乳癌的复发及治疗课件

1、Case Sharing44 yr.; Premenopausal; 12/1998 - Incidental finding of Rt breast lumpFNA - +ve for malignant cells.12/1998 - Rt Total mastectomy with axillary dissectionMetastasis workup CXR; CT abd & pelvis; bone scan; LFT; RFT No metastasisCase Sharing IIPathologyPrimary tumour: Infiltrative ductal ca

2、rcinoma; (浸潤性導管癌)Blooms and Richardsons Grade III3.5 cm largest diameterExtensive Lymphovascular invasionLVIAll resection margins clearCase Sharing IIPathology IILymph nodes:21/30 LNs 2 cm largestExtensive extracapsular extension.(廣泛囊外擴展)Biological MarkersER 200; PR 200 ; c-erbB2 +Case PresentationA

3、djuvant TherapyChemotherapy (1/99 7/99)Adriamycin 50 mg/M2Taxol 175 mg/M2Cyclophosphamide 600mg/M2Sequentially at 2 weekly intervals with GCSF support.RadiotherapyChest wall and SCF 50 Gy in 25 frsHormonal therapyTamoxifen 20 mg qd since July 1999乳癌復發分類腫瘤在同一邊乳房2. 轉移至另一邊乳房生長 3. 腫瘤擴散至其他器官Risk of local

4、-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 RT26% in 5 yrs.WBRT (+ Boost) 7% (4%)Risk factorsMarginsAgeLymph nodes status 0; 1-3; 4Estrogen receptor status + ve/- veTumour nuclear grading I/II/IIIC-erbB2 (HER2) Status +/-Tumour sizeRisk of Distant Metastasis遠距擴

5、散的高危因數AgeHistology subtypeTumour GradeTumour sizeChest wall and skin involvementLN status (0/1-3/4-9/10)ER/PR statusMultigene array expression profileBRCA statusPathology of breast cancer 1Ductal carcinomas Three histopathologic classes1.Ductal carcinomas ( 90%)2.Lobular carcinomas ( 3%)3.Special fo

6、rms of breast cancer ( 6%)Ductal carcinomasHistologic type of Breast cancer adenocarcinoma cases (%)Infiltrating ductal7080Medullary58Mucinous colloid24Tubular12Papillary12Intraductal23Molecular/Intrinsic SubtypingMicroarray identified gene expression profiles or gene signatures Consistent with the

7、heterogeneous collection of biologically distinct diseases“Molecular portrait” first pioneered by the Stanford and UNC groups (Srlie and Perou)Divides breast cancer into 2 main types, using 5 subtypes:ER-positiveER-negativeLuminal AHER2 (cerbB2) +Luminal BBasal-likeNormal-likeBreast Cancer Molecular

8、 Subtypes: Clinical Course and TreatmentSubtype % Clinical coursePrevailing treatmentHR+/ HER2-(luminal A)3038indolent(bone,soft tissue)endocrine agentsHR+/HER2+or high Ki-67 (luminal B)1524aggressive(viscera)antiHER2 agentsendocrine agentschemotherapyHER2+/HR-(HER2+)810very aggressive(viscera & CNS

9、) antiHER2 agentschemotherapyTriple Negative*(basal-like)1525very aggressive(viscera & CNS)chemotherapyPARPi promising BRCA 1/2 mutation1444Vinorelbine 20 mg/M2 weekly addedCA 153 -50 Cont. weekly VBL + Herceptin with GCSF till10 /2002 MRI brain -1 cm lesion in left cerebellum. Other lesions regress

10、edStereotactic Radiosurgery to cerebellar lesion (16 Gy X 1)Treatment IIIafter 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 153 243 PET scan /MRI multiple liver mets; no other systemic diseaseRestarted on VBL and Hercep

11、tin every 2 weeklyContinue Femara 2.5 mg daily11/03 12/04 CA 153 243 - 5007/04 MRI PR of liver metsTreatment IVVBL 1/05 - 9/05 Cont + Herceptin 02/05 MRI liver SD02/05 MRI brain - 3 new mets SRS (16 18 Gy )2/2006 CA 153 1315/2006 MBI brain & liver new lesionsTreatment V9/2006 pending Lapartinib; con

12、t VBL + Herceptin ( pt. reluctant to change chemo in fear of side effects)6/2007 Rapid progression of liver mets AST/ALT - 5008/2007 Switched to Xeloda & Laprtinib 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 75 100%5 yrs relapse free survival (無復發存

13、活率) 55 73%10 yrs survival rate (存活率) 60 - 70 %Chest wall recurrence (胸璧復發率) 10%Important prognostic factorsDisease free interval 2 yrs.Skin involvementLymph node statusER /PR statusCerbB2 StatusBRCA1/BRCA2 mutationTreatment for Local-Regional Recurrence乳房局部復發後的治療Breast conservative surgery (局部切除) 20

14、% 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Treatment Algorithm for MBCTrastuzumab + taxanesHER2+HER2+SERMSERDAIOFSHER2Trastuzumab+ capecitabineHER2HR HR +MBCTrast

15、uzumab + anastrozole(lapatinib + letrozole)Lapatinib + capecitabinePaclitaxel + BevaSingle agent chemoPolychemoRxPaclitaxel + BevaChemoRx +PARPiMetastatic Bone Disease: BisphosphonatesDenosumabBRCAmutatedDNA damaging CTOlaparibTDM-1, Pertuzumab, Neratinib, mTORiMetastatic Bone Disease - Bisphosphona

