乳腺癌新辅助治疗临床思路

1、乳腺癌新辅助治疗临床思路乳腺癌新辅助治疗临床思路 Neoadjuvant of treatment for breast cancer The first generation of neoadjuvant clinical trials - NSABP 18 The second generation of neoadjuvant clinical trials-NSABP 27 NSABP-B18/27 Neoadjuvant vs adjuvant “AC” Rastogi et al JCO 2008 1, Neo-adjuvant = Adjuvant 2, pCR is a goo

2、d surrogate marker for long-term outcome 3, NSABP-27 showed that the addition of preoperative taxanes to AC improve the response 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

3、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. Part :Proposal for the standard characterisation of the population to treat Gianni L EW, Semiglazov V,

4、 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 Subtypes by IHC -A

5、SCO/CAP guidelines Shanghai Breast Cancer Survival Study datas Su et al. BMC Cancer 2011, 11:292 HER2 positive 4cycles Neo TH LuminalB 4cycles Neo XT Tripe negative 4cycles Neo TP Pathology,IHC subtypes Luminal A subtype subtype：ER+ or + or PR + + ，HER2-,Ki6714%-,Ki6716%-,Ki6716% Luminal B subtype,H

6、er2+: HER2+subtype+subtype：ER- -PR- -，HER2+ + TNBCTNBC：ER-、PR-、HER2- - Neoadjuvant in BC - phase trial SubtypesSubtypesLuminal BHER2+veTNBC regimesCapecitabine+DocetaxelPaclitaxel+TrastuzumabPaclitaxel+DDP numbers90 (42%)90 (42%)33 (16%) Median age45 (26-69)47 (26-76)46 (29-66) 绝经前64 (71.1%) 59 (65.

7、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%) T46 (6.7%)9 (10.0%)4 (12.2%) Node N045 (50%)39 (43.3%)18

8、(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) SubtypesLuminal BHER2+ve TNBC RegimesXTTHTP number90(42%)90(42%)33(16%) clinicalclinical CR19(

9、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%) pathology pCR13(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) Results All patients 6377 Eligible with known

10、 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 OS analysis by pCR ArmNEvents positive w trast48135 positive w/o trast546

11、75 negative2606310 No pCR ArmNEvents positive w trast 1811 positive w/o trast1199 negative45414 pCR n= 662 HER2+ with trastuzumab n= 3060 HER2 negative n= 665 HER2+; no trastuzumab Log-rank vs p=0.134 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

12、，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 a

13、s 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.Findin

14、gs 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 ra

15、te 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 the neoadjuvant setting are contradictory Part : Proposal for Use of the functio

16、nal 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 meta

17、stases 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

18、 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. Study N = 71 patients N = 71 evaluable PET CT study 71 patients before neo chemothearpy 4 cycles neo Our PET ima

19、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 co

20、re needle biopsy Characteristics of patients 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 , the sensitivity is , while the specificity is. 95% CI: 0.568-0.826, , negative

21、 predictive value is 95.1%, positive predictive value is 32.4%. The SUV decrease rate and tumor response Receiver operating characteristic curve between SUV decrease rate and pathologic complete response. The and reveals a sensitivity of and specificity of 0.453. ROC curves of different subtypes A H

22、ER2: Area under curve: B Luminal A: Area under curve: C Luminal B: Area under curve: D Triple negative: Area under curve: ; Sensitivity: 1.00; Specificity:0.750; 95%CI: 0.00-1.00 AB C D Part : Proposal for Use of the functional and molecular imagine as endpoint? In our study-conclusions 1.For PET CT

23、, 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% 2. Different molecular phenotypes based on IHC reflect different metabolic properties . As our result, the luminal B subty

24、pe 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 Part :Proposal for the standard evaluation of the response to treatment 1, PCR An intermediate

25、 endpoint for breast cancer relapse and survival -To assess the pathological response to neoadjuvant treatment and to define PCR varies between clinical trials Part :Evaluation of the response to treatment 1, PCR Node- negative status after treatment have excellement survival- Retrospective analysis

26、 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 III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

27、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 2010 Abst 530. 25 30 0 5 10 15 20 患者患者 (%) ED EDC pCR EDC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. AS

28、CO 2010 Abst 530. OROR95% CI95% CIP P值值 肿瘤较小肿瘤较小 0.610.44- 0.84 0.003 组织学类型：导管组织学类型：导管 0.390.16- 0.93 0.03 HR(-)HR(-) 0.210.14- 0.34 0.0001 病理分化级别病理分化级别G3G3 3.672.3-5.90.0001 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pCR Part :Evaluation of the response to treatment 2, Ki-67 The standard

29、 cutoff for the value of Ki67 as a response endpoint ? Measurement of Ki 67 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 Part :Standard evaluation of the response to the treatment conclusion Part :Standard definition of survival endpoint? - is lacki