shaughnessy, et al (35% first-line) Chan, et al Albain, et al 不同的第三項臨床研究 Chan, et al E2100 (Klencke, et al. 2008) AVADO (15mg/kg q3w) (Miles, et al. 2008)

156 多項第三期研究測試不同化療方案的無病變存活期 (PFS) ( 擴散性乳癌一線治療 ) 15 無病變 10 存活期 ( 月 ) 單一化療 ( 紫杉醇類 ) 單一紫杉醇類化療單一多西紫杉醇類化療 兩藥化療 ( 紫杉醇類 ) 多西紫杉醇 + 卡培他濱紫杉醇 + 吉西他濱多西紫杉醇 + 吉西他濱 Avastin + 紫杉醇類化療 Avastin + 紫杉醇 Avastin + 多西紫杉醇 5 0 Albain, et al E2100 (Klencke, et al. 2008) O Shaughnessy, et al (31% first-line) AVADO (Miles, et al. 2008) O Shaughnessy, et al (35% first-line) Chan, et al Albain, et al 不同的第三項臨床研究 Chan, et al E2100 (Klencke, et al. 2008) AVADO (15mg/kg q3w) (Miles, et al. 2008)

157 第 3 級或以上的不良反應 / 事件, % 安慰劑 + 化療 (n=233) AVADO 1 研究 Avastin 化療 (n=250) Avastin 15 + 化療 (n=247) 安慰劑 (n=348) E * 研究 Avastin 10 + 化療 (n=363) 中性血細胞減少症 嗜中性白血球低下症 Avastin 與紫杉醇類化療 : 較少出現不良副作用, 安全性高 蛋白尿 高血壓 出血 傷口癒合感染 腸道破裂 充血性心臟衰竭 動脈血栓栓塞 靜脈血栓栓塞 mg/kg q3w; mg/kg q2w 1. Miles, et al. ASCO 2008; 2. Miles. Eur J Cancer Suppl 2008

158 E2100 及 AVADO 研究總結 Avastin 加紫杉醇類化療的治療組合比單獨接受化療更能提升 : 無病變存活期 (PFS) 及腫瘤的整體 (ORR) 1,2 治療組合的對治療的安全性較少影響, 常見的不良反應包括 : 高血壓 蛋白尿或鼻出血 一般而言, 不良反應都能以標準藥物, 作適當處理 2,3 1. Klencke, et al. JCO 2008; 2. Miles, et al. ASCO 2008; 3. Kabbinavar, Shah. Cancer Therapy 2008

159 RIBBON-1 研究 : 第三期研究 Avastin 用於擴散性乳癌的一線治療 小紅莓類或紫杉醇類化療組合 小紅莓或紫杉醇類化療 + Avastin 15mg/kg q3w 未曾接受治療 HER2 陰性擴散性乳癌 (N=1,200) 小紅莓或紫杉醇類化療 + 安慰劑 q3w 卡培他濱化療組合卡培他濱 + Avastin 15mg/kg q3w 卡培他濱 + 安慰劑 q3w 治療直至疾病 / 腫瘤惡化 * * 繼續療程或轉用 Avastin ( 經過研究人員的處理 )

160 整體反應率 卡培他濱 p= 紫杉醇類化療 p= 完全反應部份反應 整體反應率 (%) 安慰劑 Avastin 安慰劑 Avastin n= Includes only patients with measurable disease at baseline. N. Robert, et al. ASCO 2009

161 無病變存活期 (PFS) 紫杉醇類 / 小紅莓類化療 : 無病變存活期 (PFS) 安慰劑 Avastin (n=207) (n=415) 中位數 ( 月 ) 風險值 (95% CI) 0.64 ( ) p- 值 p< 中位數 ( 月 ) 風險值 (95% CI) 0.77 ( ) p- 值 p=0.040 INV IRC 時期 ( 個月 ) N. Robert, et al. ASCO 2009

