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Treatment of Early Breast Cancer 臺大醫院 腫瘤醫學部 盧彥伸 Outlines • Overview: – 重要性 (significance) – Inside breast tissues – Types of breast cancer • Work-up: – Diagnosis – Staging g g • Treatment modalities – Surgery – Radiotherapy – Systemic therapies: hormonal therapy, therapy chemotherapy, antibody against HER2, and others. • Treatment T t t off various i subgroups of breast cancer 台灣男女性10大癌症發生分率, 民國93、94年 (發生人數)部位 百分比 百分比 部位(發生人數) (7,051、 7,159)肝 18、18 21、22 乳房 (6,176、6,593人) (5,426、5,497 )結腸及直腸 14、14 14、14 結腸及直腸(4,109、4,107人) ( 5,537、 5,566)肺 14、14 10、9 肝(2,779、 2,757人) (4,363、4,310)口腔 11、11 9、9 肺(2,605、 2,746人) (2,660、2,704)攝護腺 7、7 8、7 子宮頸(2,292、 1,977人) (2,380、2,288)胃 6、6 5、4 胃(1,338、 1,292人) (1,374、1,403)食道 4、4 4、4 甲狀腺 (1,132、 1,146人) (1,380、1,363)膀胱 4、3 3、4 皮膚(965、 1,039人) (1,196、1,139)皮膚 3、3 3、3 子宮體(877、 987人) (1,123、1,123)鼻咽 3、3 3、3 卵巢 (841、 894人) (6,585、6,879)其他癌症 16、17 20、20 其他癌症(5,707、5,938人) 男性共(39,075、 39,431人) 備註:口腔癌含下咽及口咽 女性共(28,821、29,476人) 民國95年主要癌症死亡原因 順位 1 2 3 4 5 6 7 8 9 10 癌症死亡原因 肺癌 肝癌 結腸直腸癌 女性乳癌 胃癌 口腔癌 攝護腺癌 子宮頸癌 食道癌 胰臟癌 其他 所有癌症死亡原因 死亡人數 7,479 7,415 4,284 1,439 2 398 2,398 2,202 957 792 1,304 1,247 8,481 37,998 每十萬人口 死亡百 死亡率 分比% 32.8 19.7 32.5 19.5 18.8 11.3 12.8 3.8 10 5 10.5 63 6.3 9.6 5.8 8.3 2.5 7.0 2.1 5.7 3.4 5.5 3.3 37.2 22.3 166.5 100.0 Breast cancer: incidence increases; mortality declines in developed countries Taiwan Case No. Incidnce Mortality Patients diagnosed with breast cancer Patients died of breast cancer 5,339* 1,439 48.38* 12.9 212,930 , 40,870 , ~ 150 ~ 28 Crude rate 5 (per 10 population) U.S.# Case No. Crude rate 5 (per 10 population) * data of year 2002; the other data are for year 2005. # Estimated data of the American Cancer Society for US in year 2005 Note: In US, breast cancer is the most common malignancy in women and is second only to lung cancer as a cause of cancer death. Age-specific g p Breast Cancer Incidence 600.0 500.0 American Caucasion 400.0 台灣1994 300.0 台灣1998 台灣2002 200.0 台灣2005 100.0 00 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+ 年齡 Introduction Breast tissue and draining g lymphatics y p I Increase meatt consumption ti Decrease of fertility rate Increase age at firstfirst-term pregnancy and decrease dec ease n number mbe of pa parity it Decrease age g at menarche 急速增加的台灣年輕女性乳癌是否 單純是西方化生活方式所造成?? 單純是西方化生活方式所造成 台灣女性乳癌年齡別發生率 140.0 120.0 100 0 100.0 台灣女性結腸、直腸、乙狀結腸 連結部及肛門癌年齡別發生率 350.0 19811985 19861990 300.0 19811985 19861990 250 0 250.0 80.0 200.0 60.0 150 0 150.0 40.0 100.0 20.0 50 0 50.0 0.0 0.0 年齡(歲) 依發生年代分,1981-2005年 年齡(歲) 每十萬人口發生率 MacMahon et al, 1970 Age--specific rate: Female Age Korea 2006 許多亞洲國家有類似鐘型的乳癌年齡別發生率曲線 Shin HR et al, Cancer Causes Control. 2010 Nov;21(11):1777-85. Molecular classification of breast cancer Carey et al, JAMA. 2006;295:2492-2502 Nielsen et al, CCR 2004; 10: 5367-5374 Molecular subtype distributions among African A Americans, i non-African nonAf i Americans A i and d Taiwanese T i Age ≤ 50 years or premenopausal women Carey et al, JAMA. 2006;295:2492-2502 Lin CH et al, Cancer Epidemiol Biomarkers Prev. 2009 ;18(6):1807-14 年齡別ER表現率的變遷: 由台大醫院兩個 已發表的研究世代所做的比較 P = 0.08 P < 0.001 P=0 0.40 40 Cohort 1 (n=481): Oncologist. 