乳癌的復發及治療

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1 乳癌的復發及治療臨床腫瘤科專科醫生

2 Case Sharing 44 yr.; Premenopausal; 12/ Incidental finding of Rt breast lump FNA - +ve for malignant cells. 12/ Rt Total mastectomy with axillary dissection Metastasis workup CXR; CT abd & pelvis; bone scan; LFT; RFT No metastasis

3 Case Sharing II Pathology Primary tumour: Infiltrative ductal carcinoma; ( 浸潤性導管癌 ) Bloom s and Richardson s Grade III 3.5 cm largest diameter Extensive Lymphovascular invasionlvi All resection margins clear

4 Case Sharing II Pathology II Lymph nodes: 21/30 LN s 2 cm largest Extensive extracapsular extension.( 廣泛囊外擴展 ) Biological Markers ER 200; PR 200 ; c-erbb2 +++

5 Case Presentation Adjuvant Therapy Chemotherapy (1/99 7/99) Adriamycin 50 mg/m2 Taxol 175 mg/m2 Cyclophosphamide 600mg/M2 Sequentially at 2 weekly intervals with GCSF support. Radiotherapy Chest wall and SCF 50 Gy in 25 frs Hormonal therapy Tamoxifen 20 mg qd since July 1999

6 乳癌復發分類 1. 腫瘤在同一邊乳房 2. 轉移至另一邊乳房生長 3. 腫瘤擴散至其他器官

7 Risk of local-regional recurrence 乳房及淋巴結復發的風險因數 Risk of recurrence after lumpectomy 乳房保留手術後復發的風險 No RT 26% in 5 yrs. WBRT (+ Boost) 7% (~4%) Risk factors Margins Age Lymph nodes status 0; 1-3; > 4 Estrogen receptor status + ve/- ve Tumour nuclear grading I/II/III C-erbB2 (HER2) Status +/- Tumour size

8 Risk of Distant Metastasis 遠距擴散的高危因數 Age Histology subtype Tumour Grade Tumour size Chest wall and skin involvement LN status (0/1-3/4-9/>10) ER/PR status Multigene array expression profile BRCA status

9 Pathology of breast cancer 1 Ductal carcinomas Three histopathologic classes 1. Ductal carcinomas (> 90%) 2. Lobular carcinomas (~ 3%) 3. Special forms of breast cancer (~ 6%) Ductal carcinomas Histologic type of Breast cancer adenocarcinoma cases (%) Infiltrating ductal Medullary 5 8 Mucinous colloid 2 4 Tubular 1 2 Papillary 1 2 Intraductal 2 3

10 Molecular/Intrinsic Subtyping Microarray identified gene expression profiles or gene signatures Consistent with the heterogeneous collection of biologically distinct diseases Molecular portrait first pioneered by the Stanford and UNC groups (Sørlie and Perou) Divides breast cancer into 2 main types, using 5 subtypes: ER-positive ER-negative Luminal A HER2 (cerbb2) + Luminal B Basal-like Normal-like

11 Breast Cancer Molecular Subtypes: Clinical Course and Treatment Subtype % Clinical course Prevailing treatment HR+/ HER2- (luminal A) HR+/HER2+ or high Ki-67 (luminal B) HER2+/HR- (HER2+) Triple Negative* (basal-like) indolent (bone,soft tissue) aggressive (viscera) 8 10 very aggressive (viscera & CNS) very aggressive (viscera & CNS) endocrine agents antiher2 agents endocrine agents chemotherapy antiher2 agents chemotherapy chemotherapy PARPi promising BRCA 1/2 mutation < 5 moderately aggressive chemo (Pt-salts) PARPi promising *Apocrine, adenoid-cystic and low-grade metaplastic tumours are also included in the TNBC group; these rare subtypes have a very good prognosis

12 Normal Breast Claudin-low HER2-enriched Luminal B Basal-like Luminal A

13 Genomic Assays for Breast Cancer Prognosis Mammaprint Oncotype DX Genomic Grade Buyse, JNCI, 2006 Paik, et al. NEJM 2004 Sotiriou, JNCI, 2006

