1、乳腺癌新辅助治疗临床思路The first generation of neoadjuvant clinical trials-NSABP 18 The second generation of neoadjuvant clinical trials-NSABP 27NSABP-B18/27Neoadjuvant vs adjuvant“AC”Rastogi et al JCO 1,Neo-adjuvant=Adjuvant 2,pCR is a good surrogate marker for long-term outcome 3,NSABP-27 showed that the add
2、ition of preoperative taxanes to AC improve the responseQuestion In the second generation of neoadjuvant clinical,although addition of taxanes generally led to higher pCR rates,a clinically meaningful improvement in long-term outcomes was not shown consistently early improvements in pCR rates cannot
3、 yet act as surrogate endpoints most neoadjuvant trials undertaken so far have enrolled unselected populations of patients.Part:Proposal for the standard characterisation of the population to treatGianni L EW,Semiglazov V,et al.SABC (abstract 31/Leone JP et al.J Clin Oncol 27:15s,(suppl;abstr 625)Ch
4、ang HR et al.J Clin Oncol 26:(May 20 suppl;abstr 604)the genomic complexity of breast cancer has started to be appreciated,with several subtypes with specific molecular profiles Subtypes by IHC -ASCO/CAP guidelinesShanghai Breast Cancer Survival Study datasSu et al.BMC Cancer ,11:292biomedcentral/14
5、71-2407/11/292HER2 positive4cycles Neo THLuminalB4cycles Neo XTTripe negative4cycles Neo TPPathology,IHCsubtypesLuminal A subtype subtype：ER+or+or PR+，HER2-,Ki6714%-,Ki6716%-,Ki6716%Luminal B subtype,Her2+:HER2+subtype+subtype：ER-PR-，HER2+TNBCTNBC：ER-、PR-、HER2-Neoadjuvant in BC -phase trialSubtypesS
6、ubtypesLuminal BHER2+veTNBCregimesCapecitabine+DocetaxelPaclitaxel+TrastuzumabPaclitaxel+DDPnumbers90 (42%)90 (42%)33 (16%)Median age45(26-69)47(26-76)46 (29-66)绝经前64 (71.1%)59 (65.6%)22 (66.7%)绝经后26 (28.9%)31 (34.4%)11 (33.3%)Grade 117 (18.9%)0 (0%)0 (0%)261 (67.8%)69 (76.7%)19 (57.6%)312 (13.3%)21
7、 (23.3%)14 (42.2%)Tumor size T19 (10%)7 (7.8%)4 (12.1%)T266 (73.3%)58 (64.4%)21 (63.6%)T39 (10%)16 (17.8%)4 (12.1%)T46 (6.7%)9 (10.0%)4 (12.2%)Node N045 (50%)39 (43.3%)18 (54.5%)N136 (40%)40 (44.4%)12 (36.4%)N25 (5.6%)8 (8.9%)1 (3.0%)N34 (4.4%)3 (3.3%)2 (6.1%)Stage II71 (78.9%)66 (73.3%)25 (75.8%)II
8、I19 (21.1%)24 (26.7%)8 (24.2%)213 patients(median follow up 24months)SubtypesLuminal BHER2+ve TNBCRegimesXTTHTPnumber90(42%)90(42%)33(16%)clinicalclinicalCR19(21.1%)47(52.2%)14(42.4%)PR52(57.8%)36(40.0%)14(42.4%)SD18(20%)7(7.8%)5(15.2%)PD1(1.1%)0(0%)0(0%)pathologypCR13(14.4%)39(43.3%)11(33.3%)non-pC
9、R77(85.6%)51(56.7%)22(66.7%)Breast pCR20(22.2%)40(44.4%)20(60.6%)Total pCR29.6%(61/213)ORR85.4%(182/213)ResultsAll patients6377Eligible with known HER2-status4387HER2 negative3060HER2 positivew/o trastuzumab665HER2 positivewith trastuzumab662pCR454pCR119pCR181no pCR2606no pCR546no pCR481pCR-Rate*14.
