HE4崔恒北京大学人民医院

1、美国美国2008Chromosome 20q12- q13.1 contains a locus with several members of the WFDC family.Amplified in several cancers: ovarian, breast, Colon, pancreatic, lung cancerWFDC gene locusHE4 mRNA expression profileRestricted expression profile in normal tissueExpressed in normal epididymis, and epithelia

2、of the respiratory and reproductive tract Tumor-restricted expression 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

3、cancerHE4 antigen expression in Ovarian cancerGalgano et al Modern 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;2162-2169HE4 是一种适宜的卵巢癌血

4、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 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 immuno

5、gen Hellstrom et al, Cancer 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 detectionHE4 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.

6、52.02.53.03.54.04.55.05.56.06.57.07.50801602403204004805606407208008809601040112012001280136014400100020003000400050006000700080009000100001100012000HE4 EIA (pM)Architect CA125II (U/mL)RSRMonths from Initial DrawCA125 (U/mL)HE4 (pM)Study on 80 patients, 4,4 observations/patientMeasured concordance b

7、etween biomarker change & clinical statusCompared HE4 and CA12505001000150020002500300035004000450050005500600065007000750080008500012345678910110500100015002000250030003500400045005000550060006500700075008000850001002003004005006007008009001000110012001300140015001600170018001900200021002200230

8、0HE4 EIA (pM)Architect CA125II (U/mL)PDSSRSPDMonths from Initial DrawCA125 (U/mL)HE4 (pM)05101520253035404550556065707501234567891011121314151617181905101520253035404550556065707501002003004005006007008009001000110012001300HE4 EIA (pM)Architect CA125II (U/mL)SPDSPDPDPDMonths from Initial DrawCA125 (

9、U/mL)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 cancer051015202530354045505560657075808590951001050.00.40.81.21.62.02.42.83.23.64.04.44.85.25.6051015202530354045505560657075808590951001050

10、5101520253035404550556065707580859095100105HE4 EIA (pM)Architect CA125II (U/mL)PDSSMonths from Initial DrawCA125 (U/mL)HE4 (pM)多中心临床研究多中心临床研究检测样本分布检测样本分布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。 结论：结论：以以73.7 pM作为作为CUT-OFF值时，

11、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、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。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

12、。HE4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监测。癌的疗效监测。32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%-80.0

13、0%-60.00%-40.00%-20.00%0.00%20.00%123456 789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32卵巢癌患者姓名HE4浓度变化值（%）1 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 will be

14、 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Improved survival with surgery by ovarian cancer specialistsPaulsen et al, Int J Gynecol Ca, 2006: 16; 11-17C- 45C- 45TH: Teaching hospitalNTH: Nonteach

15、ing hospitalnType of Surgeon Impacts Survival ratesnType of Hospital Impacts Survival rates 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 = expPI / 1 + expPI x 100 Risk of

16、 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 Biomarker and ROMA ScatterplotROMA Validation trial - ConclusionsAt a specificity of 75%, the overall sensitivity for EOC

17、+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 (0.4%) had late stage (III/IV) cancer ROMA e

18、ffectively stratifies patients with pelvic mass into groups with low and high risk of having epithelial ovarian cancerC- 50Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.Pre & PostMenopausalBenign (n = 315) vs EOC (n = 124)Sensitivity* (95% CI)Specificity (95% CI)RMI85% (77% to 90%)75% (70% to 80%)ROMA94% (89% to 98%)75% (70% to 80%)Benign and EOC: All Stages*Two Sample Test of Equality of Propo