2008 Jul;13(7):751-60. Cohort 2 (n=1028): Cancer Epidemiol Biomarkers Prev. 2009 ;18(6):1807-14 Breast cancer in Taiwan does not fit the ER and age relationship described in textbook. Breast cancer- an evolving model of two diseases 飲食及飲食相關因子 賀爾蒙及生育因子 • 停經後肥胖 • 初經較早 • 停經前過瘦 • 停經較晚 • 西方飲食 輻射曝露 • 無生產紀錄 • 飲酒 • 較晚生第一胎 •少攝取蔬果 • 使用口服避孕藥 環境賀爾蒙 ?? 乳癌發生 家族乳癌病史 良性乳房疾病 Breast Cervix Uterus Ovary U US Taiwan n 證實荷爾蒙相關癌症於台灣年輕女性急速增加,也將 病因指向雌激素相關基因多樣性及環境荷爾蒙曝露 第一型子宮內膜癌 (雌激素依賴型腫瘤) 第二型子宮內膜癌 (雌激素不相關的腫瘤) Lin CH et al, Int J Cancer. 2011 Jun 23 [Epub ahead of print] Dx: pathology Types of breast malignancy diagnosed in Taiwan Dx: pathology Pathologic classification of carcinoma of the breast • Non-invasive carcinoma –Ductal carcinoma in situ –Lobular carcinoma in situ ~ WHO classification of carcinoma of the breast • Invasive carcinoma –Invasive ductal carcinoma –Invasive lobular carcinoma –Mucinous Mucinous carcinoma –Medullary carcinoma –Papillary Papillary carcinoma –Tubular carcinoma –Adenoid cystic carcinoma –Secretory (juvenile) carcinoma –Apocrine carcinoma –Metaplastic Metaplastic carcinoma –Inflammatory carcinoma Others (specify) –Others • Paget’s disease of the nipple Dx: clinical Cancer treatment bases on full knowledge of diagnosis and extent of disease…. • P Presentation: t ti symptoms t and d signs i • Diagnosis: – Diagnostic procedures – Pathology • Extent of disease (Staging): – Axillary A ill nodal d l status t t – Systemic evaluation Dx: clinical A breast lump or mass: the most common sign of breast cancer • Not everyy lump p is cancerous,, but it should p prompt p a medical evaluation. p , other signs g of breast cancer • In addition to lumps, include: – Swelling g in part p of the breast – Skin irritation or dimpling – Pain in the nipple or the nipple turning inward – Redness, itching or scaling of the nipple or breast skin – Discharge other than breast milk Dx: clinical Evaluation of a breast lump…. p • Medical history • Physical examination, including systemic and local examinations • Breast imaging studies – Mammography – Ultrasound and sonogram – MRI • Biopsy Any area that appears suspicious by being palpably abnormal or by radiological criteria deserves biopsy biopsybased diagnosis. Staging Staging g g of breast cancer • Staging= grouping of patients – Extent E t t off disease di ÆDifferent prognosis Æ ÆDifferent treatment strategies t t i • Based on history, physical exam, and the following t t may include: tests i l d – Blood tests – Chest Ch t X-ray X – Bone scan – CT – MRI – PET Staging AJCC staging of breast cancer, 6th edition diti published bli h d iin 2002 T CATEGORIES Tis T1 T2 T3 T4 Carcinoma in situ ≤ 2 cm in greatest diameter > 2 cm, but ≤ 5 cm > 5 cm Any size, with direct extension to chest wall or skin Stage N CATEGORIES g LN metastasis N0 No reginal Clinical N1 Ipsilateral axillary node(s), movable N2 Ipsilateral axillary node(s), fixed; Ipsilateral internal mammary nodes N3 Ipsilateral infraclavicular node(s); Ipsilateral supraclavicular node(s); Ipsilateral internal mammary nodes + axillary nodes M CATEGORIES M0 No distant metastasis M1 Distant metastasis T N M 0 Tis N0 M0 I T1 N0 M0 IIA T0 T1 T2 T2 T3 N1 N1 N0 N1 N0 