中山醫學大學附設醫院

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1 中山醫學大學附設醫院乳癌診療指引本臨床指引參考歐洲腫瘤學會 (ESMO) 國家衛生研究院與美國 NCCN 版本台灣乳房醫學會乳癌多專科醫療團隊編修乳癌治療指引制訂日期 2017/11/14 Version /11/15 Version /12/02 Version /11/26 Version /12/25 Version /05/22 Version /11/28 Version /11/17 Version /12/30 Version 3.0 癌症委員會主任委員癌症委員會執行長癌症中心主任團隊負責人

2 修訂內容 Chung Shan Medical University Hospital 乳癌診療指引 Clinical Guideline 2018 version 10.0 頁數原文修訂 / 增修第 4-8 頁 Tumor node metastasis(tnm) staging system for carcinoma of the breast(ajcc7th) Tis (LCIS) Lobular carcinoma in situ pn0(i ) No regional lymph node metastases histologically, negative immunohistochemistry (IHC) pn0(mol ) No regional lymph node metastases histologically, negative molecular findings (RT-PCR) N2b Metastases only in clinically detectedk ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases axillary node metastases 修訂 Tumor node metastasis(tnm) staging system for carcinoma of the breast(ajcc8th) Breast carcinoma TNM prognostic stage group AJCC UICC 2017( AJCC 8th) 刪除 Tis (LCIS) Lobular carcinoma in situ 刪除 pn0(i ) No regional lymph node metastases histologically, negative immunohistochemistry (IHC) 刪除 pn0(mol ) No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 增訂 cn1mi**micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm). pn1b Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs. pn1c pn1a and pn1b combined 修訂 N2b Metastases only ipsilateral internal mammary nodes and in the absence of axillary node metastases 第 16 頁四乳癌的治療與診療指引刪除 Lobular carcinoma in situ Tis,N0,M0

3 第 25 頁第 32 頁 ER+/HER-2 negative ABC AI 治療過後的選擇目前尚無定論可選擇 Tamoxifen, 其它不同作用機轉之 AI, 高劑量的 (HD)Fulvestrant, megestrol acetate 及 everolimus+ai 五化學治療原則 Neoadjuvant /Adjuvant chemotherapy 原文無 UFT po.cisplatin.caboplantin 修訂 ER+/HER-2 negative ABC AI 治療過後的選擇目前尚無定論可選擇 Tamoxifen,CDK4.6 抑制劑, 其它不同作用機轉之 AI, 高劑量的 (HD)Fulvestrant, megestrol acetate 及 everolimus+ai 增訂 UFT po Uracil/Tegafur 270 mg/m2/day po 7 days/week Y Park. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. British Journal of Cancer (2009), 1 7 Cisplatin Cisplatin 75 mg/m2 iv d1 Q3w Caboplantin Caboplantin 6 mg, AUC iv d1 Q3w Silver DP et al. Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol 2010;28:1145.

4 目錄一何謂乳癌...2 二乳癌的診斷...2 三乳癌的分期及風險評估...4 四乳癌的治療與診療指引...17 五化學治療原則...28 六放射線治療原則...38 七參考文獻

5 一何謂乳癌乳癌是由乳房乳腺管細胞或是腺泡細胞經由不正常分裂繁殖所形成之惡性腫瘤這些惡性腫瘤除了侵犯局部器官 ( 乳房 ), 更可能轉移到遠處器官如骨骼肺肝腻等, 而破壞身體重要器官的功能, 造成身體健康之損害, 甚至危害生命二乳癌的診斷整體健康狀況的評估原發腫瘤的評估局部淋巴結的評估病史停經狀態理學檢查全血球記數肝臟, 腎臟, 和心臟功能測試 ( 對於計畫使用 anthracycline 且 / 或 trastuzumab 的病人 ), 鹼性磷酸酶和鈣離子,B 肝及 C 肝抗原抗體的檢測理學檢查乳房攝影乳房超音波乳房磁振造影 (MRI) -optional 粗針切片以及組織學, 分化程度及 ER,PgR,HER-2,Ki67 的檢查理學檢查超音波如果懷疑轉移要做超音波指引生檢切片確認遠處轉移的評估理學檢查 Stage II 以上建議做胸腔電腻斷層檢查 Stage III 以上建議做正子造影檢查. 骨頭掃描 (optional) MRI,magnetic resonance imaging( 磁振造影 ) ER,oestrogen receptor( 雌激素接受器 ) PgR,progesterone receptor( 黃體激素接受器 ) HER2,human epidermal growth factor 2 receptor( 人類表皮生長因子 2 接受器 ) * 若要施行先導性治療時 - 腫瘤切片時, 建議在腫瘤組織中放置標誌物 ( 以確保切除正確的部位 ) optional( 自費選項 ) 2

6 乳癌亞型的定義 (ESMO 臨床指引推薦 ) 內在亞型臨床病理分級註記管腔 A 型 Luminal A Luminal A-like: ER(+) HER2(-) Ki67 <20% PR(+) >20% 分子印記檢測為低風險管腔 B 型 Luminal B HER2 過度表現類基底細胞癌 Basal-like Luminal B-like(HER2-negative): ER(+) HER2(-) 且 Ki67 高或 PgR 低分子印記檢測為高風險 Luminal B-like(HER2-positive): ER(+) HER2(+) 任何 Ki67 任何 PgR HER2-positive(non-luminal): HER2(+) ER(-) PgR(-) 三陰性 : ER(-) PgR(-) HER2(-) ER,oestrogen receptor( 雌激素接受器 ) PgR,progesterone receptor( 黃體激素接受器 ) HER2,human epidermal growth factor 2 receptor( 人類表皮生長因子 2 接受器 ) Ki 67: 臨界值為 20%(>30% 為明顯偏高.<10% 為明顯偏低 ) PR: 臨界值為 20% HER2+ 定義為 IHC+++ 或 FISH 為陽性反應大約有 80% 三陰性和 basal-like 亞型有重疊, 但是三陰性還包含了一些特別的組織學類型, 例如 :( 典型的 ) 髓質 (medullary) 和腺樣囊性癌 (adenoid cystic carcinoma), 其預後較好 3

7 三乳癌的分期及風險評估 (Staging and risk assessment) 1. 若臨床檢查和超音波評估懷疑有淋巴轉移, 建議用超音波引導的細針抽吸或粗針切片來證實 (III A) 2. 病患若計畫使用 anthracyclines and trastuzumab 作輔助治療時, 建議評估心臟功能 (I A) 3. 術後病理應根據 ptmn 系統來評估包括 : 數目, 位置, 移除的腫瘤最大直徑, 組織形態, 腫瘤分級, 血管浸潤, 生物標識分析, 切除邊緣評估, 移除總數, 淋巴結陽性數目和轉移程度 (III A) 4. 由於 B 肝在台灣盛行率高, 建議在化療前做 B 肝抗原抗體檢測, 必要時要服用抗病毒藥物, 以避免化療時 B 肝被再活化, 發生猛爆性肝炎 5. 無症狀的遠端轉移並不常見, 不建議術前大規模的實驗性檢查或影像檢查, 但若病患有淋巴轉移, 腫瘤 >5 公分, 具侵犯性的生物亞型或實驗性檢查懷疑有移轉現象, 則建議 Chest CT,Abdomenal US,Bone scan 的檢查 6. 對第三期病患或傳統檢查無法得到正確診斷時, 建議 PET CT scan 檢查 Tumor node metastasis(tnm) staging system for carcinoma of the breast(ajcc8th) Clinical 4 Pathological Primary tumor (T) Tx Primary tumor is unable to be assessed. T0 No evidence of primary tumor. Tis Carcinoma in situ. Tis (DCIS) Ductal carcinoma in situ. Tis (Paget) Paget disease of the nipple not associated with invasive carcinoma and/or DCIS in the underlying breast parenchyma. Carcinoma in the breast parenchyma associated with Paget disease is categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted. T1 Tumor 20 mm in greatest dimension. T1mi Tumor 1 mm in greatest dimension. T1a Tumor >1 mm but 5 mm in greatest dimension (round any measurement 1.0 to 1.9 mm to 2 mm). T1b Tumor >5 mm but 10 mm in greatest dimension. T1c Tumor >10 mm but 20 mm in greatest dimension. T2 Tumor >20 mm but 50 mm in greatest dimension. T3 Tumor >50 mm in greatest dimension.

