乳腺癌新輔助治療臨床思路

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) 絕經前64 (71.1%)59 (65.6%)22 (66.7%) 絕經后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、 人的價值，在招收誘惑的一瞬間被決定。22.3.7

9、22.3.7Monday, March 07, 202210、低頭要有勇氣，抬頭要有低氣。23:30:4623:30:4623:303/7/2022 11:30:46 PM11、人總是珍惜為得到。22.3.723:30:4623:30Mar-227-Mar-2212、人亂于心，不寬余請。23:30:4623:30:4623:30Monday, March 07, 202213、生氣是拿別人做錯的事來懲罰自己。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時30分46秒23:30:4622.3.

10、715、一個人炫耀什么，說明他內心缺少什么。2022年3月下午11時30分22.3.723:30March 7, 202216、業(yè)余生活要有意義，不要越軌。2022年3月7日星期一23時30分46秒23:30:467 March 202217、一個人即使已登上頂峰，也仍要自強不息。下午11時30分46秒下午11時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網站顯示全球目前正在進行中的總共有網站顯示全球目前正在進行中的總共有15項乳腺癌新輔助化療項乳腺癌新輔助化療的的III期臨床試驗期臨床試驗其中有其中有7項是基于分子分型的試驗，受試對象為三陰性乳腺癌或項是基于分子

14、分型的試驗，受試對象為三陰性乳腺癌或HER2陽性乳腺癌陽性乳腺癌未進行分子分型的試驗未進行分子分型的試驗8項，其中項，其中5項新藥試驗，項新藥試驗，3項尋求驗證新的分子標志物的項尋求驗證新的分子標志物的指導意義的試驗，指導意義的試驗，1項研究雙膦酸鹽療效的試驗項研究雙膦酸鹽療效的試驗已經沒有正在進行中的非基于分子分型的標準化療的乳腺癌新輔助化療臨床試驗已經沒有正在進行中的非基于分子分型的標準化療的乳腺癌新輔助化療臨床試驗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、隨機、對照試驗，新輔助治療期、隨機、對照試驗，新輔助治療樣本量：樣本量：512主要研究終點：主要研究終點：pCR率率ABCSG-24 試驗：主要研究終點的亞組分析試驗：主要研究終點的亞組分析N=512分層因素： 月經狀態(tài) 激素受體狀態(tài)

30、組織學分級 HER2受體狀態(tài) 研究點6 x 表柔比星表柔比星多西他賽多西他賽手手術術HER2 (-)HER2 (+)HER2 (-)HER2 (+)曲妥珠單抗曲妥珠單抗安慰劑安慰劑6 x 表柔比星表柔比星多西他賽多西他賽卡培他濱卡培他濱N=89隨隨機機化化隨隨機機化化活檢活檢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方案對于特定患者可以顯著提高方案對于特定患者可以顯著提高pCR率率Steger GG, et al. ASCO

31、2010 Abst 530.OROR95% CI95% CIP P值值腫瘤較小腫瘤較小0.610.44-0.840.003組織學類型：導管組織學類型：導管0.390.16-0.930.03HR(-)HR(-)0.210.14-0.340.0001病理分化級別病理分化級別G3G33.672.3-5.90.0001經logist回歸模型分析無關臨床淋巴結狀態(tài)、停經狀態(tài)以及HER2受體狀態(tài)均可從EDC方案中獲得一致的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