M0 M0 M0 M0 M0 IIIB T0 T1 T2 T3 T3 T4 IIIC Any T N2 N2 N2 N1 N2 N1 N2 N3 M0 M0 M0 M0 M0 M0 M0 M0 IV Any T Any N M1 IIB Pathological pN1 1~ 3 lymph nodes pN2 4~ 9 lymph nodes IIIA pN3 ≥ 10 lymph nodes Prognostic factors Prognosis of breast cancer: markers on cancer cells • Markers on cancer cells // potential or risk of occult metastasis // susceptibility p y to current anti-cancer therapies p – Histologic type – Histologic grading: grade 1 to 3 – Proliferation rate – Lymphovascular invasion – ER and PR – HER2/neu – Others: tumor angiogenesis, p53, occult metastasis in bone marrow, marrow other molecular or genomic profiles…. profiles Non-invasive carcinomas Operable, p , loco-regional g invasive carcinomas T CATEGORIES Tis T1 T2 T3 T4 Carcinoma in situ ≤ 2 cm in greatest diameter > 2 cm, but ≤ 5 cm > 5 cm Any size, with direct extension to chest wall or skin Stage N CATEGORIES N0 No reginal LN metastasis Clinical N1 Ipsilateral axillary node(s), movable N2 Ipsilateral axillary node(s), fixed; Ipsilateral internal mammary nodes N3 Ipsilateral infraclavicular node(s); Ipsilateral supraclavicular node(s); Ipsilateral internal mammary nodes + axillary nodes M CATEGORIES M0 No distant metastasis M1 Distant metastasis T N M 0 Tis N0 M0 I T1 N0 M0 IIA T0 T1 T2 T2 T3 N1 N1 N0 N1 N0 M0 M0 M0 M0 M0 IIIB T0 T1 T2 T3 T3 T4 IIIC Any T N2 N2 N2 N1 N2 N1 N2 N3 M0 M0 M0 M0 M0 M0 M0 M0 IV Any T Any N M1 IIB Pathological pN1 1~ 3 lymph nodes pN2 4~ 9 lymph nodes IIIA pN3 ≥ 10 lymph nodes Inoperable, p , loco-regional g invasive carcinomas Metastatic carcinomas Treatment of cancer patients G l Vs. Goals V Strategies St t i Goal Parameters 做法(Strategies) Cure Long-term 竭盡所能達到 (痊癒) Survival prolongation (延長存活) Symptom y p p palliation (症狀緩解) disease-free disease free 治療的要求 Median survival N-year survival QOL (Quality of life) 考量病人的需求及 生活品質 Chemotherapy py for cancer patients p Goal 做法(Strategies) Cure 竭盡所能達到治療的要求: (痊癒) 標準的劑量, 強度, 療程,…… Survival prolongation ( (延長存活) ) Symptom palliation (症狀緩解) 考量病人的需求及生活品質: 劑量, 強度, 劑量 強度 療程 相對的不是那麼 重要 Tx modality: op Treatment of breast cancer Surgery of breast • Mastectomy: removal of the entire breast – Simple (Total) mastectomy: – Modified radical mastectom mastectomy: pl pluss axillary a illar lymph l mph node dissection • Radical mastectomy: plus removing all the muscle under the breast Radical mastectomyy is no longer g a standard procedure for breast cancer. Fisher s theory : operable breast cancer has Fisher’s distant micrometastasis at very early stages of breast cancer. cancer Levels Types yp of evidence I Meta analysis of multiple well Meta-analysis well-designed, designed, controlled studies. Randomized trials with low-false positive and low falsenegative errors (high power) II At least one well-designed experimental study. Randomized trials with high false-positive and/or negative errors (low power) III Well-designed, quasi-experimental studies such as nonrandomized, controlled, single group, pre-post, cohort, and time or matched case case-control control series IV Well-designed non-experimental studies such as comparative and correlational descriptive and case studies V Case reports Levels Types yp of evidence I 多個隨機臨床試驗 (Randomized controlled trials) 經由綜合 分析 ( Meta-analysis) 所獲得的結論 II 至少一個設計完整的隨機臨床試驗所獲得的結論 III 非隨機分配或無對照組的臨床試驗 流行病學或公共衛生的觀察、分析 IV V 病例報告 Op for early-stage Treatment of breast cancer Operable loco Operable, loco-regional regional invasive Ca. Ca • Local treatment: – Modified radical mastectomy ~~Breast-conserving surgery (lumpectomy+ axillary dissection+ whole breast irradiation) Table 33.2-11: Breast-Sparing Surgery with Radiation versus Mastectomy: 1995 National Cancer Institute Update Conference Deaths/Patients Study BCT with RT Mastectomy Difference / 90/430 77/429 / None 107/456 89/422 None 17/88 18/91 None NCI—Bethesda NCI Bethesda 14/121 17/116 None NCI—Milan 74/352 84/349 None 176/515 188/492 None 478/1962 473/1899 None Denmark EORTC Institut Gustave Roussy NSABPa Total ~ Table 33.2-11 in Principle and Practice of Oncology, 7th ed., Page 1436. Op for early-stage Treatment of breast cancer Operable loco Operable, loco-regional regional invasive Ca. Ca • Breast-conserving surgery: Absolute contraindications • Previous mod mod- or high high- dose RT to breast or chest wall • Pregnant • Diffuse suspicious or malignancy-appearing g y pp g microcalcifications on mammography • Widespread ds for which cosmetically single-excision is i impossible ibl Relative contraindications • Connective tissue ds ds. of skin • Tumors > 5 cm • Focally positive pathologic margins ~ NCCN treatment guidelines version2, 2006. Tx modality: RT Treatment of breast cancer Radiotherapy • As part of breast-conserving surgery: – Whole breast irradiation +/- a boost – Nodal irradiation? • Post-mastectomy radiation: – Radiation R di ti to t chest h t wallll + one or more regional i l lymph node areas • Palliative measures for symptomatic sites in advanced diseases Tx modality: RT • Simulation films for definitive RT to left breast tangent fields – A. Fluoroscopic simulation film – B. CT-simulated film. ~ Figure 33.2-4. in Principle and Practice of Oncology, 7th ed., Page 1440. RT for early-stage Treatment of breast cancer Operable loco Operable, loco-regional regional invasive Ca. Ca • Radiotherapy py – Mandatory for breast-conserving surgery – Post-mastectomy Post mastectomy radiation: irradiation to chest wall + one or more regional lymph node areas Postmastectomy radiotherapy ↓loco-regional recurrence ↑disease-free ↑overall survival ↑Cardio-pulmonary mortalityy ~ NCCN treatment guidelines version2, 2006. RT for early-stage Treatment of breast cancer Operable loco Operable, loco-regional regional invasive Ca. Ca • Post-mastectomy radiation: irradiation to chest wall + one or more regional i l llymph h node d areas – Lymph nodes ≥ 4(+) – Lymph nodes 1~ 3, but T≥ 5 cm or positive pathologic margins – Lymph node-negative, but T≥ 5 cm and positive or very close ((< 1 cm)) pathologic p g margin g • Timing: after finishing adjuvant chemotherapy ? Any lymph nodes 1~ 3 p internal mammaryy field ? Inclusion of ipsilateral ~ NCCN treatment guidelines version2, 2006. Tx modality: op Treatment of breast cancer Surgery of (axillary) lymph nodes • Removing lymph nodes: X improve the chance of long-term survival √pro ide prognostic information and help select √provide further therapy • Side