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-B18/27Neoadjuvant vs adjuvant “AC”Rastogi et al JCO 20081, Neo-adjuvant=Adjuvant 2, pCR is a good su

2、rrogate 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 outc

3、omes 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 treatGianni L EW, Semiglazov V, et

4、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 -ASCO/C

5、AP guidelines.Shanghai Breast Cancer Survival Study datasSu et al. BMC Cancer 2011, 11:292.HER2 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+subtyp

6、e+subtype：ER- -PR- -，HER2+ +TNBCTNBC：ER-、PR-、HER2- -Neoadjuvant in BC - phase trial.SubtypesSubtypesLuminal 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

7、.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 (54.5%) N136 (40%)40 (44.4%

8、)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 TNBCRegimesXTTHTPnumber90(42%)90(42%)33(16%)clinicalclinicalCR19(21.1%)47(52.2%)14(42.4%)PR52(57.8

9、%)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-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 patients6377Eligible with known HER2-status4387HER2 negative3060HER2 positiv

10、ew/o trastuzumab665HER2 positivewith trastuzumab662pCR454pCR119pCR181no pCR2606no pCR546no pCR481pCR-Rate*14.8%pCR-Rate*17.9%pCR-Rate*27.3%*ypT0 ypN0AGO.OS analysis by pCRArmNEventspositive w trast48135positive w/o trast54675negative2606310No pCRArmNEventspositive w trast 1811positive w/o trast1199n

11、egative45414pCR n= 662 HER2+ with trastuzumab n= 3060 HER2 negative n= 665 HER2+; no trastuzumabLog-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，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

12、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 as endpoint? MRI- Ultrasonography- Mammography- PET-CT- MammographyIs controversial with

13、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. M

14、RI 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 p

15、rediction 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 functional and molecular imagine as endpoint?PET CT-1have shown that metabolic information obta

16、ined 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 o

17、f 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, 20112, Duch J, et al. . Eur J Nucl Med M

18、ol Imaging 2009; 36: 155157. 3, Straver ME, et al. Eur J Nucl Med Mol Imaging 2010; 37: 106976. .StudyN = 71 patients N = 71 evaluablePET CT study71 patients before neo chemothearpy4 cycles neoOur PET imaging study The changes in the glucose uptake value should be associated with the tumors respond

19、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 . Characteristics of patients.Primary result- For all cases AUCFigure.1. The rec

20、eiver 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 predictive value is 95.1%, positive predictive value is 32.4%. .The SUV decrease rate and tumor

21、 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 subtypesA HER2: Area under curve:B Luminal A: Area under curve:C Luminal B: Area under curve:D Triple negati

22、ve: Area under curve: ; Sensitivity: 1.00; Specificity:0.750; 95%CI: 0.00-1.00 ABCD.Part : 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 hi

23、stopathologic 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 predictive value, the less proliferation subgroup luminal A were the worst. 3. PET CT ma

24、y 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, PCRAn intermediate endpoint for breast cancer relapse and survival-To assess the pathological response to neoadjuvant treatm

25、ent and to define PCR varies between clinical trials.Part :Evaluation of the 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

26、 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

27、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 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 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G3G3

28、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 treatment2, Ki-67The standard cutoff for the value of Ki67 as a response endpoint ?Measurement of Ki 67.Part :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 sizeNodal statusER status.Part :Standard evaluation of the response to the treatmentconclusion.Part :Standard definition of survival endpoint?- is lacking STEEP syst