16、tes in Breast Cancer64% risk of skeletal complication with no bisphosphonate at 2 yrsApprox 33% risk reduction with pamidronate64%43%34%Further 20% risk reduction with zoledronic acid27%Additional 18% risk reduction with denosumabLipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2

17、003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA.Whats New ?Fulvestrant- 針對雌激素受體34 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)34Faslodex 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Duration of objective response (days)02004006008001000Fulvestrant 250mg (n=52)Anastr

18、ozole 1mg (n=45)0.00.20.40.60.81.0Without visceral metastasesProportion with objective response020040060080010000.00.20.40.60.81.0Fulvestrant 250mg (n=30)Anastrozole 1mg (n=25)With visceral metastasesFaslodex 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 21 days prior to day 1 SCREEN2:1N = 705Ra

19、ndomizeEverolimus 10 mg PO dailyExemestane 25 mg PO dailyPlacebo 10 mg PO dailyExemestane 25 mg PO daily705 patientsBOLERO-2: ER+ Adv Breast Cancer, Exemestane + Everolimus After Recurrence or Progression on Anastrozole or LetrozolePostmenopausal women with ER+ locally advanced or metastatic breast

20、cancer with prior recurrence or progression on letrozole or anastrozoleStratification by sensitivity to prior hormonal therapy and visceral metastasesPFS Survival ORR CBRPSQoLSafetyPKBiomarkers 21 days prior to day 1 SCREEN2:1N = 705RandomizeEverolimus 10 mg PO dailyExemestane 25 mg PO dailyPlacebo

21、10 mg PO dailyExemestane 25 mg PO daily705 patientsBOLERO-2: ER+ Adv Breast Cancer, Exemestane + Everolimus After Recurrence or Progression on Anastrozole or Letrozolemedian progression-free survival was 6.9 months with everolimus plus exemestane Vs. 2.8 months with placebo plus exemestane, (hazard

22、ratio for progression or death, 0.43; 95% confidence interval CI, 0.35 to 0.54; P0.001).PFS Survival ORR CBRPSQoLSafetyPKBiomarkersDoes Lapatinib Work in Trastuzumab Resistant HER2 Positive Cells?702040608001001020304050600Time (weeks)CapecitabineLapatinib + capecitabine0.001P-value 72 49Progressed

23、or died4.4 8.4Median TTP, mo161163No. of pts0.49 (0.34, 0.71)Hazard ratio (95% CI)% of patients free from progression*Time to progression - ITT populationIndependent assessmentStudy EGF100151Geyer C, et al. NEJM 2006;355:2733-2743. MBC RCTs After A/T failure in Unselected PatientsTrialStudy populati

24、onPts #ORR %PFS/TTPmonthsOSmonthsIxabepilone+capecitabineVs capecitabine1A/T resistant75235 vs 14P 0.00015.8 vs 4.2P 0.000312.9 vs 11.1Ixabepilone+capecitabineVs capecitabine2A/T pretreated112143 vs 29p0.00016.2 vs 4.2P 0.000516.4 vs 15.6Gemcitabine+vinorelbineVs vinorelbine3A/T pretreated25236 vs 2

25、6P 0.096 vs 4P 0.002815.9 vs 16.4Bevacizumab+capecitabineVs capecitabine4A/T pretreated46220 vs 9P 0.0014.9 vs 4.215.1 vs 14.51Thomas et al, J Clin Oncol 2007, 25:5210-17; 2Sparano et al, J Clin Oncol 2010, 28:3256-63; 3Martin et al, Lancet Oncology 2007, 8: 219-25; 4Miller et al, J Clin Oncol 2005,

26、23:792-9; EMBRACE Phase III Trial of Eribulin in Heavily-Pretreated MBCPatients (N = 762)Locally recurrent or MBC2-5 prior chemotherapies2 for advanced diseasePrior anthracycline and taxaneProgression 6 monthsof last chemotherapyNeuropathy grade 2ECOG 2Eribulin mesylate1.4 mg/m2, 2-5 min IVDay 1, 8

27、q21 daysTreatment of PhysiciansChoice (TPC)Any monotherapy (chemotherapy,hormonal, biological) orsupportive care onlyR2:1Global, randomized, open-labelPrimary endpoint: OSFinal analysis after 422 deathsMedian age 55.2 yrs, 16% HER2+, 19% TNBC, median 4 prior agentsTwelves C, et al. J Clin Oncol 28:7

28、s, 2010 (suppl; abstr CRA1004)Novel Taxoids: Improved Tubulin Targeting Profile*Minimally recognized by P-gp (MDR-1).Bissery MC, et al. Proc Am Assoc Cancer Res 2000;41:214OShaughnessy et al. ASCO 2010. Abstract 1005.Pooled Efficacy Analysis of Bevacizumab + Chemotherapy vs Chemotherapy Alone OutcomeChemotherapy + Bevacizumab(n = 1439) Chemotherapy Alone(n = 1008)Median PFS, mos9.26.7HR (95% CI)0.64 (0.57-0.71)ORR,* %4932Median OS, mos26.726.4H