乳腺癌新辅助治疗临床思路PPT课件

乳腺癌新辅助治疗临床思路,1,Neoadjuvant of treatment for breast cancer,2,The first generation of neoadjuvant clinical trials - NSABP 18,3,The second generation of neoadjuvant clinical trials-NSABP 27,4,NSABP-B18/27 Neoadjuvant vs adjuvant “AC”,Rastogi et al JCO 2008,1, Neo-adjuvant = Adjuvant,2, pCR is a good surrogate marker for long-term outcome,3, NSABP-27 showed that the addition of preoperative taxanes to AC improve the response,5,Question,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 consistentlyearly improvements in pCR rates cannot yet act as surrogate endpointsmost neoadjuvant trials undertaken so far have enrolled unselected populations of patients.,6,Part :Proposal for the standard characterisation of the population to treat,Gianni L EW, Semiglazov V, et al. SABC 2008 (abstract 31/ Leone JP et al.J Clin Oncol 27:15s, 2009 (suppl; abstr 625) Chang HR et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 604),the genomic complexity of breast cancer has started to be appreciated, with several subtypes with specific molecular profiles,7,Subtypes by IHC -ASCO/CAP guidelines,8,Shanghai Breast Cancer Survival Study datas,Su et al. BMC Cancer 2011, 11:292 http:/www.biomedcentral.com/1471-2407/11/292,9,HER2 positive 4cycles Neo TH,LuminalB 4cycles Neo XT,Tripe negative 4cycles Neo TP,Pathology,IHC,subtypes Luminal A subtype：ER+ or PR +，HER2-,Ki6716% Luminal B subtype,Her2+: HER2+subtype：ER-PR-，HER2+ TNBC：ER-、PR-、HER2-,Neoadjuvant in BC - phase trial,10,213 patients (median follow up 24months),11,Results,12,All patients 6377,Eligible with known HER2-status 4387,HER2 negative 3060,HER2 positive w/o trastuzumab 665,HER2 positive with trastuzumab 662,pCR 454,pCR 119,pCR 181,no pCR 2606,no pCR 546,no pCR 481,pCR-Rate* 14.8%,pCR-Rate* 17.9%,pCR-Rate* 27.3%,*ypT0 ypN0,AGO,13,OS analysis by pCR,No pCR,pCR,n= 662 HER2+ with trastuzumabn= 3060 HER2 negativen= 665 HER2+; no trastuzumab,Log-rankvs p=0.058vs p=0.134,vs p=0.295vs p=0.384,14,ClinicalTrial.gov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III期临床试验 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HER2阳性乳腺癌 未进行分子分型的试验8项，其中5项新药试验，3项寻求验证新的分子标志物的指导意义的试验，1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,15,Part : Proposal for Use of the functional and molecular imagine as endpoint?,MRI-Ultrasonography-Mammography- PET-CT-Mammography,Is controversial with respect to both assessment of disease extent and response to treatment. False-positive findings on breast MRI can arise after 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 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 pathologicaloutcome is poor, especially when calcifications are present.,Results available on use of (FDG) PET-CT in the neoadjuvant setting are contradictory,16,Part : Proposal for Use of the functional and molecular imagine as endpoint?,PET CT- have shown that metabolic information obtained from FDG-PET provides a reliable marker of tumour viability and treatment response, being associated with response to neoadjuvant chemotherapy 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 (1 cm) or low grade, the relatively low sensitivity for detection of axillary nodal metastases,1, National Cancer Institute. Breast cancer treatment (PDQ). Nov 21, 2011 2, Duch J, et al. . Eur J Nucl Med Mol Imaging 2009; 36: 155157. 3, Straver ME, et al. Eur J Nucl Med Mol Imaging 2010; 37: 106976.,17,Study N = 71 patients,N = 71 evaluable,PET CT study 71 patients before neo chemothearpy,4 cycles neo,Our PET imaging study,The changes in the glucose uptake value should be associated with the tumors respond to NAC, we conducted this retrospective study to investigate the value of PET imaging in the evaluation of respond to NAC in breast cancer.,histological diagnosis and subtype by IHC of breast cancer by core needle biopsy,18,Characteristics of patients,19,Primary result- For all cases AUC,Figure.1. The receiver operating characteristic curve of the overall predictive value of all the cases in the study. The area under curve is 0.697 , the sensitivity is 0.72, while the specificity is 0.674. 95% CI: 0.568-0.826, , negative predictive value is 95.1%, positive predictive value is 32.4%.,20,The SUV decrease rate and tumor response,Receiver operating characteristic curve between SUV decrease rate and pathologic complete response. The AUC is 0.797 and reveals a sensitivity of 0.852 and specificity of 0.453.,21,ROC curves of different subtypes,A HER2: Area under curve: 0.679; Sensitivity: 0.500; Specificity: 0.857; 95% CI:0.370-0.987 B Luminal A: Area under curve: 0.188; Sensitivity: 0.00; Specificity:0.375; 95% CI:0.00-1.00 C Luminal B: Area under curve: 0.889; Sensitivity: 1.00; Specificity:0.778; 95% CI:0.353-0.916 D Triple negative: Area under curve: 0.875; Sensitivity: 1.00; Specificity:0.750; 95%CI: 0.00-1.00,A,B,C,D,22,Part : Proposal for Use of the functional and molecular imagine as endpoint? In our study-conclusions,For PET CT, the metabolic response obtained on the end of neoadjuvant chemotherapy may be useful in determining histopathologic non-responders with high negative predictive value of 95.1%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 and molecular imagine as the predicitive response for LuminalB /TNBC subtypes,23,Part :Proposal for the standard evaluation of the response to treatment 1, PCR,An intermediate endpoint for breast cancer relapse and survival -To assess the pathological response to neoadjuvant treatment and to define PCR varies between clinical trials,24,Part :Evaluation of the response to treatment 1, PCR,Node- 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 DCIS,25,III期、随机、对照试验，新辅助治疗 样本量：512 主要研究终点：pCR率,ABCSG-24 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 多西他赛,手术,HER2 (-),HER2 (+),HER2 (-),HER2 (+),曲妥珠单抗,安慰剂,6 x 表柔比星 多西他赛 卡培他滨,N=89,随机化,随机化,活检,Steger GG, et al. ASCO 2010 Abst 530.,1.2.2,26,患者 (%),ED EDC pCR,16.0,24.3,p=0.02,EDC方案对于特定患者可以显著提高pCR率,Steger GG, et al. ASCO 2010 Abst 530.,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pCR,27,Part :Evaluation of the response to treatment 2, Ki-67,The standard cutoff for the value of Ki67 as a response endpoint ?,Measurement of Ki 67,28,Part :Evaluation of the response to treatment 3 , Preoperative Endocrine Prognostic Index(PEPI),Predict long-term outcome (relapse-free/OS) in patients treated with neoadjuvant Endocrine therapy: Ki67 index Pathological tumor size Nodal status ER status,29,Part :Standard evaluation of the response to the treatment conclusion,30,Part :Standard definition of survival endpoint? - is lacking,STEEP system -standardised definition for efficacy endpoint Issue: how to define the starting point for assessment of time-to-event 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 surgery,31,Systemic treatment pCR vs long-term outcomes in neoadjuvant,32,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.,33,Thank you!,34,