8 Regional lymph nodes (N) T4 Tumor of any size with direct extension to the chest wall and/or the skin (ulceration or macroscopic skin nodules). *Invasion of the dermis alone does not qualify as T4. T4a Extension to chest wall, not including only pectoralis muscle adherence/invasion. T4b Ulceration and/or ipsilateral satellite nodules and/oredema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma. T4c Both (T4a and T4b). T4d Inflammatory carcinoma**inflammatory carcinoma is restricted to cases with typical skin changes involving onethird or greater of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer NX Regional lymph nodes cannot be assessed (e.g. previously removed) N0 No regional lymph node metastases N1 Metastases to movable ipsilateral level I, II axillary lymph node(s) cn1mi**micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm). N2 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detectedk ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures N2b Metastases only in ipsilateral internal mammary nodes and in the absence of axillary node metastases. N3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement. N3a Metastases in ipsilateral infraclavicular lymph node(s) 5 pnx Regional lymph nodes cannot be assessed (e.g. previously removed or not removed for pathological study) pn0 No regional lymph node metastasis identified or isolated tumor cells (ITCs) only. pn0(i+) Malignant cells in regional lymph node(s) not >0.2 mm [detected by haematoxylin and eosin (H&E) staining or IHC including isolated tumour cell clusters (ITCs)] pn0(mol+) Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC pn1 Micrometastases, or metastases in 1-3 axillary lymph nodes, and/or clinically negative internal mammary nodes with micro- or macrometastases detected by sentinel lymph node biopsy. pn1mi Micrometastases (>0.2 mm and/or >200 cells, but none >2.0 mm) pn1a Metastases in 1-3 axillary lymph nodes, at least one metastasis >2.0 mm pn1b Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs. pn1c pn1a and pn1b combined pn2 Metastases in 4-9 axillary lymph nodes, or

9 Distant metastasis (M) N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N3c Metastases in ipsilateral supraclavicular lymph node(s) 6 positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases. pn2a Metastases in 4-9 axillary lymph nodes (at least one tumour deposit >2.0 mm) pn2b Metastasis only in clinically detected internal mammary nodes with or without microscopic confirmation; with pathologically negative axillary nodes. pn3 Metastases in 10 axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected; or in ipsilateral supraclavicular lymph nodes. pn3a Metastases in 10 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes. pn3b pn1a or pn2a in the presence of cn2b (positive internal mammary nodes by imaging); or pn2a in the presence of pn1b pn3c Metastases in ipsilateral supraclavicular lymph nodes * The suffixes (sn) and (f) should be added to the N descriptor to note confirmation by sentinel lymph node biopsy or fine needle aspiration/core needle biopsy, respectively, with no further resection of lymph nodes. M0 No clinical or radiographic evidence of distant metastases cm0(i+) No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumour cells in circulating blood, bone marrow or other non-regional nodal tissue that are not >0.2 mm in a

10 patient without symptoms or signs of metastases M1 Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm Primary tumor (T) 取消小葉原位癌 (LCIS) 的 ptis 定義 LCIS 為良性病变, 從 TNM 分期中删除 Breast carcinoma TNM prognostic stage group AJCC UICC 2017( AJCC 8 th ) When T is... And N is... And M is... And G is... And HER2 status* is... And ER status is... And PR status is... Then the prognostic stage group is... Tis N0 M0 1-3 Any Any Any 0 T1 N0 M0 1 Positive Any Any IA T1 N0 M0 1-2 Negative Positive Positive IA T1 N0 M0 2 Positive Positive Positive IA T1 N0 M0 3 Positive Positive Any IA T0-1 N1mi M0 1 Positive Any Any IA T0-1 N1mi M0 1-2 Negative Positive Positive IA T0-1 N1mi M0 2 Positive Positive Positive IA T0-1 N1mi M0 3 Positive Positive Any IA MultiGene panel** - Oncotype Dx recurrence score less than 11 T1-2 N0 M0 1-3 Negative Positive Any IA 7

11 T1 N0 M0 1 Negative Positive Negative IB T1 N0 M0 1 Negative Negative Positive IB T1 N0 M0 2 Positive Positive Negative IB T1 N0 M0 2 Positive Negative Any IB T1 N0 M0 2 Negative Negative Positive IB T1 N0 M0 3 Positive Negative Any IB T1 N0 M0 3 Negative Positive Positive IB T0-1 N1mi M0 1 Negative Positive Negative IB T0-1 N1mi M0 1 Negative Negative Positive IB T0-1 N1mi M0 2 Positive Positive Negative IB T0-1 N1mi M0 2 Positive Negative Any IB T0-1 N1mi M0 2 Negative Negative Positive IB T0-1 N1mi M0 3 Positive Negative Any IB T0-1 N1mi M0 3 Negative Positive Positive IB T2 N0 M0 1-3 Positive Positive Positive IB T2 N0 M0 1,2 Negative Positive Positive IB T1 N1 M0 1-3 Positive Positive Positive IB T1 N1 M0 1-2 Negative Positive Positive IB 8

12 T2 N1 M0 1 Negative Positive Positive IB Δ T2 N1 M0 2 Positive Positive Positive IB Δ T0-2 N2 M0 1-2 Positive Positive Positive IB Δ T3 N1-2 M0 1 Positive Positive Positive IB Δ T3 N1-2 M0 2 Positive Positive Positive IB Δ T1 N0 M0 1 Negative Negative Negative IIA Δ T1 N0 M0 2 Negative Negative Negative IIA Δ T1 N0 M0 3 Negative Positive Negative IIA Δ T1 N0 M0 3 Negative Negative Positive IIA Δ T1 N0 M0 3 Negative Negative Negative IIA Δ T0-1 N1mi M0 1 Negative Negative Negative IIA T0-1 N1mi M0 2 Negative Negative Negative IIA T0-1 N1mi M0 3 Negative Positive Negative IIA T0-1 N1mi M0 3 Negative Negative Positive IIA T0-1 N1mi M0 3 Negative Negative Negative IIA T0-1 N1 M0 1 Positive Positive Negative IIA T0-1 N1 M0 1-2 Positive Negative Any IIA T0-1 N1 M0 1 Negative Positive Negative IIA 9

