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OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENTMediterranean School of OncologyRome,March 30,2012NEOADJUVANT THERAPYLucia MentucciaOncologia Medica,SoraOPEN ISSUES IN MULTIDISCIPLINA1To improve surgical outcomes and optionsFor operable breast cancer,the aim is to increase the chance of breast conserving surgery in patients who would otherwise require mastectomyFor inoperable locally advanced breast cancers,the aim is to achieve operabilityTo gain information on tumor responseTo define short-term surrogate markers of response Goals of Neoadjuvant Theapy in Breast CancerTo improve surgical outcomes a21523 pts with clinical T1-3,N0-N1 breast cancer Stratification Age Clinical Tumor Size Clinical Nodal StatusOperationOperationNSABP B-18Wolmark N t al;J Natl Cancer Inst Monogr.2001AC x 4AC x 41523 pts with clinical T1-3,N336%20%43%cCR(249 pts)cPR(296 pts)cSD+cPD(140 pts)23%4%9%pInv(160 pts)pNon-Inv(26 pts)pCR(63 pts)NSABP B-18:Clinical and Pathologic Breast Tumor ResponseWolmark N t al;J Natl Cancer Inst Monogr.200136%20%43%cCRcPRcSD+cPD23%4%94NSABP B-18:Surgery Performed100806040200%P 5 cmER or PgR+vs.ER&PgR N 0-1 vs.N 2Conservative surgery or notInvasive operableHER2+BCT 2 cm(inflammatory BC excluded)LVEF 50%N=450 34 weeks52 weeks of anti-HER2 therapylapatinibtrastuzumablapatinibtrastuzumabFEC X3SURGERYRANDOMIZElapatinib trastuzumablapatinibtrastuzumabpaclitaxel paclitaxel paclitaxel+12 wks6 wksStudy DesignStratification:Inv37Efficacy pCR and tpCREfficacy pCR and tpCR38Efficacy Overall(Clinical)Responseat 6 weeks(w/o chemo)and at surgeryL:lapatinib;T:trastuzumab;L+T:lapatinib plus trastuzumabEfficacy Overall(Clinical)39SafetyNo major cardiac dysfunctionOne death in L+T immediately after end of treatmentL(N=154)T(N=149)L+T(N=152)Diarrhea36(23%)3(2%)32(21%)Hepatic*20(13%)2(1%)13(9%)Neutropenia24(16%)4(3%)13(9%)Skin disorders10(7%)4(3%)10(7%)Number(%)of patients with AEs at Grade 3 L:lapatinib;T:trastuzumab;L+T:lapatinib plus trastuzumab*Includes 2 patients with Hys Law criteria in T,and one patient in LSafetyNo major cardiac dysfunc40 RANDOMIZATIONLapatinib 1000 mg/dailyLapatinib 1500 mg/dailyCOREBIOPSYSURGERY ChemotherapyABCTXL 80 mg/m2Trastuzumab 2 mg/kg5 FU 600 mg/m2Epi 75 mg/m2CTX 600 mg/m2CHER LOB Trial:study planGuarneri V,ASCO 2011121 paz RANDOMILapatinib 1000 mg/dai41pCR (breast&axilla)Node negativityBreast conservation0102030405060708090Arm A:CT+trastuzumabArm B:CT+lapatinibArm C:CT+trastuzumab/lapatinibCHER-LOB:EFFICACY OUTCOMESGuarneri V,ASCO 2011pCR (breast&axilla)Node neg42NeoSphere:study designTHP(n=107)docetaxel+trastuzumab+pertuzumabHP(n=107)trastuzumab+pertuzumabTP(n=96)docetaxel+pertuzumabSURGERYdocetaxelq3wx4FECq3wx3trastuzumabq3wcycles517FECq3wx3trastuzumabq3wcycles517FECq3wx3trastuzumabq3wcycles517FECq3wx3trastuzumabq3wcycles521Study dosing:q3w x 4TH(n=107)docetaxel+trastuzumabPatientswithoperableorlocallyadvanced/inflammatory*HER2-positiveBCChemo-nave&primarytumors2cm(N=417)BC,breastcancer;FEC,5-fluorouracil,epirubicinandcyclophosphamide*Locallyadvanced=T23,N23,M0orT4ac,anyN,M0;operable=T23,N01,M0;inflammatory=T4d,anyN,M0H,trastuzumab;P,pertuzumab;T,docetaxelGianni L et al.SABCS 2010NeoSphere:study designTHP(n=43H,trastuzumab;P,pertuzumab;T,docetaxelNeoSphere pCR rates:ITT population summaryp=0.014150403020100THTHPHPTPpCR,%95%CIp=0.0198p=0.0198p=0.00329.045.816.824.06Gianni L et al.SABCS 2010H,trastuzumab;P,pertuzuma44010203040506070THTHPHPTPER or PR posER and PR neg20.026.017.436.829.130.063.25.9pCR,%95%CIH,trastuzumab;P,pertuzumab;T,docetaxelGianni L et al.SABCS 2010NEOSPHERE:pCR and hormone receptors status010203040506070THTHPHPTPER or 45L:lapatinib;T:trastuzumab;L+T:lapatinib plus