effects: – Numbness in the skin on the inside of the upper arm – Limitation of shoulder movements – Lymphedema: 10% of women receiving axillary lymph node dissection Op for early-stage Treatment of breast cancer Operable loco Operable, loco-regional regional invasive Ca. Ca • Axillaryy lymph y p node dissection – Standard approach: a formal level I and level II dissection of ≥ 10 lymph nodes; level III nodes need to be dissected when gross disease is apparent. – Sentinel lymph node dissection: considered as an option for certain group of patients. ~ NCCN treatment guidelines version2, 2006. Tx modality: op Treatment of breast cancer Surgery of (axillary) lymph nodes • Sentinel lymph node dissection: 手術後的全身性輔助性 (adjuvant) 治療 Fisher’s theoryy : operable p breast cancer has distant micrometastasis at very early stages of breast cancer. Introduction • Adjuvant systemic treatment: (chemotherapy / endocrine therapy) – Aim: to eradicate “micrometastasis” • No target to evaluate efficacy – End-point: End point: • Disease-free survival • Overall survival – Long g wayy to g go 乳癌術後的輔助性治療 • • • • 化學治療 荷爾蒙治療 放射線治療 其他 • 減少局部復發及 遠處轉移 • 延長無病存活期 間 (disease-free survival) i l) • 增加治癒率 Systemic Tx Treatment of breast cancer Systemic therapy • Types: – Hormonal therapy – Chemotherapy – Antibody against HER2 – …….. • Timing: – Adjuvant – Neoadjuvant – For metastatic disease Treatment,, based on considering: g • Diagnosis • Disease extent (staging) • Prognostic factors: – Tumor type/grade; – Tumor size; – LN status; – ER/PR? – HER2/neu? – ….. Disease Host = • Age g • Co-morbid disease • Patient preference Annuall Hazard A H d off Recurrence R b by Estrogen g Receptor p Status Recu urrence haazard ratte 0.3 Negative (n=1305) Positive (n=2257) 0.2 0.1 0 0 1 2 3 4 5 6 Years Saphner et al. J Clin Oncol. 1996;14:2738. 1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451. 2. Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582. 7 8 9 10 11 12 Recurrence Hazard Rates Are Dependent on Known Prognostic Factors Haz zard of re ecurrenc ce by yea arly iinterval Prominent early peak of recurrences (~ 3 yrs) in absence of adjuvant therapy, particularly in ER- disease 25 Total Node 0 20 Node 1-3 Node (4+) 15 Tumour size (<1cm) Tumour size (1.1-3cm) 10 Tumour size (>3cm) ER+ 5 ERPremen Postmen 0 0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 Year Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451 ; Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582 ; Saphner et al., J Clin Oncol. 14: 2738-2746, 1996 Adjuvant Tx for earlystage Adjuvant systemic therapy for early early-stage stage breast cancer ER+ or PR+ ER-- or PR-- T1a or T1b & N0 ±Tamoxifen ±Combination py chemotherapy T1c-T2 & N0 Combination chemotherapy Ætamoxifen x 5 years Any T & N1 Combination chemotherapy ± Taxane ± Dose dense Ætamoxifen x 5 years ± Aromatase A t inhibitor i hibit Combination chemotherapy Combination chemotherapy py ± Taxane ± Dose dense ~ Modified from Table 33,2-19B, Chapter 33.2 of Cancer: PPO 7th Ed. Adjuvant Tx for earlystage Estimate risk of recurrence by computer computer-based based model: Online: www.adjuvantonline.com Adjuvant Tx for earlystage Treatment of early-stage breast cancer What is adjuvant therapy for.. for • ↓chance of recurrence, ↑chance of cure 不用做也 會好! 