13 T0-1 N1 M0 1 Negative Negative Positive IIA T0-1 N1 M0 3 Negative Positive Positive IIA T2 N0 M0 1 Positive Positive Negative IIA T2 N0 M0 1-2 Positive Negative Any IIA T2 N0 M0 1 Negative Positive Negative IIA T2 N0 M0 1 Negative Negative Positive IIA T2 N0 M0 3 Negative Positive Positive IIA T0-2 N2 M0 1 Negative Positive Positive IIA Δ T3 N1-2 M0 1 Negative Positive Positive IIA T0-1 N1 M0 1 Negative Negative Negative IIB T0-1 N1 M0 2 Positive Positive Negative IIB T0-1 N1 M0 2 Negative Positive Negative IIB T0-1 N1 M0 2 Negative Negative Positive IIB T0-1 N1 M0 3 Positive Positive Negative IIB T0-1 N1 M0 3 Positive Negative Any IIB T2 N0 M0 1 Negative Negative Negative IIB T2 N0 M0 2 Positive Positive Negative IIB T2 N0 M0 2 Negative Positive Negative IIB 10

14 T2 N0 M0 2 Negative Negative Positive IIB T2 N0 M0 3 Positive Positive Negative IIB T2 N0 M0 3 Positive Negative Any IIB T2 N1 M0 1 Positive Any Any IIB T2 N1 M0 1 Negative Negative Positive IIB T0-2 N2 M0 2 Negative Positive Positive IIB T0-2 N2 M0 3 Positive Positive Positive IIB T3 N1-2 M0 2 Negative Positive Positive IIB T3 N1-2 M0 3 Positive Positive Positive IIB T0-1 N1 M0 2 Negative Negative Negative IIIA Δ T0-1 N1 M0 3 Negative Positive Negative IIIA T0-1 N1 M0 3 Negative Negative Any IIIA T2 N0 M0 2 Negative Negative Negative IIIA Δ T2 N0 M0 3 Negative Positive Negative IIIA Δ T2 N0 M0 3 Negative Negative Any IIIA Δ T2 N1 M0 1 Negative Positive Negative IIIA T2 N1 M0 2 Positive Negative Negative IIIA T2 N1 M0 2 Negative Positive Negative IIIA 11

15 T2 N1 M0 3 Positive Positive Negative IIIA T2 N1 M0 3 Positive Negative Negative IIIA T3 N0 M0 1 Negative Positive Negative IIIA T3 N0 M0 2 Positive Negative Negative IIIA T3 N0 M0 2 Negative Positive Negative IIIA T3 N0 M0 3 Positive Positive Negative IIIA T3 N0 M0 3 Positive Negative Negative IIIA T0-2 N2 M0 1 Positive Positive Negative IIIA T0-2 N2 M0 1 Positive Negative Any IIIA T0-2 N2 M0 1 Negative Positive Negative IIIA T0-2 N2 M0 1 Negative Negative Positive IIIA T0-2 N2 M0 2 Positive Positive Negative IIIA T0-2 N2 M0 2 Positive Negative Any IIIA T3 N1-2 M0 1 Positive Positive Negative IIIA T3 N1-2 M0 1 Positive Negative Any IIIA T3 N1-2 M0 1 Negative Positive Negative IIIA T3 N1-2 M0 1 Negative Negative Positive IIIA T3 N1-2 M0 2 Positive Positive Negative IIIA 12

16 T3 N1-2 M0 2 Positive Negative Any IIIA T4 N0-2 M0 1 Negative Positive Positive IIIA Any N3 M0 1 Negative Positive Positive IIIA Δ T2 N1 M0 1-2 Negative Negative Negative IIIB Δ T2 N1 M0 3 Negative Positive Negative IIIB Δ T3 N0 M0 1-2 Negative Negative Negative IIIB T3 N0 M0 3 Negative Positive Negative IIIB T0-2 N2 M0 2 Negative Positive Negative IIIB T0-2 N2 M0 2 Negative Negative Positive IIIB T0-2 N2 M0 3 Positive Positive Negative IIIB T0-2 N2 M0 3 Positive Negative Any IIIB T0-2 N2 M0 3 Negative Positive Positive IIIB T3 N1-2 M0 2 Negative Positive Negative IIIB T3 N1-2 M0 2 Negative Negative Positive IIIB T3 N1-2 M0 3 Positive Positive Negative IIIB T3 N1-2 M0 3 Positive Negative Any IIIB T3 N1-2 M0 3 Negative Positive Positive IIIB T4 N0-2 M0 1 Positive Any Any IIIB 13

17 T4 N0-2 M0 2 Positive Positive Positive IIIB T4 N0-2 M0 2 Negative Positive Positive IIIB T4 N0-2 M0 3 Positive Positive Positive IIIB Any N3 M0 1 Positive Any Any IIIB Any N3 M0 2 Positive Positive Positive IIIB Any N3 M0 2 Negative Positive Positive IIIB Any N3 M0 3 Positive Positive Positive IIIB T2 N1 M0 3 Negative Negative Any IIIC Δ T3 N0 M0 3 Negative Negative Any IIIC T0-2 N2 M0 2 Negative Negative Negative IIIC Δ T0-2 N2 M0 3 Negative Positive Negative IIIC Δ T0-2 N2 M0 3 Negative Negative Any IIIC Δ T3 N1-2 M0 2 Negative Negative Negative IIIC Δ T3 N1-2 M0 3 Negative Positive Negative IIIC Δ T3 N1-2 M0 3 Negative Negative Any IIIC Δ T4 N0-2 M0 1 Negative Positive Negative IIIC T4 N0-2 M0 1 Negative Negative Any IIIC T4 N0-2 M0 2 Positive Positive Negative IIIC 14

18 T4 N0-2 M0 2 Positive Negative Any IIIC T4 N0-2 M0 2 Negative Positive Negative IIIC T4 N0-2 M0 2 Negative Negative Any IIIC T4 N0-2 M0 3 Positive Positive Negative IIIC T4 N0-2 M0 3 Positive Negative Any IIIC T4 N0-2 M0 3 Negative Any Any IIIC Any N3 M0 1 Negative Positive Negative IIIC Any N3 M0 1 Negative Negative Any IIIC Any N3 M0 2 Positive Positive Negative IIIC Any N3 M0 2 Positive Negative Any IIIC Any N3 M0 2 Negative Positive Negative IIIC Any N3 M0 2 Negative Negative Any IIIC Any N3 M0 3 Positive Positive Negative IIIC Any N3 M0 3 Positive Negative Any IIIC Any N3 M0 3 Negative Any Any IIIC Any T Any N M1 1-3 Any Any Any IV TNM: tumor, node, metastasis; AJCC: American Joint Committee on Cancer; UICC: Union for International Cancer Control. 15

19 * For cases where HER2 is determined to be "equivocal" by ISH (FISH or CISH) testing under the 2013 ASCO/CAP HER2 testing guidelines, HER2 "negative" category should be used for staging in the prognostic stage group table. [1,2] **If OncotypeDx is not performed, not available, or if the OncotypeDx score is 11 or greater for patients with T1-2 N0 M0 HER2 negative ER positive cancer, then the prognostic stage group is assigned based on the anatomic and biomarker categories shown above. OncotypeDx is the only multigene panel included to classify prognostic stage because prospective level I data support this use for patients with a score <11. Future updates may include results from other multigene panels to assign cohorts of patients to prognostic stage groups when there are high level data to support these assignments. Δ Denotes a stage group for which the use of grade and prognostic factors changed the group more than one stage group from the anatomic stage group (eg, from anatomic stage group IIB to prognostic stage group IB). 16

