現代醫學控制癌症的方法 Surgery Remove known tumor masses Radiation Chemotherapy Hormonal therapy 分子標靶治療 Kill rapidly dividing tumor cells, including tumor cells in adjacent tissues Kill rapidly dividing tumor cells Inhibit the growth and survival of hormone-dependent tumor cells 特異性地抑制腫瘤細胞生長所必需的分子路徑
化學治療 Chemotherapy 全身性的治療 相對藥物作用特異性不高 可使用劑量被可能毒性反應限制 療效也為潛在的或後天得來的抗藥性所限
化學治療可以 延長轉移患者的存活期 @ Primary chemotherapy 減輕癌症引起的不適 @ Palliative chemotherapy 增加手術或放射治療的療效 @ Neoadjuvant & adjuvant @ Concommitent radiosensitizer 改善臨床的治療方式
多變相的乳癌 ER/PR Status Menopausal Status Her2/neu Status Axillary Node Status Other Prognostic Factors Histological Feature Mastectomy /Lumpectomy +/-Axillary Dissection Radiation Therapy Adjuvant Therapy Chemotherapy regimen? Hormonal therapy Tamoxifen? AI? Neoadjuvant Therapy Sentinal Node Biopsy Biological Therapy HER2 IHC -FISH Herceptin Single/Chemo Combination Hormonal Therapy Palliative Therapy Chemotherapy regimen? Hormonal therapy? Chemotherapy regimen? Combo/sequence? Hormonal therapy Tamoxifen? AI? Sequence?
晚期乳癌化學治療的演進 Vinorelbine Jones 1995 Mitomycin C/ vinblastine Nabholtz 1999 Taxotere Nabholtz 1999 Melphalan Jones 1995 平均存活 (months) 6 7 8 9 10 11 12 13 14 15 16
E1193: Combination therapy more effective than sequential therapy? R A N D O M I Z A T I O N First-line Doxorubicin 60mg/m 2 Paclitaxel 175mg/m 2 Doxorubicin 50mg/m 2 + paclitaxel 150mg/m 2 + G-CSF Second-line Paclitaxel 175mg/m 2 Doxorubicin 60mg/m 2 Sledge G et al. J Clin Oncol 2003;21:588 92
晚期乳癌的化學治療 E1193 RR% CR% TTF(mo.) 存活期 (mo.) A 36 6 6 19.1 T 34 3 6.3 22.5 AT 47 9 8.2 22.4 P= A 0.017 T 0.006 A 0.002 T 0.057
Intergroup/ECOG 1193 Delay of disease progression but no impact on survival A Taxol TTF 6.0? Survival 19.1 R Taxol A TTF 6.3? Survival 22.5 ATaxol TTF 8.6 Survival 22.4 Median Months 0 2 4 6 8 10 12 14 16 18 20 22
Combinations... For Whom? Younger Patients? Visceral Dominant Disease? Aggressive Molecular Phenotype? Tempo of Disease Progression? Short relapse-free interval after adjuvant therapy? Lack of durable (or any) response to prior mono-chemotherapy for MBC? Rapid Volumetric tempo of progression?
Combination Chemotherapy Chemo-naïve: Anthracyclines containing regimens FAC, FEC Cardiac risk CMF Prior anthracyclines(s/p Adjuvant) XT (capecitabine/doxetaxel) GT (gemcitabine/paclitaxel)
>>2nd line Chemotherapy Prior anthracyclines(2 nd line) XT GT After Anthracyclines/taxanes Single agent preferred Capecitabine Navelbine
Chemotherapy for MBC Fragile patient, poor performance Usually single agent Consider liver and renal function Closed monitoring May worth trying due to good chance of response
Her-2(+) MBC Taxol (weekly) +/- Carboplatin Taxotere Navelbine In combination with Herceptin
乳癌輔助性化學治療可以 減少術後復發 增加治癒的機會
5-Year Survival 乳癌 : 五年存活期 相對於陽性淋巴結的數目 80% 60% 40% 20% 0% 0 1 2 3 4 5 6-10 11-15 16-20 >20 Number of Positive Nodes Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1557-1616.