做了也不 會好! Systemic Tx Treatment of breast cancer Hormonal therapy LHRH agonists Pituitary gland FSH/LH Aromatase inhibitors Adrenal Ovary Ovarian O i ablation Anti--estrogens Anti ↑Cell survival, proliferation… Systemic Tx Treatment of breast cancer Hormonal therapies Ovarian ablation by LHRH agonists Other ovarian ablations Selective estrogen receptor modulators (SERMs) Progestins Aromatase inhibitors ER down-regulators (pure anti estrogens) anti-estrogens) Goserelin ((Zoladex)) Leuprolide (Lupron) Oophorectomy Ovarian irradiation Tamoxifen Toremifene Megestrol acetate (Megace) Medroxyprogesterone yp g acetate Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) Fulvestrant (Faslodex) Adjuvant HT for earlystage Adjuvant hormonal therapy Early stage breast cancer Early-stage • Previous standard: tamoxifen x 5 years • The role of aromatase inhibitors become increasingly gy important. ~ Koeberle D & Thurlimann B: The breast 2005; 14: 446. Systemic Tx Treatment of breast cancer Chemotherapy: active drugs Anthracyclines Alkylating agents Platinums Vinca alkaloids & related drugs Taxanes Anti-metabolites Doxorubicin (adriamycin) E i bi i Epirubicin Liposomal doxorubicin Cyclophosphamide Melphalan Cisplatin p or carboplatin p Etoposide Vinblastine Vi Vinorelbine lbi Paclitaxel (Taxol) Docetaxel (Taxotere) 5-FU Capecitabine p ((Xeloda)) Methotrexate Gemcitabine (Gemzar) Development of Adjuvant Chemotherapy Breast Cancer 1970s • • 1980s • 1990s • 2000s Before anthracyclines – CMF, CMF CMFVP With anthracyclines – Combinations: C bi ti AC AC, FAC FAC, AVCMF, AVCMF FEC, FEC CEF – Sequence and Alternating (Milan A & B) – Dose intensity,dose intensity dose density, density HDCT Taxanes (Paclitaxel/Docetaxel) – Sequential: A⇒ T⇒ C or AC⇒ T – Combinations: TA, TAC Biologic Modifiers: Herceptin – Integration in chemotherapy strategies Nabholtz; May, 2002 Istituto Nazionale Tumori, Milan, Italy Gianni Bonadonna et al. 1973 1975 1973-1975 386 pts LN: positive Menopausal: both Hormone: N/A RFS CMF x 12 None Classic CMF C: 100mg/m2/d, D1-14 q4w 4 M: 40mg/m2, 0 / 2 D1,8 8 F: 600mg/m2, D1,8 20 yrs follow-up f ll OS 20yr RR ↓Risk Recur 65% 35% OS 76% 24% New England Journal of Medicine 1976; 294: 405-410 New England Journal of Medicine 1995; 322: 901-966 Istituto Nazionale Tumori, Milan, Italy Gianni Bonadonna et al. 1973 1975 1973-1975 Dose delivery and efficacy RFS OS New England Journal of Medicine 1976; 294: 405-410 New England Journal of Medicine 1995; 322: 901-966 Adjuvant Tx for earlystage √ CMF- based chemotherapy for breast cancer Oral CMF IV CMF Cyclophosphamide, PO 100 mg /m2/d ↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓ ↓ Methotrexate, IV 40 mg/m2/d ↓ ↓ 5-FU, IV 600 mg/m2/d ↓ W k 1 Week-2 Week-1 W k 2 Week-3 W k3 Cyclophosphamide, IV 600 mg /m2/d ↓ Cyclophosphamide Methotrexate, IV 40 mg/m2/d ↓ 5-FU, IV 600 mg/m2/d ↓ Week-1 x 6 cycles W k4 Week-4 x 8 cycles Week-2 ↓ Cyclophosphamide, IV 600 mg /m2/d ↓ ↓ Methotrexate, IV 40 mg/m2/d ↓ ↓ 5-FU, IV 600 mg/m2/d ↓ Week-1 Week-2 Week-3 x 6 cycles Week-3 Week-4 Adjuvant Tx for earlystage Anthracycline- based chemotherapy