20 四乳癌的治療與診療指引 DIAGNOSIS WORK-UP PRIMARY TREATMENT FOLLOW-UP Observation after wide excision Yearly physical examination Yearly mammography and/or ultrasonography of breast if observation is chosen after excision Ductal carcinoma in situ Tis,N0,M0 Stage0 Bilateral Mammography Ultrasonography of breast Pathology review Unicentric negative resection margins Multicentric Wide spread Diffuse microcalcifications positive resection margins Wide excision alone (Level 2B) Wide excision+radiotherapy * as recommended by NSABP (Level 2B) Total mastectomy ± SLNB dissection ±Reconstructive surgery (Level 2B) Tamoxifen 10 years for ER(+) (Level 2B) Physical examination every 6 months Mammography and/or Ultrasonography every 6 months for 2 years then every 12 months Pathologic status of ER PR Herb-2 Score please see page 7 *refer to page: principle of radiation therapy 17

21 stagei.ii.iii 不想保留乳房或無法施行乳房保留手術腫瘤 2cm 且 / 或可以施行乳房保留手術 ( 註 ) 腫瘤 >2cm 或無法施行乳房保留手術以及乳房保留手術可以在降階 (down staging) 後施行全乳房切除術 +/- 乳房重建效果不佳先導性治療術後化療 +/-trastuzumab 乳房保留術效果良好術後放療 ( 在乳房保留術後建議要做 ) 同時施行術後賀爾蒙治療 ( 若賀爾蒙接受體為陽性 ) 註 : 個案符合 ( 三陰性 or Her-2 type or 管腔 B 型 )2 公分以下的條件, 亦可以考慮先導性治療 18

22 Figure: 全身性輔助 (systemic adjuvant) 治療或新輔助 (neo-adjuvant) 治療以生物標識的表現與乳癌的亞型來決定 (ER, oestrogen receptor; HER2, human epidermal growth factor 2 receptor; ChT, chemotherapy; ET, endocrine therapy; Ttrastuzumab.) 19

23 乳癌的治療依生物標誌來決定 Biomarker Prognostic Predictive Technical validation Clinical validation Test and scoring recommendations Patient selection ER 證據等級 IB PgR 證據等級 IB HER 證據等級 IB yes 免疫組織 (IHC) 內分泌治療 No 免疫組織 (IHC) 若 PgR(-), 多數需要化療 Yes 免疫組織 >10% 細胞膜完抗 HER2 標靶藥物全染色 ISH 原位雜交 :HER2 基因複體 6 或 HER2/ 染色體比例 17 2 Ki No no >20% 高 >20% 則建議化療 Intrinsic subtypes Yes yes 當 IHC 無法準確預測預後時可考慮 Gene expression profile(oncotype 或 mammaprint) 新輔助化療對於每種亞型的反應會有所不同 20

24 對於乳癌亞型的系統性治療建議 Subtype 建議療法 Comments Luminal A-like 內分泌治療若淋巴結為陽性 (>2mm 之轉移腫瘤 ) 則可考慮先用化學藥物治療 Luminal B-like(HER2- 內分泌治療 + 化學藥物治療 negative) Luminal B-like(HER2- 化學藥物治療 + 抗 HER2 標靶若不適合化學藥物治療, 可考慮內分泌治 positive) 藥物治療 + 內分泌治療療 + 抗 HER2 標靶藥物治療 HER2-positive(non-luminal) 化學藥物治療 + 抗 HER2 標靶藥物治療 Triple-negative(ductal) 化學藥物治療 ( 對於特殊的組織學型態, 依照 ST GALLEN 2013 建議 ) ( 一 ) 區域性局部治療 (Local-regional): 治療策略應基於腫瘤亞型以及期別和患者年齡, 喜好和總體的身體健康狀況來評估高風險的遺傳性癌症 (BRCA1/BRCA2 基因突變或以前胸腔因為淋巴瘤接受放射線治療的婦女 ) 手術前需要應預先討論諮詢 (III A) 保乳手術可用於原位癌 (DCIS) 的治療, 但須有安全的切緣 (>2mm), 全乳切除也是 DCIS 治療的選項對於 DCIS,BCS 後進行全乳照射治療 (WBRT) 或全乳切除可降低局部復發的風險 (I A) 乳房原位癌術後服用 Tamoxifen 可降低病患對側乳房發生惡性腫瘤的機會 (II B) 乳房保留手術是大部分早期乳癌治療的選擇在某些情況下乳房全切除仍是必要選項, 應考慮腫瘤大小 ( 相對於乳房大小 ), 多病灶的腫瘤, 先前已進行過胸部或乳房的放射線治療或病人自己的選擇乳房整形腫瘤切除手術 (oncoplasty) 可以有比較美的外觀乳房全切除後立即重建是可行的矽膠的植入對於乳房重建是安全且可接受的 [III,A] 前哨淋巴結切除為目前治療早期乳癌的標準, 除非腋下淋巴結證實有被侵犯到才考慮全腋下淋巴結切除 [II,A] 21

25 手術前評估若沒有淋巴轉移, 即使前哨淋巴切除後病理證實有孤立腫瘤細胞 (<0.2mm) 且僅有少數淋巴轉移, 若病患接受術後的放射線治療, 則可考慮不需要更進一步的腋下手術 [II,B] 在接受先導性化療的病患中, 若治療前評估腋下淋巴為陰性, 則前哨淋巴切除可在治療後再實施在接受先導性化療的病患中, 若治療前臨床評估有腋下淋巴轉移, 在治療後臨床評估轉為陰性, 仍可考慮手術前哨淋巴結切除手術但必須符合下列條件 :1. 前哨淋巴必須切除至少 3 顆以上, 2. 必須用 dual mapping(blue dye and radioactivity material), 否則建議施行腋下淋巴全切除術 [V,B] 乳房保留手術後強烈建議術後進行放射治療 [I,A] 但 70 歲低風險復發的病患 ( 腫瘤 <2 公分, 淋巴無轉移, ER(+)), 同時接受內分泌治療的病患則可考慮追蹤, 不需要術後放射治療術中放射線治療之選擇 (IORT): Suitable candidate: age > 50 & ER (+) & tumor < 2 cm & Invasive Ductal Carcinoma & clinical axillary lymph node negative(cn0) 術前不須另外 consult RTO, 可直接進行術中放射線治療 Other cautionary candidate: 不符合 suitable criteria, 請先轉診 RTO 諮商, 留下門診諮詢紀錄後, 再予以安排乳房切除後輔助性的放射線治療建議用於有侵犯到腋下淋巴結且 / 或 >5cm 的腫瘤, 特別是有額外危險因子的病患 (HER 2 陽性,ER 陰性 ) [I,A] ( 二 ) 全身性治療 (Systemic-treatment): ER 表現為陽性的病人 (>=1%), 應該接受雌激素療法 [I,A] 在停經前的婦女,Tamoxifen 為標準 [I,A], 接受化療後的停經前婦女, 卵巢抑制劑可以改善存活率儘管缺乏長期追蹤和存活率的數據, 對於部分停經前的婦女, 芳香環轉化酶抑制劑以及卵巢抑制的合併療法是一項選擇對於停經後的婦女, 芳香環轉化酶抑制劑 ( 類固醇和非類固醇 ) 和 Tamoxifen 是有效的治療選擇 [I,B] 使用 Tamoxifen 的病人建議避免使用高強度以及中等的 CYP2D6 的抑制劑如果此類藥物無法被替換, 應該考慮使用芳香酶抑制劑 ( 在停經前婦女合併使用卵巢抑制劑 )[IV,B] 對於高風險荷爾蒙受體陽性病患 ( 淋巴結陽性 ) 建議延長內分泌治療時間到十年, 但需和病患討論治療藥物的副作用及帶來的好處 22

