1、型卵巢癌标记物HE4研究进展1型卵巢癌标记物HE4研究进展2美国美国2008型卵巢癌标记物HE4研究进展3型卵巢癌标记物HE4研究进展4型卵巢癌标记物HE4研究进展5型卵巢癌标记物HE4研究进展6型卵巢癌标记物HE4研究进展7型卵巢癌标记物HE4研究进展8型卵巢癌标记物HE4研究进展9型卵巢癌标记物HE4研究进展10型卵巢癌标记物HE4研究进展11型卵巢癌标记物HE4研究进展12型卵巢癌标记物HE4研究进展13型卵巢癌标记物HE4研究进展14型卵巢癌标记物HE4研究进展15Chromosome 20q12-q13.1 contains a locus with several members
2、of the WFDC family.Amplified in several cancers:ovarian,breast,Colon,pancreatic,lung cancerWFDC gene locus型卵巢癌标记物HE4研究进展16HE4 mRNA expression profileRestricted expression pro normal tissueExpressed in normal epididymis,and epithelia of the respiratory and reproductive tract Tumor-restricted expressi
3、on in ovarian cancer 90%of serous ovarian cancerHE4 mRNA highly expressed in lung adenocarcinomas 60%high expression in AdC 10%high expression in SqCFrom Galgano et al Modern Pathol(2006)19;847-853Expression of HE4 mRNA in cancer型卵巢癌标记物HE4研究进展17HE4 antigen expression in Ovarian cancerGalgano et al M
4、odern Pathol(2006)19;847-853HE4 antigen is highly expressed in serous,endometroid and clear cell ovarian cancerMucinous,germ cell or sex cord ovarian cancer barely express HE4Drapkin et al Cancer Res(2005)65;2162-2169型卵巢癌标记物HE4研究进展18HE4 是一种适宜的卵巢癌血清标志物是一种适宜的卵巢癌血清标志物 HE4 可分泌入体液可分泌入体液 正常卵巢不表达，而在卵巢癌高表达正
5、常卵巢不表达，而在卵巢癌高表达-特异特异性好性好 在早期和晚期在早期和晚期HE4表达均呈高度上调表达均呈高度上调 早早期病例具有高度敏感性期病例具有高度敏感性 HE4的表达独立于的表达独立于CA125的表达的表达 联合检联合检测将较各自单独检测获得更测将较各自单独检测获得更 多的信息多的信息型卵巢癌标记物HE4研究进展19型卵巢癌标记物HE4研究进展20 HE4 EIA 方法的建立方法的建立 主要试剂：主要试剂：2H5 and 3D8 MAb established using HE4-Mouse Ig fusion protein as immunogen Hellstrom et al,C
6、ancer Research 63,3695 3700,2003 检测原理：检测原理：Two-step forward sandwich immunoassay based on Bio 2H5 MAb for catching of HE4 and HRP 3D8 MAb for detection型卵巢癌标记物HE4研究进展21HE4 用于监测卵巢癌用于监测卵巢癌约约 80%患者患者HE4与与CA125相符，与病情一致相符，与病情一致0801602403204004805606407208008809601040112012001280136014400.00.51.01.52.02.53
7、.03.54.04.55.05.56.06.57.07.50801602403204004805606407208008809601040112012001280136014400100020003000400050006000700080009000100001100012000HE4 EIA(pM)Architect CA125II(U/mL)RSRMonths from Initial DrawCA125 (U/mL)HE4 (pM)Study on 80 patients,4,4 observations/patientMeasured concordance between biom
8、arker change&clinical statusCompared HE4 and CA125050010001500200025003000350040004500500055006000650070007500800085000123456789101105001000150020002500300035004000450050005500600065007000750080008500010020030040050060070080090010001100120013001400150016001700180019002000210022002300HE4 EIA(pM)Archi
9、tect CA125II(U/mL)PDSSRSPDMonths from Initial DrawCA125 (U/mL)HE4 (pM)型卵巢癌标记物HE4研究进展2205101520253035404550556065707501234567891011121314151617181905101520253035404550556065707501002003004005006007008009001000110012001300HE4 EIA(pM)Architect CA125II(U/mL)SPDSPDPDPDMonths from Initial DrawCA125 (U/mL)
10、HE4 (pM)HE4 在卵巢癌的动态监测中与在卵巢癌的动态监测中与CA125具有良好的互补性具有良好的互补性Conclusion:HE4 and CA 125 show equivalent but complementary performance for monitoring of ovarian cancer051015202530354045505560657075808590951001050.00.40.81.21.62.02.42.83.23.64.04.44.85.25.60510152025303540455055606570758085909510010505101520
11、253035404550556065707580859095100105HE4 EIA(pM)Architect CA125II(U/mL)PDSSMonths from Initial DrawCA125 (U/mL)HE4 (pM)型卵巢癌标记物HE4研究进展23型卵巢癌标记物HE4研究进展24型卵巢癌标记物HE4研究进展25型卵巢癌标记物HE4研究进展26型卵巢癌标记物HE4研究进展27型卵巢癌标记物HE4研究进展28型卵巢癌标记物HE4研究进展29多中心临床研究多中心临床研究型卵巢癌标记物HE4研究进展30检测样本分布检测样本分布型卵巢癌标记物HE4研究进展31型卵巢癌标记物HE4研究