10 年無病存活比率與淋巴結的數目 4 MDACC FAC Studies (N=982) Groups 1 2 3 4 第二期 1-3 64% 73% 86% 65% 4-10 55% 49% 56% 51% 10+ 36% 28% 22% 36% 第三期 32% 31% 37% 41% Buzdar A, et al, Adjuvant Therapy of Cancer VIII, 1997
Breast Cancer: Adjuvant CMF (12 months) or Surgery Alone All Patients Premenopausal % Relapse-free survival 100 CMF Surgery 100 % Overall survival CMF Surgery 50 50 51% 36% 35% LOG-RANK : P = 0.002 WILCOXON : P = 0.0001 26% LOG-RANK : P = 0.02 WILCOXON : P = 0.02 0 1 3 5 7 9 11 13 15 years 0 1 3 5 7 9 11 13 15 years Adapted from Bonadonna G. Cancer Res. 1992. BCIRG JUNE 23, 2002
BREAST CANCER Commonly assessed prognostic factors Number of positive axillary nodes Nuclear grade Tumor size Lymphatic and vascular invasion Histologic tumor type Estrogen/progesterone receptors HER2/neu overexpression Histologic grade Slamon DJ. Chemotherapy Foundation. 1999;46. Harris J, et al. Cancer: Principles & Practice of Oncology. 1997;1557-1616.
Disease-Free Survival: 1998 EBCTCG Meta-Analysis of Doxorubicin Polychemotherapy vs CMF Study Therapy N Better than CMF Worse than CMF NASBP B-15 4AC 3CMF vs 6CMF (+R) 1552/1562 SECSG2 6FAC vs 6CMF 260/268 ONCOFRANCE 12FACV vs 12CMF 138/113 Austrian BCSG 3 6CMFVA vs 6CMF 121/124 NSABC Israel 2CMF+4AVbCMF vs 6CMF 55/50 SE Swedenl 8AC vs 7CMF (+R) 21/22 Meta Analysis (6 studies) 2157/2129 0.91 P = 0.063 Analysis derived from EBCTCG Lancet. 1998; Data on file, Pharmacia 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Hazard Ratio (Compared to CMF)
Disease-Free Survival: 1998 EBCTCG Meta-Analysis of Epirubicin Polychemotherapy vs CMF Study Therapy Better than CMF N Worse than CMF NCI-C MA-5 6CEF vs 6CMF 356/360 Brussels, Belgium 8EC vs 6CMF 462/464 ICCG CharingCross 8/6FEC vs 6CMF 256/259 GABG Germany 6FEC vs 6CMF ( Tam) 142/146 GUN-3 Naples, Italy) 6CMFEV vs 6CMF 105/115 Meta Analysis (5 studies) 1321/1344 0.84 P = 0.030 Analysis derived from EBCTCG Lancet. 1998; Data on file, Pharmacia 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Hazard Ratio (Compared to CMF)
NCIC CTG MA.5 Trial: CEF-120 vs CMF in Node-Positive Breast Cancer N = 710 Patient Population Pre- or perimenopausal Node-positive Stratification Total vs partial mastectomy HR status No. + nodes R A N D O M I Z A T I O N * No prophylactic G-CSF administered. Levine et al. J Clin Oncol. 1998;16:2651-2658. C 75 mg/m 2 po q d days 1 14 E 60 mg/m 2 IV days 1 and 8 q 4 wk x 6 F 500 mg/m 2 IV days 1 and 8 + Prophylactic antibiotics* C 100 mg/m 2 po q d days 1 14 M 40 mg/m 2 IV days 1 and 8 q 4 wk x 6 F 600 mg/m 2 IV days 1 and 8 = Cyclophosphamide = Epirubicin = Fluorouracil = Methotrexate
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: 1-3 4+ Center T A C Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, day 5-14
NSABP B-31 Control: AC T Arm 1 Arm 2 NCCTG N9831 Arm A Arm B Investigational: AC T+H Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
Can Doxorubicin Be Eliminated? BCIRG 006 AC T 4 x AC 4 x Docetaxel 60/600 mg/m 2 100 mg/m 2 HER2 + FISH N=3150 AC TH TCH 1 Year Trastuzumab 6 x Docetaxel and Platinum salts 75 mg/m 2 75 mg/m 2 or AUC 6 1 Year Trastuzumab
傳統化學治療藥物 非特異性及細胞毒殺 對正常組織也有作用 療效與腫瘤特性有關 腫瘤縮小 視為療效 有療效 不見得存活上有助益
標靶治療 選擇性的同時也是 Cytostatic 毒性低 有標靶才有活性 療效 不一定須見到腫瘤縮小
化學治療的演進 目前在使用的藥物 Biosynthetic Enzymes DNA Topoisomerase Tubulin Hormonal Manipulation 發展中的藥物 Signal Transduction (Her2, EGFR) Angiogenesis (MMPI S, VEGF) Cell Cycle (cdk s) Apoptosis (bcl2) Immunotherapy /Vaccines Gene Therapy/Antisense Monoclonal Antibodies