for breast cancer Cyclophosphamide, C l h h id IV 600 mg //m2/d ↓ Doxorubicin, IV 60 mg/m2/d ↓ Week-1 AC: CAF oral: CAF IV: x 4 cycles Week-2 Week-3 Cyclophosphamide, PO 100 mg /m2/d ↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓ 2 ↓ Doxorubicin, IV g /d ↓ 25 mg/m 2 ↓ 5-FU, IV 500 mg/m /d ↓ Week-1 Week-2 Week-3 Cyclophosphamide, IV 500 mg /m2/d ↓ 2 Doxorubicin, IV 50 mg/m /d ↓ ↓ 5 FU IV 5-FU, 500 mg/m2/d ↓ Week-1 Week-2 AC x 4 // equivalent to oral CMF x 6 cycles y Week-4 x 6 cycles Week-3 Note: Doxorubicin Æ Epirubicin (in 2 x dose) 6 cycles of Acontaining regimen Æ better than CMF Adjuvant Tx for earlystage Taxane- containing adjuvant chemotherapy for breast Cancer AC followed by T Cyclophosphamide, IV 600 mg /m2/d ↓ 2 Doxorubicin, IV 60 mg/m /d ↓ Week-1 Paclitaxel, IV 175 or 225 2 mg/m /d x 4 cycles Week-2 Week-3 x 4 cycles ↓ Week-1 ee Week-2 ee Week-3 ee 3 Adjuvant Tx for earlystage Taxane- containing adjuvant chemotherapy for breast Cancer • CALGB 9344 (INT (INT-0148) 0148) AC AC+T AC T Efficacy Hazard reduction Node(+) Breast Ca ~ Henderson IC et al: JCO 2003;21:976. 2003;21:976 5-year DFS 65% 70% 5-year OAS 77% 80% ↓ recurrence ↓17% ↓ death ↓18% Adjuvant Tx for earlystage Taxotere-containing adjuvant chemotherapy for breast cancer : BCIRG-001 R A N D Axillary LN(+) O Breast cancer M (1491 patients) I After surgery Z A T I O N FAC x 6 cycles 2 Doxorubicin, IV 50 mg/m /d ↓ Cyclophosphamide, IV 500 mg /m2/d ↓ 2 55-FU, FU, IV 500 mg/m /d ↓ Week-1 x 6 cycles Week-2 Week-3 TAC x 6 cycles l 2 Doxorubicin, IV g /d ↓ 50 mg/m Cyclophosphamide, IV 500 mg /m2/d ↓ Docetaxel, IV 75 mg/m2/d ↓ Week-1 x 6 cycles Week-2 Week-3 Adjuvant Tx for earlystage Taxotere-containing adjuvant chemotherapy for breast cancer : BCIRG-001 R A N D Axillary LN(+) O Breast cancer M (1491 patients) after surgery g y I Z A T I O N FAC FAC x 6 cycles TAC x 6 cycles ~ Martin M et al: N Engl J Med 2005;352:2302. Efficacy Hazard reduction TAC 5-year DFS 68% 75% 5-year OAS 81% 87% ↓ recurrence ↓28% ↓ death ↓30% Adjuvant Tx for earlystage Taxotere-containing adjuvant chemotherapy for breast cancer : BCIRG-001 Axillary LN(+) Breast cancer (1491 patients) After surgery R A N D O M I Z A T I O N FAC x 6 cycles Gr 3 or 4 toxicity (%) FAC TAC Neutropenia 49 3 49.3 Febrile neutropenia 2.5 Infection 6.3 Thrombocytopenia 1.2 Any non-hematologic 26.6 CHF 07 0.7 65.55 65 24.7 12.5 2.0 36.3 16 1.6 TAC x 6 cycles ~ Martin M et al: N Engl J Med 2005;352:2302. 毒性明顯增加! I it worth? Is th? Any A better b tt way? ? Adjuvant Tx for earlystage Adjuvant chemotherapy for early stage breast cancer early-stage • Anthracycline-based regimens better > conventional CMF (annual odd of recurrence by CMF: 12%) – ↓↓annual odd of recurrence: 11% further reduction – Recommended for any node- positive, especially those with HER2/neu HER2/neu-overexpressing overexpressing, cases • More drugs are better (?): adding taxanes • Alternating Alt ti dosing d i is i better b tt (?) • Dose-dense is better? 