trastuzumabpCR pathologic complete response HR:hormone receptors pCR by hormone receptor statusBaselga J et al.SABCS 2010L:lapatinib;T:trastuzumab;46T:trastuzumab;L:lapatinib;T+L:trastuzumab plus lapatinibCHER-LOB:pCR rate by HR25%22.7%0102030405060Arm A(CT+T)Arm B(CT+L)Arm C(CT+T+L)26.6%35.7%56.2%35.7%HR+HR+HR+HR-HR-HR-T:trastuzumab;L:lapatinib;47Trial/author pts#RegimenHR+%pCRHR-HR+Kemeny54FACVb6620.07.7Ring435CMF,A/E7121.68.1Bear1211AC5913.65.7Bear565AC+T5722.814.1GEPARDO250ddAD+/-T5615.41.1GEPARDUO913ddAD/CA-D7422.86.2GEPARTRIO286TAC/TAC-NX6836.610.1Guarneri1731FAC+/-P6823.87.8Gianni438A+/P/CMF6342.211.6Guarneri201FEC/ET/GET7416.63.5Colleoni399ECF/EC/ET/ViFuP6833.37.6HORMONE RECEPTOR STATUS AND pCR%pCRHR-HR+Kemeny54FACVb6620.048Neoadjuvant therapy in HER2+operable breast cancer:Key FindingsPatient selection is mandatory for the integration of novel agents in cancer treatment Chemotherapy+trastuzumab is the gold standardDouble-HER2 blockade increases the pCR rateEndocrine pathway is still important even in presence of HER2 co-expressionThe preoperative setting is ideal to test new combinations through the“window of opportunity model”Neoadjuvant therapy in HER2+o49Should neoadjuvant regimens for HER2-positive disease always contain anti-HER2 drug?Yes No AIs dual HER2-targeting a reasonable option for the preoperative setting for HER2 disease?Yes No A8.5%87.2%4.3%67.4%21.7%10.9%Neo Adjuvant Systemic TherapySt Gallen 2011Should neoadjuvant regimens fo50VonMinckwitzG,SABCS2010Von Minckwitz G,SABCS 201051VonMinckwitzG,SABCS2010Von Minckwitz G,SABCS 201052VonMinckwitzG,SABCS2010Von Minckwitz G,SABCS 201053OBJECTIVESVonMinckwitzG,SABCS2010OBJECTIVESVon Minckwitz G,SAB54VonMinckwitzG,SABCS2010Von Minckwitz G,SABCS 201055CHARACTERISTICS OF PATIENTSCHARACTERISTICS OF PATIENTS56VonMinckwitzG,SABCS2010Von Minckwitz G,SABCS 201057Neoadjuvant Bevacizumab and Anthracycline-Taxane Based Chemotherapy in 684 Triple Negative Primary Breast Cancers:Secondary Endpoint Analysis of the GEPARQUINTO Study(GBG 44)Gerber B et al.Proc ASCO 2011;Abstract 1006.Gerber B et al.Proc ASCO 2011;Abstract 1006.Gerber B et al.Proc ASCO 2011;Abstract 1006.Neoadjuvant Bevacizumab and An58GEPARQUINTO:Benefit of Bevacizumab Added to Neoadjuvant Chemotherapy in TNBC SubgroupGerber B et al.Proc ASCO 2011;Abstract 1006.Benefit of bev limited to TNBC subgrouppCRbreast(with bev vs without bev)*TNBC patients:36.4 vs 27.8%(p=0.021)All patients:15.0 vs 17.5%(p=NS)*pCRbreast=no inv/non-inv in breast and nodesGerber B et al.Proc ASCO 2011;Abstract 1006.GEPARQUINTO:Benefit of Bevaci59The Effect of pCR of Bevacizumab and/or Antimetabolites Added to Standard Neoadjuvant Chemotherapy:NSABP Protocol B-40Bear HD et al.Proc ASCO 2011;Abstract LBA1005.Bear HD et al.Proc ASCO 2011;Abstract LBA1005.The Effect of pCR of Bevacizum60NSABP B-40:Chemotherapy Bevacizumab in Patients with Operable HER2-Negative Breast CancerOperableBreastCancerRTissue forBiomarkersSURGERYTissue forBiomarkers+/-+/-X10T docetaxelX capecitabine G gemcitabine B bevacizumab NSABP B-40:Chemotherapy Bev61NSABP B-40:Benefit of Adding Bevacizumab to Standard ChemotherapyBear HD et al.Proc ASCO 2011;Abstract LBA1005.Benefit of bev predominant in HR+and not TNBC patient subgrouppCRbreast(with bev vs without bev):HR+patients:23.3 vs 15.2%(p=0.008)TNBC patients:51.3 vs 47.3%(p=0.44)NSABP B-40:Benefit of Adding 62Yes No AIf YES,for which duration(choose one)?2.2%97.8%0%Neo Adjuvant Systemic TherapyIs neodjuvant endocrine therapy alone a reasonable option for postmenopausal pts with highly endocrine-responsive disease?-3-4 months -4-8 months-Maximal response15.2%39.1%45.7%St Gallen 2011Yes No 63Grazie!Grazie!64
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