癌細胞相關重要分子路徑 Aberant signal transduction Growth factor and receptor deregulation Autocrine growth factor secretion Angiogenic factors secretion Matrix Metaloproteinase secretion Oncogene expression Loss of tumor supressor genes
理想的標靶藥物 大部分有該癌症的患者均有存在 標靶與腫瘤發生或形成相關 對腫瘤細胞而言是必須的 正常細胞不須此標靶相關的功能
表皮生長因子藉接受器將訊號傳入細胞而引起反應 細胞膜 B1 B1 抗凋亡 Anti-Apoptosis 細胞核 細胞分裂 組織侵犯 分泌生長因子 轉移
乳癌的 Her-2 表現增加會引起 HER2 overexpression is the result of HER2 gene amplification 3 1. Gene amplification increased gene copies 2. 增加 mrna transcription 3. 增加 HER2 受體的數目 protein overexpression 4. Released extracellular domain (ECD, sher2) 1 2 4
Effect of HER2 amplification on human breast cancer cells Human breast cancer cells DNA synthesis 50 75% Cell growth rate 30 50% MCF-7 HER2 ve Transfect with HER2 gene MCF-7 HER2 +ve Growth in soft agar 225% Tumourigenicity in nude mice Metastatic potential 220% in nude mice Transformed phenotype
Cumulative probability 1.00 Her-2 表現程度與早期乳癌手術後的預後有關 Not amplified 0.75 0.50 Amplified 0.25 0 Amplified: >10 copies/nucleus Not amplified: <3 copies/nucleus Borderline: excluded Log rank p<0.001 0 24 48 72 96 120 144 Time to death (months) Ross JS, Fletcher JA. Stem Cells 1998; 16: 413 428
Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 Targets HER2 protein High affinity (K d = 0.1 nm) and specificity 95% human, 5% murine Decreases potential for immunogenicity Increases potential for recruiting immune effector mechanisms
Probability of survival Herceptin 在晚期乳癌 合併使用化學治療的療效 FISH+ FISH 1.0 Trast. + CT (n = 176) CT (n = 169) 1.0 Trast. + CT (n = 50) CT (n = 56) 0.8 RR = 0.71 p = 0.007 0.8 RR = 1.11 p = NS 0.6 0.4 20.0 mo 26.2 mo 0.6 0.4 19.8 mo 24.0 mo 0.2 0.2 0 0 10 20 30 40 50 0 0 10 20 30 40 50 Months Months Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.
晚期乳癌的化學治療 M77001 HER2-positive MBC (IHC 3+ and/or FISH+) n=188 n=94 Two patients did not receive study medication n=92 Docetaxel* 100mg/m 2 q3w x 6 *Patients progressing on docetaxel alone could crossover to receive Herceptin Docetaxel 100mg/m 2 q3w x 6 + Herceptin 4mg/kg loading, 2mg/kg weekly until PD
Estimated probability M77001: 疾病平均惡化期 1.0 0.8 Herceptin + docetaxel Docetaxel alone 0.6 0.4 0.2 0 p=0.0001 5.7 10.6 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Intent-to-treat population, 12-month cut-off
Estimated probability M77001: 存活期比較 1.0 0.8 Herceptin + docetaxel Docetaxel alone 0.6 0.4 0.2 p=0.0062 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 8.4 months Intent-to-treat population, 12-month cut-off Documented crossover = 48% 22.1 30.5
M77001: 治療效果總結 Outcome Herceptin + docetaxel (n=92) Docetaxel alone (n=94) p-value 緩解比率 61.0 34.0 0.0002 DR (median, months) 11.4 5.1 0.0011 TTP (median, months) 10.6 5.7 0.0001 平均存活期 30.5 22.1 0.0062 *Kaplan-Meier estimate Intent-to-treat population, 12-month cut-off
NSABP B-31 Control: AC T Arm 1 Arm 2 NCCTG N9831 Arm A Arm B Arm C Investigational: AC T+H = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
THE HERA TRIAL Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 1 year Observation
Does adjuvant trastuzumab improve disease-free survival? 輔助性的治療可否延長無病存活期? 使用 Herceptin 可否減少復發甚至避免復發?
Disease-Free Survival AC TH % AC T 87% 75% 85% 67% N Events AC T 1679 261 AC TH 1672 134 HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831
% alive and disease free 乳癌的術後輔助化學治療無病存活期
Ethnic Difference Japanese Study 1 Carolina Breast Cancer Study 2 Japanese Non-AA AA No. of Pts. 793 300 196 Luminal A 63.3% 54.0% 47.4% Luminal B 19.5% 17.3% 12.8% HER2+/ER- 6.9% 5.7% 8.2% Basal-like 8.4% 16.0% 26.5% Unclassified 1.8% 7.0% 5.1% Prognosis Good Poor 49