14 復診和追蹤檢查 : 局部復發 : 檢查原開刀部位附近之胸壁遠處轉移 : 檢查肺骨骼及肝臟定期復診及檢查 : 肺部 X 光骨骼攝影超聲波電腦掃描或正電子掃描乳房造影術 ( 以 X 光檢查乳房 ) 超聲波 ( 利用聲波製造腫塊的影像 ) 磁力共振利用磁場掃描, 製造出病人身體橫切面的圖像癌症指數 : CA 15.3 ; CEA; CA125 肝功能 : ALP 及 AST

15 手術後首一至兩年是復發高風險期乳癌復發手術後的五至六年期間, 復發風險會逐漸減低 1 1.Saphner T et al. J Clin Oncol 1996; 14:

16 Basal-like Breast Cancer: Frequent and Early Relapse Higher risk of early relapse Constant risk of relapse Dent, Clin Cancer Res 2007

17 如何減少乳癌復發的風險減少雌激素減少高脂肪, 高碳水化合物的食物健康飲食少吃 : 紅肉, 含高飽和脂肪及高膽固醇的食物多吃 : 蔬果多做運動每日三十分鐘遠離煙酒

18 Case Sharing -Treatment I 5/2001 CA Ix : CT thorax; PET/CT scan; MRI brain MRI brain Multiple secondaries

19 Common Sites of Metastasis 乳癌擴散 Most common Bone (~40%) Others Brain (triple negative; HER2 +) Leptomingeal Lymph Nodes (Contralateral axilla, SCF, IMC Medinstinal etc) Liver Lung Soft tissue

20 Workup for recurrence Physical examination Blood Tests: LFT, Tumour markers (CA15.3, CEA, CA125) Local and contralateral breast: MMG, U/S breast (MRI breast) Metastatic workup: CXR, U/S liver and abdomen (CT, PET/CT, Whole body MRI, NM/MR Bone scan Biopsy of metastasis : histological confirmation/ Change of biological marker status

21 Individualized Therapy and Personalized Medicine Individualized Therapy Adjusting treatment to the tumor characteristics 針對癌細胞的治療 Personalized Medicine ( 個人化的治理 ) Adjusting treatment to the patient characteristics The right treatment For the right patient At the right time 因應患的情况作出治療的方向

22 因人而異, 考慮因素 : 1. 年齡 ( 是否停經 ) 2. 腫瘤的生長速率 3. 淋巴擴散及轉移其它部位 4. 雌激素受體 (ER)/ 黃體酮受體 (PR) 7. HER2 過度表達 8. 病人的意願及其健康狀況治療方法

23 Treatment of Metastasis Aim of Treatment : 對擴散病者的治療目的 Control disease 控制腫瘤 Prolong life(curative intent for a selected group) 延長生命 Relieve symptoms 舒解症狀 Maintain quality of life 保恃生活質素

24 如何選擇治療方法? 1. 外科手術切除 2. 電療 3. 化學藥物治療 4. 內分泌 ( 賀爾蒙 ) 治療 5. 標靶治療 6. 其他葯物單一或合併起來?? 來提高治愈率

25 Treatment II 7/01 Whole brain RT Stopped Tamoxifen 9/01 Herceptin 2mg/Kg weekly CA >1444 Vinorelbine 20 mg/m2 weekly added CA Cont. weekly VBL + Herceptin with GCSF till 10 /2002 MRI brain -1 cm lesion in left cerebellum. Other lesions regressed Stereotactic Radiosurgery to cerebellar lesion (16 Gy X 1)

26 Treatment III after 52 courses of VBL + Herceptin, stopped VBL and continue with Herceptin every 3 weekly and started Femara 2.5 mg q.d. 11/03 CA PET scan /MRI multiple liver mets; no other systemic disease Restarted on VBL and Herceptin every 2 weekly Continue Femara 2.5 mg daily 11/03 12/04 CA /04 MRI PR of liver mets

27 Treatment IV VBL 1/05-9/05 Cont + Herceptin 02/05 MRI liver SD 02/05 MRI brain - 3 new mets SRS (16 18 Gy ) 2/2006 CA /2006 MBI brain & liver new lesions

28 Treatment V 9/2006 pending Lapartinib; cont VBL + Herceptin ( pt. reluctant to change chemo in fear of side effects) 6/2007 Rapid progression of liver mets AST/ALT - > 500 8/2007 Switched to Xeloda & Laprtinib