26 使用卵巢抑制劑的病人以及使用芳香酶抑制劑的病人有較高風險的骨質流失且建議服用適量鈣離子以及維他命 D3 此外, 定期評估骨頭礦物質密度是必要的 [I,A] 三陰性 HER2(+) 的乳癌以及高風險的 luminal HER2(-) 腫瘤建議化療 [I,A] docetaxel 和 cyclophosphamide 4 次, 對於某些病人 ( 例如處於心臟併發症的危險的患者 ) 可以當作 anthracycline-based 4 次的替代療法 [I,A] 大部分 luminal A 的病人不須化療除非復發風險高 ( 廣泛侵犯的淋巴結 >4 顆 ) 的病患 [I,A] luminal B HER2(+) 應使用化學藥物, 抗雌激素和 Trastuzumab 來治療 [I,A] HER2(+)( 非 luminal) 應該使用化療及 trastuzumab 治療 [I,A] 除了低風險的特殊組織學亞型, 例如分泌型早期型 (secretory juvenile), 頂漿分泌型或腺樣囊性癌 (apocrine or adenoid cystic carcinoma), 三陰性乳癌建議接受輔助性化療 [I,A] Chemotherapy 通常為四到八個 cycle- 以 anthracycline 或 taxane 為主建議可以接替 (sequential) 使用而不要同時使用 anthracycline 與 taxane (IB) 高度分化性的惡性腫瘤可以考慮使用劑量密集 (dose dense) 的化療 ( 加上白血球生成劑 ) (I,B) 有 HER2 過度表現的患者, 併用 Trastuzumab+ chemotherapy 與單純化療相比可以減少復發機率至一半, 並提高總存活率 (I,A) 乳癌病患若有 HER2 過度表現, 若淋巴結有轉移或淋巴無轉移但腫瘤大於 >1cm 建議使用 Trastuzumab, 而 <1cm 沒有淋巴轉移, 若 ER 為 (-), 也可考慮 Trastuzumab 的使用在 HER2 過度表現的病患, 新輔助治療可以考慮雙標靶藥物及化療藥物使用 (trastuzumab + pertuzumab), 因可提高 PCR 的比例由於 Trastuzumab 有心臟毒性, 不應同時與 Anthracycline 使用, 與 Taxanes 類藥物合併使用是安全的並已被證實比交替使用效果更好 (I,A) 接受卵巢抑制治療的病患或停經後婦女可以預防性給予 Bisphosphonate 或 Denasumab, 減少治療相關的骨質流失及降低骨骼併發症的風險 (I,A) 即使在年老患者, 在允許的情況下還是應該給予 full dose 的藥物適用 standard chemotherapy 的患者, 應遵循 multidrug regimen 的方案進行治療 (II, D) 對局部晚期的病患, 或是腫瘤較大但尚可進行全乳切除的病患, 在開刀前先給予 primary systemic therapy 23

27 可以增加手術的可能性與減少手術難度 (I,A) 若使用新輔助化療, 建議都應打完計劃的療程, 再進行手術 (V,B) 化療前應先確認病患肝功能狀況及 B 肝,C 肝病毒檢測 * 後續追蹤與存活率 : 後續追蹤的目的是希望能發現早期局部復發或對側乳癌, 評估與治療相關產生的併發症, 並提供心理支持與專業知識以便讓病人能夠盡快恢復正常的生活建議頭兩年每 3-6 個月追蹤一次, 第三到五年後可改為每 6-12 個月追蹤一次, 五年以上改成每年追蹤一次 (V,A) 行乳房保留手術 (BCS) 後建議每年追蹤同側與對側的乳房攝影與超音波 (II,A) 在無症狀的患者中目前沒有其他研究顯示這兩者之外的 image 或 lab 檢查對存活率有影響 Lobular invasive carcinoma 患者可使用超音波做後續追蹤 (III,B) 接受內分泌治療 (ET) 的病人應定期做血液檢查因此類藥物對血脂方面副作用較大 (V,A) 使用 Tamoxifen 的患者, 建議每年行婦科檢查包括腹部超音波 (V,B) 使用 AIs 的患者建議定期追蹤骨質密度 (I,A) 應鼓勵病患在治療乳癌後養成定期運動的習慣 (II,B) 使用雌激素替代療法 (hormone replacement therapy) 會增加復發風險, 不鼓勵使用 (I,A) 通論轉移性乳癌 (MBC) 準則一但被診斷出有轉移性乳癌, 應視情況納入或啟動全人照顧之通報, 將相關醫療人員, 病患及家屬, 集合於一隱密空間, 討論治療方向, 並做成記錄雖然例行性的腻部影像檢查並不需要, 但檢查的閾值應降低, 一但有任何頭部的症狀或不適建議施行腻部的影像檢查約 2-4 個月要評估內分泌治療反應,2-4 cycle 化療後也要評估療效腫瘤指數的變化, 僅有參考價值若病患全身狀況穩定, 只有腫瘤指數上升, 並不需要改變現有的治療儘可能在移轉的腫瘤進行生檢 (biopsy), 確定組織型態, 並檢驗 ER, PR, Her2 及 Ki67 24

28 若生物標記與原發腫瘤不同, 只要任何一次生檢之 ER 或 Her2 為陽性, 則可考慮相對應的標的來治療治療通則 Treatment general quidelines 治療選擇應考慮以下因素 :HR( 賀爾蒙接受體 ) 和 HER-2 狀態, 之前治療及毒性, 無病期間, 腫瘤量 ( 定義為轉移的位置及個數 ), 年紀, 體能狀態, 共病項目, 月經狀態, 症狀或快速疾病控制, 社經地位及心理因素, 病患所能獲得之治療及病患對治療方法之喜好 ER+/HER-2 negative ABC 內分泌治療是賀爾蒙受體陽性乳癌的首要選項, 即使是有內臟轉移, 除非證明有內分泌治療抗性或需要快速控制病情時對停經前女性來說, 抑制卵巢功能或摘除, 結合其他的內分泌治療是首選 Tamoxifen 應被考慮的藥物, 除非證明對它有藥物抗性 AI 也是選擇之一, 但應配合卵巢抑制或卵巢摘除 Fulvestrant 在停經前女性臨床研究尚不足 AI 治療過後的選擇目前尚無定論可選擇 Tamoxifen,CDK4.6 抑制劑, 其它不同作用機轉之 AI, 高劑量的 (HD)Fulvestrant,megestrol acetate 及 everolimus+ai 化療後的維持性的內分泌治療是合理的, 但仍需隨機試驗的研究同時給予化療及內分泌治療沒有增加存活期的好處, 最好不要同時使用 HER-2-positive ABC 除非有禁忌, 抗 HER-2 療法應及早使用於轉移性乳癌病人對 ER+/HER-2+ 的 MBC 病患, 優先選擇內分泌治療 (ET) 而非化療, 抗 HER-2 療法加內分泌治療應在治療之初即開始使用, 因為相對單獨內分泌治療 (ET) 有較佳的 PFS 好處加上抗 HER-2 療法沒有增加總體存活期在抗 HER-2 療法結合化療或內分泌治療期間有疾病進展時, 應考慮加上另一種標靶治療, 因為可以抑制另一 HER-2 路徑標靶治療 MBC 的時間長短目前尚無定論若使用 trastuzumab 時疾病有進展, 使用 trastuzumab +lapatinib 也是合理的選擇 25