12、进展32各中心健康人各中心健康人CUT-OFF值的评价值的评价各分中心评价中国健康人群的各分中心评价中国健康人群的CUT-OFF值基本一致，可以选择值基本一致，可以选择73.7pM作为中国作为中国正常健康人群的参考范围正常健康人群的参考范围。型卵巢癌标记物HE4研究进展33结论：结论：以以73.7 pM作为作为CUT-OFF值时，可以大大提高对上皮性卵巢癌病人的诊断率，避值时，可以大大提高对上皮性卵巢癌病人的诊断率，避免漏检。免漏检。以以150 pM作为作为CUT-OFF值时，值时，HE4在健康人群及良性疾患等对照组中的具高特在健康人群及良性疾患等对照组中的具高特异性，能有效的鉴别诊断卵巢良、
13、恶性肿瘤，为临床上皮性卵巢癌的辅助诊断提异性，能有效的鉴别诊断卵巢良、恶性肿瘤，为临床上皮性卵巢癌的辅助诊断提供有力帮助。供有力帮助。型卵巢癌标记物HE4研究进展34入组患者血清入组患者血清HE4水平分布水平分布说明：在干扰样本中，提示高胆红素可能对说明：在干扰样本中，提示高胆红素可能对HE4的检测有干扰，与国外研究结果的检测有干扰，与国外研究结果 一致。一致。型卵巢癌标记物HE4研究进展35型卵巢癌标记物HE4研究进展36HE4浓度变化与病程发展情况统计浓度变化与病程发展情况统计临床动态监测符合率临床动态监测符合率:61/64=95.3%，HE4 可以用于上皮性卵巢可以用于上皮性卵巢癌的疗效
14、监测。癌的疗效监测。型卵巢癌标记物HE4研究进展3732例患者术前例患者术前/术后术后HE4HE4浓度变化图浓度变化图 备注：备注：HE4HE4浓度变化值浓度变化值=（手术后（手术后HE4HE4浓度浓度-手术前手术前HE4HE4浓度）浓度）/手术前手术前HE4HE4浓度浓度100%100%其中其中1-251-25号为阴转样本，号为阴转样本，26-3226-32号为非阴转样本。号为非阴转样本。-120.00%-100.00%-80.00%-60.00%-40.00%-20.00%0.00%20.00%123456 789 10 11 12 13 14 15 16 17 18 19 20 21 2
15、2 23 24 25 26 27 28 29 30 31 32卵巢癌患者姓名HE4浓度变化值（%）型卵巢癌标记物HE4研究进展38型卵巢癌标记物HE4研究进展39型卵巢癌标记物HE4研究进展40型卵巢癌标记物HE4研究进展41型卵巢癌标记物HE4研究进展42型卵巢癌标记物HE4研究进展431 out of 5 women will be diagnosed with an adnexal mass during their lifetime15-10%of women will have surgery for an ovarian neoplasm 13-21%of these masses
16、 will be malignant由妇科肿瘤专科医生施行手术将改善卵巢癌的预后由妇科肿瘤专科医生施行手术将改善卵巢癌的预后问题是：问题是：How do we identify malignant pelvic masses from benign masses?术前确诊可改善卵巢癌预后术前确诊可改善卵巢癌预后型卵巢癌标记物HE4研究进展44Improved survival with surgery by ovarian cancer specialistsPaulsen et al,Int J Gynecol Ca,2006:16;11-17C-45C-45TH:Teaching hosp
17、italNTH:Nonteaching hospitalnType of Surgeon Impacts Survival ratesnType of Hospital Impacts Survival rates型卵巢癌标记物HE4研究进展45型卵巢癌标记物HE4研究进展46 ROMAPremenopausal women Predictive Index(PI)=-12.0+2.38*LNHE4+0.0626*LNCA125 Postmenopausal womenPredictive Index(PI)=-8.09+1.04*LNHE4+0.732*LN CA125 ROMA value
18、=expPI/1+expPI x 100 Risk of Ovarian Malignancy Algorithm(ROMA)valueEstimate of the risk of ovarian cancer given that the patient had a pelvic mass;their HE4 and CA125 values;and their menopausal status 型卵巢癌标记物HE4研究进展47Biomarker and ROMA Scatterplot型卵巢癌标记物HE4研究进展48ROMA Validation trial-ConclusionsAt
19、 a specificity of 75%,the overall sensitivity for EOC+LMP was 89%Overall sensitivity for EOC was 94%Pre-menopausal women 89%Post-menopausal women 95%NPV 94%for EOC+LMP in Pre-and postmenopausal women combinedNPV 97%for EOC 17/279(6%)patients classified as low risk had EOC or LMP 9/17 had LMP tumor 1
20、(0.4%)had late stage(III/IV)cancer ROMA effectively stratifies patients with pelvic mass into groups with low and high risk of having epithelial ovarian cancer型卵巢癌标记物HE4研究进展49C-50Jacobs I et al.Br J Obstet Gynecol.1990;97:992-929.型卵巢癌标记物HE4研究进展50Benign and EOC:All Stages*Two Sample Test of Equality
21、of Proportions p=0.0129CI:Confidence Interval型卵巢癌标记物HE4研究进展51Benign and EOC:Stage I&II*Two Sample Test of Equality of Proportions p=0.0510CI:Confidence Interval型卵巢癌标记物HE4研究进展52型卵巢癌标记物HE4研究进展53型卵巢癌标记物HE4研究进展54型卵巢癌标记物HE4研究进展55型卵巢癌标记物HE4研究进展56型卵巢癌标记物HE4研究进展57型卵巢癌标记物HE4研究进展58r=0.14P=0.125r=0.475P0.05型卵巢癌标记物HE4研究进展59HE4:ROC-AUC=0.453 HE4:ROC-AUC=0.453 型卵巢癌标记物HE4研究进展60HE4:ROC-AUC=0.933 CA125:ROC-AUC=0.821 HE4+CA125:ROC-AUC=0.936 型卵巢癌标记物HE4研究进展61型卵巢癌标记物HE4研究进展62型卵巢癌标记物HE4研究进展63型卵巢癌标记物HE4研究进展64型卵巢癌标记物HE4研究进展65型卵巢癌标记物HE4研究进展66
