乳腺癌新辅助治疗临床思路

1、Neoadjuvant of treatment for breast cancer12021/4/26The first generation of neoadjuvant clinical trials - NSABP 18 22021/4/26The second generation of neoadjuvant clinical trials-NSABP 2732021/4/26NSABP-B18/27Neoadjuvant vs adjuvant “AC”Rastogi et al JCO 20081, Neo-adjuvant=Adjuvant 2, pCR is a good

2、surrogate marker for long-term outcome 3, NSABP-27 showed that the addition of preoperative taxanes to AC improve the response42021/4/26Question In the second generation of neoadjuvant clinical,although addition of taxanes generally led to higher pCR rates, a clinically meaningful improvement in lon

3、g-term outcomes was not shown consistently early improvements in pCR rates cannot yet act as surrogate endpoints most neoadjuvant trials undertaken so far have enrolled unselected populations of patients. 52021/4/26Part :Proposal for the standard characterisation of the population to treatGianni L E

4、W, 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 6202

5、1/4/26Subtypes by IHC -ASCO/CAP guidelines72021/4/26Shanghai Breast Cancer Survival Study datasSu et al. BMC Cancer 2011, 11:292biomedcentral/1471-2407/11/29282021/4/26HER2 positive4cycles Neo THLuminalB4cycles Neo XTTripe negative4cycles Neo TPPathology,IHCsubtypesLuminal A subtype subtype：ER+ or +

6、 or PR + +，HER2-,Ki6714%-,Ki6716%-,Ki6716%Luminal B subtype,Her2+:HER2+subtype+subtype：ER- -PR- -，HER2+ +TNBCTNBC：ER-、PR-、HER2- -Neoadjuvant in BC - phase trial92021/4/26SubtypesSubtypesLuminal BHER2+veTNBCregimesCapecitabine+DocetaxelPaclitaxel+TrastuzumabPaclitaxel+DDPnumbers90 (42%)90 (42%)33 (16

7、%)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 (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

8、%) 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%) III19 (21.1%)24 (26.7%)8 (24.2%)213 patients (median follow up 24months)102021/4/269、 人的价值，在招收诱惑的一瞬间被决定。22.3.7

9、22.3.7Monday, March 07, 202210、低头要有勇气，抬头要有低气。23:30:4623:30:4623:303/7/2022 11:30:46 PM11、人总是珍惜为得到。22.3.723:30:4623:30Mar-227-Mar-2212、人乱于心，不宽余请。23:30:4623:30:4623:30Monday, March 07, 202213、生气是拿别人做错的事来惩罚自己。22.3.722.3.723:30:4623:30:46March 7, 202214、抱最大的希望，作最大的努力。2022年3月7日星期一下午11时30分46秒23:30:4622.3.

10、715、一个人炫耀什么，说明他内心缺少什么。2022年3月下午11时30分22.3.723:30March 7, 202216、业余生活要有意义，不要越轨。2022年3月7日星期一23时30分46秒23:30:467 March 202217、一个人即使已登上顶峰，也仍要自强不息。下午11时30分46秒下午11时30分23:30:4622.3.7SubtypesLuminal BHER2+ve TNBCRegimesXTTHTPnumber90(42%)90(42%)33(16%)clinicalclinicalCR19(21.1%)47(52.2%)14(42.4%)PR52(57.8%)3

11、6(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-pCR77(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)Results122021/4/26All patients6377Eligible with known HER2-status4387HER2 negative3060HER2

12、positivew/o trastuzumab665HER2 positivewith trastuzumab662pCR454pCR119pCR181no pCR2606no pCR546no pCR481pCR-Rate*14.8%pCR-Rate*17.9%pCR-Rate*27.3%*ypT0 ypN0AGO132021/4/26OS analysis by pCRArmNEventspositive w trast48135positive w/o trast54675negative2606310No pCRArmNEventspositive w trast 1811positi

13、ve w/o trast1199negative45414pCR n= 662 HER2+ with trastuzumab n= 3060 HER2 negative n= 665 HER2+; no trastuzumabLog-rank vs p=0.058 vs p=0.134 vs p=0.295 vs p=0.384 142021/4/26ClinicalT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项乳腺癌新辅助化疗的的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

14、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152021/4/26Part : Proposal for Use of the functional and molecular imagine as endpoint?

15、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 neoadjuvant chemotherapy. It could overestimate the extent of residual disease.Findings suggest th

16、at 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-p

17、ositive 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 the neoadjuvant setting are contradictory 162021/4/26Part : Proposal for Use of the functiona

18、l 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 chemotherapy at an early stage , and accurately visualising lymph-node metastas

19、es 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 Inst

20、itute. Breast cancer treatment (PDQ). Nov 21, 20112, 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. 172021/4/26StudyN = 71 patients N = 71 evaluablePET CT study71 patients before neo chemothearpy4 cycles neoOur PET ima

21、ging 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 cor

22、e needle biopsy 182021/4/26 Characteristics of patients192021/4/26Primary result- For all cases AUCFigure.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.

23、674. 95% CI: 0.568-0.826, , negative predictive value is 95.1%, positive predictive value is 32.4%. 202021/4/26The 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.

24、852 and specificity of 0.453.212021/4/26ROC curves of different subtypesA HER2: Area under curve: 0.679; Sensitivity: 0.500; Specificity: 0.857; 95% CI:0.370-0.987B Luminal A: Area under curve: 0.188; Sensitivity: 0.00; Specificity:0.375; 95% CI:0.00-1.00C Luminal B: Area under curve: 0.889; Sensiti

25、vity: 1.00; Specificity:0.778; 95% CI:0.353-0.916D Triple negative: Area under curve: 0.875; Sensitivity: 1.00; Specificity:0.750; 95%CI: 0.00-1.00 ABCD222021/4/26Part : Proposal for Use of the functional and molecular imagine as endpoint?In our study-conclusions1.For PET CT, the metabolic response

26、obtained on the end of neoadjuvant chemotherapy may be useful in determining histopathologic non-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 predictiv

27、e 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 subtypes232021/4/26Part :Proposal for the standard evaluation of the response to treatment 1, PCRAn intermediate endpoint for bre

28、ast cancer relapse and survival-To assess the pathological response to neoadjuvant treatment and to define PCR varies between clinical trials242021/4/26Part :Evaluation of the response to treatment1, PCRNode- negative status after treatment have excellement survival-Retrospective analysis of a datab

29、ase including 2302 patients with neoadjuvant chemotherapy at MD Anderson Cancer Center indicated no significant difference in DFS and OS between PCR and residual DCIS252021/4/26III期、随机、对照试验，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

30、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 2010 Abst 5262021/4/26 25 30 0 5 10 15 20患者患者 (%)ED EDCpCR16.024.3p=0.02EDC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

31、2010 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pCR272021/4/26Part :Evaluation of the response to treatment2, Ki-67The standard cutoff for th

32、e value of Ki67 as a response endpoint ?Measurement of Ki 67282021/4/26Part :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 indexPathological tumor sizeNod

33、al statusER status292021/4/26Part :Standard evaluation of the response to the treatmentconclusion302021/4/26Part :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-event dat

34、a-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 surgery312021/4/26Systemic treatment pCR vs long-term outcomes in n

35、eoadjuvant 322021/4/26Future 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 o