29 Her-2 陽性之轉移性病患, 第一線藥物治療應考慮雙標靶加上化療 (trastuzumab + pertuzumab + Doxetaxel), 第二線則考慮 TDM1 來治療 (I.A) Chemotherapy and biological therapy 在沒有藥物禁忌或病人因素之下, 若之前未使用過 anthracycline 或 taxane 為主的配方時, 此兩種藥物可做為 HER-2 陰性 MBC 的第一線治療, 但建議單處方使用其它如 capecitabine 和 vinorelbine 在擔心掉髮病人身上可考慮在未使用過 taxane 及對 anthracycline 有抗性之 MBC 或者是考慮到 anthracycline 累積劑量及心毒性的病人要化療時, 單一處方的 taxane 首選其它如 capecitabine 和 vinorelbine 在擔心掉髮病人身上可考慮在輔助化學治療時, 若已使用 taxane, 可以再使用於轉移之病患, 尤其是已有一年以上的無病存活期的病人處方期間及種類應量身訂做通常每一配方 (anthracyclines 除外 ) 應使用至疾病進展或 " 毒性無法接受 " 而 " 毒性無法接受 " 之決定應和病患共同討論 Bevacizumab 結合化療作為 MBC 第一或第二線治療有些許 PFS 的好處, 但 OS 無差別 Bevacizumab 建議用於篩選過之病人使用, 不建議使用於第一 / 第二線後的治療對於骨頭, 腻轉移的治療建議 : 已確診有轉移, 特別是侵犯到骨頭的乳癌病人, 針對骨轉移的藥物 (bisphosphonate or denosumab) 應常規性的與其他全身性治療合併使用 (1A) 有骨轉移並持續有局部疼痛的病人應該安排影像評估, 以確定是否有病理性骨折如果懷疑或已發現有長骨骨折, 則需請骨科醫師評估是否需要手術固定, 以及術後做局部 RT 如果沒有明顯的骨折風險,RT 為首選治療 (1A) 有神經系統症狀且懷疑有脊髓壓迫的病人必須盡快安排相關的影像學檢查, MRI 為首選, 照射部位應包括懷疑的脊椎以及鄰近部位盡快照會神經外科醫師或骨科醫師來評估是否需要手術減壓, 或是放射性治療 RT (1B) 單顆或數顆小型但仍可切除的腻轉移腫瘤應該予以手術切除或立體定位放射手術 (radiosurgery) 治療. 如果無法切除則建議用 Radiosurgery 來治療 (1B) 26

30 支持性療法與安寧緩和治療支持性療法應該被納入為乳癌治療計劃的一部分, 讓乳癌患者可以安全地且更容易接受其他支持性的治療 (1A) 治療初期就應該與緩和醫療的專家合作, 給病人最有效的疼痛控制及舒緩其他副作用 (1A) 需要緩解疼痛的病人應該要給予有效的疼痛控制 ( 包括 morphine) (1A) 在理想狀況下, 應該在轉移性乳癌早期診斷出來的時候就與病人討論臨終的意願當積極治療已經無法控制疾病的進展, 或是治療的副作用大於益處, 醫師及醫療團隊應該主動與病人和家屬討論安寧治療 (expert opinion) 轉移性男性乳癌 ER+ 的男性轉移性乳癌可以使用 endocrine therapy 治療, 除非乳癌表現有 endocrine resistance 或是進展快速需要用到化療時 (expert opinion) ER+ 的男性轉移性乳癌, 建議使用 Tamoxifen (expert opinion) 名詞解釋 EBC:Early breast cancer ABC:Advanced breast cancer MBC:Metatitis breast cancer 證據等級 Level I: 有顯著意義的隨機對照研究 (Randomized controlled trials, RCT) 報告包括大型且 low bias 的 RCT, 此類 RCT 延伸出來的 meta-analyses Level II: 小型的 RCT 或是大型但懷疑有 bias 的 RCT, 此類 RCT 延伸出來的 meta-analysis Level III: 前瞻性世代研究報告 prospective cohort Level IV: 回顧性世代研究 (retrospective cohort) 及病例對照組研究 (Case-control study) Level V: 無對照組的研究, 個案報告, 專家意見 (Expert opinion) 建議等級 Group A: 有強烈證據顯示有顯著的臨床益處, 強烈建議 Group B: 較無強烈的研究證據顯示, 尚有臨床益處, 一般建議 27

31 Group C: 證據不足功效或利益不大, 風險或缺點大於臨床益處 ( 副作用, 費用等 ) 無特別推薦 Group D: 有適度的證據顯示無臨床益處或療效不佳, 一般不推薦使用 Group E: 有強烈的證據顯示療效不佳或無臨床益處, 不建議五化學治療原則 Neoadjuvant /Adjuvant chemotherapy AC Doxorubicin 60 mg/m2 iv d1 Cyclophosphamide 600 mg/m2 iv d1 Q3w x 4 cycles or Q2W x 4 cycles ( with GCSF support) Muss HB et al. Standard chemotherapy (CMF or AC) versus capecitabine in early-stage breast cancer (BC) patients agec 65 or older: results of CALGB/CTSU ASCO annual meeting. Abstract 507. Fisher, B et al. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 2004; 96:1823. EC Epirubicin mg/m2 iv d1 Cyclophosphamide 600 mg/m2 iv d1 Q3w x 4 cycles or Q2W x 4-6 cycles ( with GCSF support) Piccart MJ et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.. J Clin Oncol 2001; 19:3103. LC(Liposomal doxorubicin-optional) Liposmal doxorubicin mg/m2 iv d1 Cyclophosphamide 600 mg/m2 iv d1 Q3w x 4 cycles or Q4w x 4 cycles Pegylated Liposomal Doxorubicin as Adjuvant Therapy for Stage I-III Operable Breast Cancer. Lu YC, Ou-Yang FU, Hsieh CM, Chang KJ, Chen DR, Tu CW, Wang HC, Hou MF. In Vivo Mar-Apr;30(2):

32 TC Docetaxel mg/m2 iv d1 Cyclophosphamide 600 mg/m2 iv d1 Q3w x 4 cycles or Q2W x 4 cycles ( with GCSF support) Jones SE et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006; 24:5381. *Docetaxel 健保申請條件如下 ~ 1. 局部晚期或轉移性乳癌 2. 與 anthracycline 合併使用於腋下淋巴結轉移之早期乳癌之術後輔助性化學治療 (99/6/1) 3. 早期乳癌手術後, 經診斷為三陰性反應且無淋巴轉移的病人, 得作為與 cyclophosphamide 併用 doxorubicin 的化學輔助療法 4. 除以上條件, 其餘皆自費 Docetaxel+ Cisplatin Docetaxel 60-75mg/m2 iv d1 Cisplatin mg/m2 iv d1 Q3w x 4 cycles or Q2W x 4 cycles ( with GCSF support) A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/ , multicenter study. (Abstract in PubMed)Breast Cancer Res Treat (2012) 136: CMF po Cyclophosphamide 100 mg/m2/d po d1-14 Methotrexate 40 mg/m2 iv d1, 8 5- FU 600 mg/m2 iv d1, 8 Q4w x 6 cycles Muss HB et al. Standard chemotherapy (CMF or AC) versus capecitabine in early-stage breast cancer (BC) patients agec 65 or older: results of CALGB/CTSU ASCO annual meeting. Abstract