162 卡培他濱 : 無病變存活期 (PFS) 無病變存活期 (PFS) 安慰劑 (n=206) Avastin (n=409) 中位數 ( 月 ) 風險值 (95% CI) 0.69 ( ) p- 值 p= 中位數 ( 月 ) 風險值 (95% CI) 0.68 ( ) p- 值 p= INV IRC 時期 ( 個月 ) N. Robert, et al. ASCO 2009

163 反應 (%) 卡培他濱紫杉醇類化療小紅莓類化療安慰劑 Avasti 安慰劑 Avasti 安慰劑 Avasti (n=201)(n=404) (n=102)(n=203) (n=100)(n=210) 出血反應 發熱性嗜中性球減少症 RIBBON-1 研究 : 第三級以上的不良反應 腸道破裂 高血壓 左心室功能障礙 中性血細胞減少症 蛋白尿 感覺神經元病變 靜脈血栓栓塞 N. Robert, et al. ASCO 2009

164 RIBBON-1 研究結果 第三期隨機抽樣臨床研究 RIBBON-1, 證實 Avastin ( 為 VEGF 直接抑制劑 ) 配合化療使用, 用於擴散性乳癌一線治療的治癌療效和安全性 RIBBON-1 研究亦再次證實 Avastin 配合非紫杉醇類化療藥, 用於擴散性乳癌一線治療的療效 Avastin 配合化療的安全性與其他第三期臨床試驗相若 N. Robert, et al. ASCO 2009

165 MBC Hormone treatments-as long as the tumor is ER+ and in the absence of indications for chemotherapy;adequate trial of each line of hormone;sequencing and rechallenge Role of m-tor inhibition and anti-igfr treatments

166 FASLODEX: Trial Designs Trial 0020: International, randomised 1:1, open, parallel-group Trial 0021: North American, randomised 1:1, double-blind, double-dummy, parallel-group Recruitment between May 1997 and August 1999 Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer FASLODEX 250mg i.m. once monthly Trial 0020: 1 x 5ml (n=222) Trial 0021: 2 x 2.5ml (n=206) ARIMIDEX 1mg daily, orally Trial 0020: (n=229) Trial 0021: (n=194) Analysis after 340 events (progression or death prior to progression)

167 FASLODEX: Trials 0020 & 0021 Patient Characteristics FASLODEX (n=428) ARIMIDEX (n=423) Mean age (years)/range Mean weight (kg)/range Hormone receptor status (%) ER and/or PgR+ve ER/PgR unknown ER/PgR ve Prior treatment (%) Cytotoxic chemotherapy Endocrine therapy for advanced disease Adjuvant endocrine therapy 63 (33 89) 63 (33 94) 70 (37 127) 70 (40 134) Robertson JFR, et al. Cancer 2003; 98:

168 FASLODEX: Trials 0020 & 0021 Time to Progression (TTP) Trial 0020 Trial 0021 Proportion without progression Median TTP: FASLODEX 5.5 months (n=222) ARIMIDEX 5.1 months (n=229) Time to progression (months) Median TTP: FASLODEX 5.4 months (n=206) ARIMIDEX 3.4 months (n=194) Time to progression (months) Hazard ratio (95% CI): 0.98 ( ); p=0.84 Hazard ratio (95% CI): 0.92 ( ); p=0.43 FASLODEX 250mg ARIMIDEX 1mg Howell A et al. J Clin Oncol 2002; 20: Osborne CK et al. J Clin Oncol 2002; 20:

169 Evaluation of FASLODEX and Exemestane Clinical Trial: Rationale Postmenopausal women with hormone receptor-positive advanced breast cancer, with disease progressing after prior NSAI therapy (USA/Europe/ROW) FASLODEX (LD)* + placebo for exemestane (n=351) exemestane 25mg orally daily + placebo for FASLODEX (n=342) Primary endpoint: TTP LD 500mg i.m. at day mg i.m. at days 14 and 28, thereafter 250mg i.m. monthly until progression Chia et al. J Clin Oncol Published Ahead of Print as /JCO