29 Treatment for Local-Regional Recurrence 乳房局部復發後的治療 Surgery ( 手術 ) Mastectomy( 全乳房切除 ) operability rate % 5 yrs relapse free survival ( 無復發存活率 ) 55 73% 10 yrs survival rate ( 存活率 ) % Chest wall recurrence ( 胸璧復發率 ) < 10% Important prognostic factors Disease free interval <2yrs. Vs. > 2 yrs. Skin involvement Lymph node status ER /PR status CerbB2 Status BRCA1/BRCA2 mutation

30 Treatment for Local-Regional Recurrence 乳房局部復發後的治療 Breast conservative surgery ( 局部切除 ) 20% to 30% with residual disease ( 遺留 ) Local recurrence ( 復發率 )14 % - 48% Re-irradiation ( 電療 ) External beam RT( 外放射 ) Brachytherapy ( 近距放射 ) Selected patients; high complication rate 高度選擇性 ; 後遺症較嚴重

31 Treatment Algorithm for MBC MBC HR + HR HER2 HER2+ HER2+ HER2 BRCA mutated SERM SERD AI OFS Trastuzumab + anastrozole (lapatinib + letrozole) Trastuzumab + taxanes PolychemoRx Paclitaxel + Beva ChemoRx +PARPi DNA damaging CT Olaparib Paclitaxel + Beva Single agent chemo Lapatinib + capecitabine Trastuzumab+ capecitabine TDM-1, Pertuzumab, Neratinib, mtori Metastatic Bone Disease: Bisphosphonates Denosumab

32 Metastatic Bone Disease - Bisphosphonates in Breast Cancer 64% risk of skeletal complication with no bisphosphonate at 2 yrs Approx 33% risk reduction with pamidronate Further 20% risk reduction with zoledronic acid Additional 18% risk reduction with denosumab 64% 43% 34% 27% Lipton A, et al. Cancer. 2000;88: Rosen LS, et al. Cancer. 2003;100: Stopeck A, et al. ECCO/ESMO Abstract 2LBA.

33 What s New?

34 Fulvestrant- 針對雌激素受體能與雌激素受體結合, 阻礙其運作, 再將其分解 ; 作用是阻止癌細胞的生長及擴散其運作模式有別於他莫昔芬及芳香化酶抑制劑 (AI) 35 35

35 Proportion with objective response Faslodex 的功效功效與 Arimidex 大致相同 ; 包括癌症有轉移到其他内臟的病人延遲或減少接受化療的需要 Without visceral metastases With visceral metastases Fulvestrant 250mg (n=52) Anastrozole 1mg (n=45) Fulvestrant 250mg (n=30) Anastrozole 1mg (n=25) Duration of objective response (days)

36 Faslodex 的功效 Faslodex 能延長對治療有反應的患者的癌症受控制時間 ( 治療反應期 ) 重新及持續控制病情

37 BOLERO-2: ER + Adv Breast Cancer, Exemestane + Everolimus After Recurrence or Progression on Anastrozole or Letrozole Postmenopausal women with ER+ locally advanced or metastatic breast cancer with prior recurrence or progression on letrozole or anastrozole Stratification by sensitivity to prior hormonal therapy and visceral metastases PFS S C R E E N < 21 days prior to day 1 Randomize 2:1 N = patients Everolimus 10 mg PO daily Exemestane 25 mg PO daily Placebo 10 mg PO daily Exemestane 25 mg PO daily Survival ORR CBR PS QoL Safety PK Biomarkers

BOLERO-2: ER + Adv Breast Cancer, Exemestane + Everolimus After Recurrence or Progression on Anastrozole or Letrozole median progression-free survival was 6.

38 BOLERO-2: ER + Adv Breast Cancer, Exemestane + Everolimus After Recurrence or Progression on Anastrozole or Letrozole median progression-free survival was 6.9 months with everolimus plus exemestane Vs. 2.8 months with placebo plus exemestane, (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). PFS S C R E E N < 21 days prior to day 1 Randomize 2:1 N = patients Everolimus 10 mg PO daily Exemestane 25 mg PO daily Placebo 10 mg PO daily Exemestane 25 mg PO daily Survival ORR CBR PS QoL Safety PK Biomarkers

39 Does Lapatinib Work in Trastuzumab Resistant HER2 Positive Cells?

40 % of patients free from progression* Time to progression - ITT population Independent assessment Lapatinib + capecitabine Capecitabine No. of pts Progressed or died Median TTP, mo Hazard ratio (95% CI) 0.49 (0.34, 0.71) P-value < Time (weeks) Study EGF Geyer C, et al. NEJM 2006;355:

44 MBC RCTs After A/T failure in Unselected Patients Trial Study population Pts # ORR % PFS/TTP months OS months Ixabepilone+capecitabine A/T resistant vs 14 Vs capecitabine 1 P < Ixabepilone+capecitabine Vs capecitabine 2 Gemcitabine+vinorelbine Vs vinorelbine 3 Bevacizumab+capecitabine Vs capecitabine 4 A/T pretreated A/T pretreated A/T pretreated vs 29 p< vs 26 P vs 9 P vs 4.2 P vs 4.2 P vs 4 P vs vs vs vs vs Thomas et al, J Clin Oncol 2007, 25: ; 2 Sparano et al, J Clin Oncol 2010, 28: ; 3 Martin et al, Lancet Oncology 2007, 8: ; 4 Miller et al, J Clin Oncol 2005,23:792-9;

EMBRACE Phase III Trial of Eribulin in Heavily- Pretreated MBC Patients (N = 762) Locally recurrent or MBC

chemotherapy Neuropathy grade 2 ECOG 2 R 2:1 Eribulin mesylate 1.

hormonal, biological) or supportive care only Global, randomized, open-label Primary endpoint: OS Final

45 EMBRACE Phase III Trial of Eribulin in Heavily- Pretreated MBC Patients (N = 762) Locally recurrent or MBC 2-5 prior chemotherapies 2 for advanced disease Prior anthracycline and taxane Progression 6 months of last chemotherapy Neuropathy grade 2 ECOG 2 R 2:1 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Treatment of Physician's Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological) or supportive care only Global, randomized, open-label Primary endpoint: OS Final analysis after 422 deaths Median age 55.2 yrs, 16% HER2+, 19% TNBC, median 4 prior agents Twelves C, et al. J Clin Oncol 28:7s, 2010 (suppl; abstr CRA1004^)

46 Novel Taxoids: Improved Tubulin Targeting Profile *Minimally recognized by P-gp (MDR-1). Bissery MC, et al. Proc Am Assoc Cancer Res 2000;41:214

49 Pooled Efficacy Analysis of Bevacizumab + Chemotherapy vs Chemotherapy Alone Outcome Chemotherapy + Bevacizumab (n = 1439) Chemotherapy Alone (n = 1008) Median PFS, mos HR (95% CI) 0.64 ( ) ORR,* % Median OS, mos HR (95% CI) 0.97 ( ) 1-yr OS, % *Assessed in patients with measurable disease at baseline: n = 1105 for chemotherapy plus bevacizumab; n = 788 for chemotherapy alone. O Shaughnessy et al. ASCO Abstract 1005.

50 Types of Drugs for Inhibiting VEGF-Pathway Bevacizumab Aflibercept Drugs that target circulating VEGF Soluble VEGFR decoy receptors that target circulating VEGF Ramucirumab Antibodies that target VEGFR2 and VEGFR1 TKIs that target multiple tyrosine kinases, VEGF receptors, and other receptors Sunitinib, sorafenib

(visceral vs non-visceral) Extent of metastatic spread (oligo vs polymets) Endocrine, biologic or chemotherapy Combined

51 Tailored Management of MBC Tumor Biology Tumor Aggressiveness Prior Adjuvant Treatments Feasibility of multidisciplinary treatments Patient Hormone receptor status HER2 status Duration of RFI since primary diagnosis Location of mets (visceral vs non-visceral) Extent of metastatic spread (oligo vs polymets) Endocrine, biologic or chemotherapy Combined treatments Oligometastatic disease Surgery, radiofrequency ablation, stereotactic radiotherapy Preferences Symptoms Comorbidities

Microsoft PowerPoint - Jt HKBCF Ca breast SE Talk_Nov 13_2010[PDF]

Microsoft PowerPoint - Jt HKBCF Ca breast SE Talk_Nov 13_2010[PDF] 如何處理乳癌治療的副作用 : 疲勞認知功能減弱性功能障礙更年期症狀等曾詠恆醫生香港大學臨床腫瘤學系助理教授香港大學內科學系榮譽助理教授二零一零年十一月十三日專題內容乳癌確診類型乳癌的發展及趨勢治療發展治療引