33 CMF iv Cyclophosphamide 600 mg/m2 iv d1 Methotrexate 40 mg/m2 iv d1 5-FU 600 mg/m2 iv d1 Q3w x 6 cycles Weiss RB et al. Adjuvant chemotherapy after conservative surgery plus irradiation versus modified radical mastectomy. Analysis of drug dosing and toxicity. Am J Med 1987; 83:455. FAC 5-FU 500 mg/m2 iv d1 Doxorubicin 50 mg/m2 iv d1 Cyclophosphamide 500 mg/m2 iv d1 Q3w x 6 cycles Martin M et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen d1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen d1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol 2003; 14:833. FEC 5-FU mg/m2 iv d1 Epirubicin mg/m2 iv d1 Cyclophosphamide mg/m2 iv d1 Q3w x 6 cycles or Q2W x 4-6 cycles ( with GCSF support) Bonneterre J et al. Epirubicin increase long term survival in adjuvant chemotherapy of patients with poor prognosis, node positive, early breast cancer: 10 years follow up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005; 23:

34 AC/EC Paclitaxel Qw (or Paclitaxel AC/EC) Paclitaxel 80 mg/m2 iv d1 Qw x 12 cycles Sparano JA et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med 2008; 358:1663. AC/EC Docetaxel Q3w (or Docetaxel AC/EC) Docetaxel mg/m2 iv d1 Q3w x 4 cycles Sparano JA et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med 2008; 358:1663. *Docetaxel 健保申請條件如下 ~ 1. 局部晚期或轉移性乳癌 2. 與 anthracycline 合併使用於腋下淋巴結轉移之早期乳癌之術後輔助性化學治療 (99/6/1) 3. 早期乳癌手術後, 經診斷為三陰性反應且無淋巴轉移的病人, 得作為與 cyclophosphamide 併用 doxorubicin 的化學輔助療法 4. 除以上條件, 其餘皆自費 TAC Docetaxel mg/m2 iv d1 Doxorubicin 50 mg/m2 iv d1 Cyclophosphamide 500 mg/m2 iv d1 Q3w x 6 cycles Martin M et al. Adjuvant docetaxel for node-positive breast cancer. N Eng J Med 2005; 352:2302. TEC Docetaxel mg/m2 iv d1 Epirubicin mg/m2 iv d1 Cyclophosphamide 500 mg/m2 iv d1 Q3w x 6 cycles P Piedbois et al. Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study. Ann Oncol. 2007; 18:

35 UFT po Uracil/Tegafur 270 mg/m2/day po 7 days/week Y Park. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. British Journal of Cancer (2009), 1 7 Cisplatin Cisplatin 75 mg/m2 iv d1 Q3w Caboplantin Caboplantin 6 mg, AUC iv d1 Q3w Silver DP et al. Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol 2010;28:1145. Adjuvant Targeted therapy Trastuzumab Trastuzumab can be given after completion of chemotherapy as well,loading dose 8 mg/kg,followed by 6 mg/kg,iv q3w for a total of 1 year. Trastuzumab 4 mg/kg loading dose followed by 2 mg/kg iv qw during chemotherapy,then 6 mg/kg iv q3w,for a total of 1 year Smith I et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial. Lancet 2007; 369:29. Romond EH et al. Trastuzumab plus adjuvant chemotherapy for operable Her2-positive breast cancer. N Eng J Med 2005; 353:1673 健保申請條件如下 ~ 1. 早期乳癌 :: (1) 外科手術前後化學療法 ( 術前輔助治療或輔助治療 ) 治療後, 具 HER2 過度表現 (IHC 3+ 或 FISH+), 且具腋下淋巴結轉移但無遠處臟器轉移之早期乳癌患者, 作為輔助性治療用藥 (2) 使用至多以一年為限 2. 轉移性乳癌 32

36 (1) 單獨使用於治療腫瘤細胞上有 HER2 過度表現 (IHC 3+ 或 FISH+), 曾接受過一次以上化學治療之轉移性乳癌病人 (2) 與 paclitaxel 或 docetaxel 併用, 使用於未曾接受過化學治療之轉移性乳癌病患, 且為 HER2 過度表現 (IHC 3+ 或 FISH+) 者 (3) 轉移性乳癌且 HER2 過度表現之病人, 僅限先前未使用過本藥品者方可使用 3. 經事前審查核准後使用 4. 除以上條件, 其餘皆自費 Chemotherapy for Metastatic breast cancer Doxorubicin Doxorubicin mg/m2 iv d1 Q3w or Doxorubicin 20 mg/m2 iv d1 Qw Chan S et al. Prospective randomized trial of docotaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999;17:2341. Gasparini G et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinial trial. Am J Clin Oncol 1991;14:38. Epirubicin Epirubicin mg/m2 iv d1 Q3w or Epirubicin 20 mg/m2 iv d1 Qw Bastholt L et al. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 1996;14:1146. Gasparini G et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinial trial. Am J Clin Oncol 1991;14:38. 33

37 Liposomal doxorubicin Liposmal doxorubicin mg/m2 iv d1 Q3-4w O Brien ME et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCL versus conventional doxorubicin for first line treatment of metastatic breast cancer. Ann Oncol 2004;15:440. 健保申請條件如下 ~ 1. 用於單一治療有心臟疾病風險考量之轉移性乳癌患者 2. 除以上條件, 其餘皆自費 Cisplatin Cisplatin 75 mg/m2 iv d1 Q3w Caboplantin Caboplantin 6 mg, AUC iv d1 Q3w Silver DP et al. Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol 2010;28:1145. Docetaxel Docetaxel mg/m2 iv d1 Q3w or Docetaxel mg/m2 iv d1 Qw Harvey V et al. Phase III trial of comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006; 24:4963. Burstein, HJ et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18:1212. Paclitaxel Paclitaxel 80 mg/m2 iv d1 Qw Bishop, JF et al. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 1999; 17:2355. Seidman AD et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all Her-2 overexpressors and random assignment to trastuzumab or not in Her-2 nonoverexpressors: Final results of Cancer and Leukemia Group B Protocol J Clin Oncol 2008; 26:

38 Gemcitabine Gemcitabine mg/m2 iv d1, 8, 15 Q4w Carmichael, J et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 1995; 13:2731. Vinorelbine Vinorelbine mg/m2 iv mg/m2 po d1,8 Q3w Gasparini, G et al. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol 1994; 12:2094. 限用於 : (1.) 晚期或無法手術切除之非小細胞肺癌及轉移性乳癌病患 (2.) 病理分期第二期及第三期前半 (stage II & stage IIIA) 非小細胞肺癌於接受根治性手術後與鉑金類藥品併用之輔助治療, 需事前審查後使用, 最長以 4 療程為限 2. 本成分之口服劑型與注射劑型不得併用 Capecitabine Capecitabine mg/m2 po bid d1-14 Q3w Fumoleau, P et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40: capecitabine 與 docetaxel 併用於治療對 anthracycline 化學治療無效之局部晚期或轉移性乳癌病患 2. 單獨用於對 taxanes 及 anthracycline 化學治療無效, 或無法使用 anthracycline 治療之局部晚期或轉移性乳癌病患 AC Doxorubicin 60 mg/m2 iv d1 Cyclophosphamide 600 mg/m2 iv d1 Q3w Nabholtz JM et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 2003;21:

39 EC Epirubicin 75 mg/m2 iv d1 Cyclophosphamide 600 mg/m2 iv d1 Q3w, or Q2W( and GCSF support) Langley RE et al. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute Trial AB01. J Clin Oncol 2005; 23:8322. Target therapy for Metastatic breast cancer Trastuzumab +/- Chemotherapy Trastuzumab 6mg/kg iv over 90 min first wk followed by 2 mg/kg iv over 30 min q3w Cobleigh, MA et al. Multinational study of the efficacy and safety of humanized anti-her2 monoclonal antibody in women who have HER2- overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639. Bevacizumab( 自費 ) + Chemotherapy Bevacizumab 10 mg/kg iv d1 Q2w or Bevacizumab 15 mg/kg iv d1 Q3w Miller KD et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Eng J Med 2007; 357:2666. Miles D et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab (BV) with docetaxel (D) or docetaxel with placebo (PL) as first-line therapy for patients with locally recurrent or metastatic breast cancer (mbc): AVADO ASCO annual meeting. LBA

40 Lapatinib + Xeloda Lapatinib 1250mg Xeloda 2000mg/m(2) d1-14 Lancet Oncol 2013 Jan;14(1):64-71.doi: /S (12) Epub 2012 Nov. 1. Xeloda (capecitabine) 與 docetaxel 併用於治療對 anthracycline 化學治療無效之局部晚期或轉移性乳癌病患 2. 單獨用於對 taxanes 及 anthracycline 化學治療無效, 或無法使用 anthracycline 治療之局部晚期或轉移性乳癌病患 BEEP Bevacizumab 15 mg/kg iv d1 Etoposide 70 mg/m2/d d2, 3, 4 Cisplatin 70 mg/m2 d2 Q3w Lu YS, et al. Bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast cancer progressing from radiotherapy result of a multi-center phase II study. ECC 2013:1878. Eribulim Eribulim 1.4mg/m2 d1,8 Q3w Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy. Pivot X1, Marmé F2, Koenigsberg R3, Guo M4, Berrak E5, Wolfer A Aug;27(8): doi: /annonc/mdw203. Epub 2016 May

41 六放射線治療原則 Principles of radiation therapy: Indication of breast/chest wall RT: 1.early stage breast cancer s/p BCS;DCIS s/p lumpectomy with moderate risk Target:breast tissue with/without IMN & SCN Dose Design:45~50Gy / Fxs boost tumor bed 10-16Gy/5-8Fxs if high risk for recurrence ( young age, N+, LVI+, close margin) 2.locally advanced stage s/p neoadjuvant chemotherapy followed by BCS Target:breast tissue + chest wall & SCN +/- IMN Dose Design:45~50Gy / Fxs then boost tumor bed 10-16Gy/5-8Fxs 3.locally advanced stage (tumor>5cm) or positive surgical lymphnodes( 4or1-3 # )with patient had 3 risk factor nuclear grade 2or3,LVI(+),ECS(+),tumor>2cm(T2),age<40y,ER(-) Target:chest wall + SCN + IMN Dose Design:45~50Gy / Fxs then boost tumor bed 10-16Gy/5-8Fxs Indication of Axillary region RT 1.cN+ without axillary lymph node dissection / sentinel lymph node sampling Target:Level I, II, III axillary lymph nodes Dose Design:45~50Gy / Fxs 術中放射線治療 (IORT): Suitable candidate: age > 50 & ER (+) & tumor < 2 cm & Invasive Ductal Carcinoma & clinical axillary lymph node negative(cn0) 術前不須另外 consult RTO, 可直接進行術中放射線治療, 治療劑量 20 格雷 (Gy) Other cautionary candidate: 不符合 suitable criteria, 請先轉診 RTO 諮商, 留下門診諮詢紀錄後, 再予以安排名詞解釋 : Early stage breast cancer:stage I, II Locally advanced breast cancer:stage III, IV DCIS s/p lumpectomy with moderate risk:new Van Nuys Prognostic Index Scoring System 7 DCIS:Ductal carcinoma in situ BCS:Breast-conservative surgery 38

42 SCN:supra-clavicular lymph nodes IMN:internal mammary lymph nodes IORT: Intra-operative Radiotherapy 七參考文獻 (Reference) 1.Annals of Oncology 26(Supplement 5):v8-v30,2015 dol:10,1093/annonc/mdv NCCN Clinical Practice Guidelines in Breast cancer V American Brachytherapy Society Guidelines for APBI 4. American Society of Breast Surgeons Guidelines for APBI Astro Guidelines ESTRO Guidelines for PBI 7. Muss HB et al. Standard chemotherapy (CMF or AC) versus capecitabine in early-stage breast cancer (BC) patients agec 65 or older: results of CALGB/CTSU ASCO annual meeting. Abstract Fisher, B et al. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 2004; 96: Piccart MJ et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.. J Clin Oncol 2001; 19: Jones SE et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006; 24: Weiss RB et al. Adjuvant chemotherapy after conservative surgery plus irradiation versus modified radical mastectomy. Analysis of drug dosing and toxicity. Am J Med 1987; 83: Martin M et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen d1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen d1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol 2003; 14: Bonneterre J et al. Epirubicin increase long term survival in adjuvant chemotherapy of patients with poor prognosis, node positive, early breast cancer: 10 years follow up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005; 23: Sparano JA et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med 2008; 358: Sparano JA et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med 2008; 358: Martin M et al. Adjuvant docetaxel for node-positive breast cancer. N Eng J Med 2005; 352: P Piedbois et al. Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study. Ann Oncol. 2007; 18: Smith I et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial. 39

43 Lancet 2007; 369: Romond EH et al. Trastuzumab plus adjuvant chemotherapy for operable Her2-positive breast cancer. N Eng J Med 2005; 353: Chan S et al. Prospective randomized trial of docotaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999;17: Gasparini G et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinial trial. Am J Clin Oncol 1991;14: Bastholt L et al. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 1996;14: Gasparini G et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinial trial. Am J Clin Oncol 1991;14: O Brien ME et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCL versus conventional doxorubicin for first line treatment of metastatic breast cancer. Ann Oncol 2004;15: Silver DP et al. Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol 2010;28: Harvey V et al. Phase III trial of comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006; 24: Burstein, HJ et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18: Seidman AD et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all Her overexpressors and random assignment to trastuzumab or not in Her-2 nonoverexpressors: Final results of Cancer and Leukemia Group B Protocol J Clin Oncol 2008; 26: Carmichael, J et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 1995; 13: Gasparini, G et al. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol 1994; 12: Fumoleau, P et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40: Nabholtz JM et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 2003;21: Langley RE et al. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute Trial AB01. J Clin Oncol 2005; 23: Cobleigh, MA et al. Multinational study of the efficacy and safety of humanized anti-her2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17: Miller KD et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Eng J Med 2007; 357: Miles D et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab (BV) with docetaxel (D) or docetaxel with placebo (PL) as first-line therapy for patients with locally recurrent or metastatic breast cancer (mbc): AVADO ASCO annual meeting. 40

44 LBA Lu YS, et al. Bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast cancer progressing from radiotherapy result of a multi-center phase II study. ECC 2013: Lancet Oncol 2013 Jan;14(1):64-71.doi: /S (12) Epub 2012 Nov. 40. Pegylated Liposomal Doxorubicin as Adjuvant Therapy for Stage I-III Operable Breast Cancer.Lu YC, Ou-Yang FU, Hsieh CM, Chang KJ, Chen DR, Tu CW, Wang HC, Hou MF.In Vivo Mar-Apr;30(2): Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy.pivot X1, Marmé F2, Koenigsberg R3, Guo M4, Berrak E5, Wolfer A Aug;27(8): doi: /annonc/mdw203. Epub 2016 May A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/ , multicenter study. (Abstract in PubMed)Breast Cancer Res Treat (2012) 136: Y Park. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. British Journal of Cancer (2009),

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