10、8%pCR-Rate*17.9%pCR-Rate*27.3%*ypT0 ypN0AGOOS analysis by pCRArmNEventspositive w trast48135positive w/o trast54675negative2606310No pCRArmNEventspositive w trast 1811positive w/o trast1199negative45414pCR n=662 HER2+with trastuzumab n=3060 HER2 negative n=665 HER2+;no trastuzumabLog-rank vs p=0.134
11、 vs p=0.384 网站显示全球目前正在进行中的总共有网站显示全球目前正在进行中的总共有15项乳腺癌新辅助化疗的项乳腺癌新辅助化疗的III期临床试验期临床试验其中有其中有7项是基于分子分型的试验，受试对象为三阴性乳腺癌或项是基于分子分型的试验，受试对象为三阴性乳腺癌或HER2阳性乳腺癌阳性乳腺癌未进行分子分型的试验未进行分子分型的试验8项，其中项，其中5项新药试验，项新药试验，3项寻求验证新的分子标志物的项寻求验证新的分子标志物的指导意义的试验，指导意义的试验，1项研究双膦酸盐疗效的试验项研究双膦酸盐疗效的试验已经没有正在进行中的非基于分子分型的标准化疗的乳腺癌新辅助化疗临床试验已经没有正
12、在进行中的非基于分子分型的标准化疗的乳腺癌新辅助化疗临床试验Part:Proposal for Use of the functional and molecular imagine as endpoint?MRI-Ultrasonography-Mammography-PET-CT-MammographyIs controversial with respect to both assessment of disease extent and response to treatment.False-positive findings on breast MRI can arise after
13、 neoadjuvant chemotherapy.It could overestimate the extent of residual disease.Findings suggest that the value of MRI could be of particular importance for some BC subtype.MRI to be the most promising research imaging method to investigate in the neoadjuvant setting at present tends to overestimate
14、residual tumour volume and,compared with mammography and MRI,it has the highest rate of false-positive findings and low specificity specificity of mammography is low and prediction of pathological outcome is poor,especially when calcifications are present.Results available on use of (FDG)PET-CT in t
15、he neoadjuvant setting are contradictory Part:Proposal for Use of the functional and molecular imagine as endpoint?PET CT-1have shown that metabolic information obtained from FDG-PET provides a reliable marker of tumour viability and treatment response,being associated with response to neoadjuvant c
16、hemotherapy at an early stage,and accurately visualising lymph-node metastases 2 Current guidelines do not support use of FDG-PET or FDG-PET with CT for staging of breast cancer because of the high false-negative rate for detection of lesions that are small(16%EDC方案对于特定患者可以显著提高pCR率绝经前biomedcentral/1
17、471-2407/11/292HER2 positiveHER2 positive1 (3.Capecitabine+Docetaxel18 (54.21 (63.Retrospective analysis of a database including 2302 patients with neoadjuvant chemotherapy at MD Anderson Cancer Center indicated no significant difference in DFS and OS between PCR and residual DCISPaclitaxel+DDPT400;
18、Specificity:0.Eur J Nucl Med Mol Imaging ;37:106976.4 (12.HER2 positivePart:Proposal for Use of the functional and molecular imagine as endpoint?In our study-conclusions1.For PET CT,the metabolic response obtained on the end of neoadjuvant chemotherapy may be useful in determining histopathologic no
19、n-responders with high negative predictive value of 95.1%2.Different molecular phenotypes based on IHC reflect different metabolic properties.As our result,the luminal B subtype obtain a best predictive value,the less proliferation subgroup luminal A were the worst.3.PET CT may be a good functional
20、and molecular imagine as the predicitive response for LuminalB/TNBC subtypes90 (42%)Characteristics of patientsn=3060 HER2 negativeFuture perspectives and conclusionsN=71 evaluableTumor size T124 (26.69 (76.绝经前4 cycles neo9 (10%)Paclitaxel+DDP1,National Cancer Institute.Part :Evaluation of the respo
21、nse to treatment1,PCR31 (34.Part :Proposal for the standard evaluation of the response to treatment 1,PCRAn intermediate endpoint for breast cancer relapse and survival-To assess the pathological response to neoadjuvant treatment and to define PCR varies between clinical trialsPart :Evaluation of th
22、e response to treatment1,PCRNode-negative status after treatment have excellement survival-Retrospective analysis of a database including 2302 patients with neoadjuvant chemotherapy at MD Anderson Cancer Center indicated no significant difference in DFS and OS between PCR and residual DCISIII期、随机、对照
23、试验，新辅助治疗期、随机、对照试验，新辅助治疗样本量：样本量：512主要研究终点：主要研究终点：pCR率率ABCSG-24 试验：主要研究终点的亚组分析试验：主要研究终点的亚组分析N=512分层因素：月经状态 激素受体状态 组织学分级 HER2受体状态 研究点6 x 表柔比星表柔比星多西他赛多西他赛手手术术HER2(-)HER2(+)HER2(-)HER2(+)曲妥珠单抗曲妥珠单抗安慰剂安慰剂6 x 表柔比星表柔比星多西他赛多西他赛卡培他滨卡培他滨N=89随随机机化化随随机机化化活检活检Steger GG,et al.ASCO Abst 530.25 30 0 5 10 15 20患者患者(%
24、)ED EDCpCREDC方案对于特定患者可以显著提高方案对于特定患者可以显著提高pCR率率Steger GG,et al.ASCO Abst 530.OROR95%CI95%CIP P值值肿瘤较小肿瘤较小0.610.44-0.840.003组织学类型：导管组织学类型：导管0.390.16-0.930.03HR(-)HR(-)0.210.14-0.340.0001病理分化级别病理分化级别G3G33.672.3-5.90.0001经logist回归模型分析无关临床淋巴结状态、停经状态以及HER2受体状态均可从EDC方案中获得一致的pCRPart :Evaluation of the respon
25、se to treatment2,Ki-67The standard cutoff for the value of Ki67 as a response endpoint?Measurement of Ki 67Part :Evaluation of the response to treatment3,Preoperative Endocrine Prognostic Index(PEPI)Predict long-term outcome(relapse-free/OS)in patients treated with neoadjuvant Endocrine therapy:Ki67
26、 indexPathological tumor sizeNodal statusER statusPart :Standard evaluation of the response to the treatmentconclusionPart:Standard definition of survival endpoint?-is lacking STEEP system-standardised definition for efficacy endpointIssue:how to define the starting point for assessment of time-to-e
27、vent data-DFS has been defined inconsistently either from the date of study entry or from the date of surgery-STEEP system in adjuvant setting,the starting point of these events,either the date of the first course of treatment,or the date surgerySystemic treatment pCR vs long-term outcomes in neoadj
28、uvant Future perspectives and conclusions the neoadjuvant setting can be used for both therapeutic and research purposes,one can envisage a future in which neoadjuvant treatment could be recommended to all patients eligible for adjuvant chemotherapy on the basis of their clinical and molecular characteristics.Further insights into understanding the mechanism of action of new drugs and identification of predictive and prognostic biomarkers could instead derive from implementation of biological window or other presurgical trials.Thank you!谢谢观看！