越強, 越密集,越多, …….. Æ 似乎越好! Tx for LABC Patients with inflammatory breast cancer (T4 disease) • Aggressive combined modality therapy: – A small and real fraction of patients have long-term o g e survival. ~ Figure 33.2-8 in Principle and Practice of Oncology, 7th ed., Page 1453. Actuarial overall survival curves for patients with inflammatory breast cancer undergoing combined modality treatment according to whether a pathologic complete response (Path CR) was achieved based on the pathologic findings at the time of mastectomy. (From Harris EE, Schultz D, Bertsch H, et al. Ten-year outcome after combined modality therapy for inflammatory breast cancer. Int J Radiat Oncol Biol Phys 2003;55:1200, with permission.) Systemic Tx Targeting growth factor receptors or signaling pathways ~ Gross ME, Shazer RL, and Agus DB: Targeting the HER-Kinase Axis in Cancer. Sem Oncol 2004; 31(Suppl 3):9. Systemic Tx Treatment of breast cancer Monoclonal antibody against HER2 • Trastuzumab ((Herceptin): p ) a humanized monoclonal antibody against the EC domain of HER2/neu (c-erbB2).) • In 1998, HerceptinTM , a monoclonal antibody against HER2/neu was approved for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. Adjuvant anti-HER2 for early-stage Adjuvant Trastuzumab (Herceptin) HER2 positive early breast cancer HER2-positive ~ Baselga J et al: Oncologist 2006; 11 (suppl 1): 4-12. Adjuvant anti-HER2 for early-stage Adjuvant Trastuzumab (Herceptin) HER2 positive early breast cancer HER2-positive • All showed ↓risk of recurrence • All showed ↑cardiac events: slightly higher (0.6~ 3.3%) of CHF ~ Baselga J et al: Oncologist 2006; 11 (suppl 1): 4-12. Adjuvant Tx for early-stage Adjuvant therapy for early stage breast cancer early-stage • Chemotherapy: more drugs, more complex schedules • Hormonal therapy: Aromatase inhibitors (AIs) should be offered for menopausal women. • Trastuzumab for HER2-positive cases 越強, 越密集, 越多, …….. Æ 似乎越好! ¾毒性! ¾適用的病人族群 Tx for early-stage Treatment of breast cancer Operable loco Operable, loco-regional regional invasive Ca. Ca How to increase the chance of cure! • Local treatment: – Breast-conserving surgery Vs. Vs mastectomy • Regional treatment: – Axillary A ill llymph h node d dissection di i – Radiation • Systemic treatment: (adjuvant) – Chemotherapy – Hormonal therapy – Herceptin H ti ~ NCCN treatment guidelines version2, 2006. Tx for LABC Inoperable, loco-regional invasive Ca. or Locally advanced breast Ca. Ca To increase the chance of cure! • Local treatment: – Mastectomy Start with highly effective – Breast-conserving surgery chemotherapy Æ • Regional eg o a treatment: ea e – Axillary lymph node dissection ↑likelihood of proper local control;; – Radiation • Systemic treatment: (Neoadjuvant) ↑elimination of occult – Chemotherapy py systemic metastasis – Hormonal therapy – Herceptin p ~ NCCN treatment guidelines version2, 2006. Conclusion Treatment of breast cancer • 更多, 更強, 更密集, 更複雜, …….. • 更individualized,更target更i di id li d 更 or mechanism-based,…….. h i b d Surgery 1. Breast-conserving surgery 2. Mastectomy Axiallry LN 1. LN dissection 2. Sentinel LN dissection Radiation Systemic therapy 1. Hormonal therapy 2. Chemotherapy 3. Ab against HER2 Non-invasive carcinomas Operable, loco-regional invasive carcinomas Inoperable, loco-regional invasive carcinomas Metastatic or recurrent Multi-discipline Teamwork Dedicated & professional Thank You V Very M Much h