HE4崔恒北京大學(xué)人民醫(yī)院

1、美國美國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 是一種適宜的卵巢癌血

4、清標志物是一種適宜的卵巢癌血清標志物 HE4 可分泌入體液可分泌入體液 正常卵巢不表達，而在卵巢癌高表達正常卵巢不表達，而在卵巢癌高表達-特異特異性好性好 在早期和晚期在早期和晚期HE4表達均呈高度上調(diào)表達均呈高度上調(diào) 早早期病例具有高度敏感性期病例具有高度敏感性 HE4的表達獨立于的表達獨立于CA125的表達的表達 聯(lián)合檢聯(lián)合檢測將較各自單獨檢測獲得更測將較各自單獨檢測獲得更 多的信息多的信息 HE4 EIA 方法的建立方法的建立 主要試劑：主要試劑：2H5 and 3D8 MAb established using HE4-Mouse Ig fusion protein as immuno

5、gen Hellstrom et al, Cancer Research 63, 3695 3700, 2003 檢測原理：檢測原理：Two-step forward sandwich immunoassay based on Bio 2H5 MAb for catching of HE4 and HRP 3D8 MAb for detectionHE4 用于監(jiān)測卵巢癌用于監(jiān)測卵巢癌約約 80%患者患者HE4與與CA125相符，與病情一致相符，與病情一致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 在卵巢癌的動態(tài)監(jiān)測中與在卵巢癌的動態(tài)監(jiān)測中與CA125具有良好的互補性具有良好的互補性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)多中心臨床研究多中心臨床研究檢測樣本分布檢測樣本分布各中心健康人各中心健康人CUT-OFF值的評價值的評價各分中心評價中國健康人群的各分中心評價中國健康人群的CUT-OFF值基本一致，可以選擇值基本一致，可以選擇73.7pM作為中國作為中國正常健康人群的參考范圍正常健康人群的參考范圍。 結(jié)論：結(jié)論：以以73.7 pM作為作為CUT-OFF值時，

11、可以大大提高對上皮性卵巢癌病人的診斷率，避值時，可以大大提高對上皮性卵巢癌病人的診斷率，避免漏檢。免漏檢。 以以150 pM作為作為CUT-OFF值時，值時，HE4在健康人群及良性疾患等對照組中的具高特在健康人群及良性疾患等對照組中的具高特異性，能有效的鑒別診斷卵巢良、惡性腫瘤，為臨床上皮性卵巢癌的輔助診斷提異性，能有效的鑒別診斷卵巢良、惡性腫瘤，為臨床上皮性卵巢癌的輔助診斷提供有力幫助。供有力幫助。入組患者血清入組患者血清HE4水平分布水平分布說明：在干擾樣本中，提示高膽紅素可能對說明：在干擾樣本中，提示高膽紅素可能對HE4的檢測有干擾，與國外研究結(jié)果的檢測有干擾，與國外研究結(jié)果 一致。一致

12、。HE4濃度變化與病程發(fā)展情況統(tǒng)計濃度變化與病程發(fā)展情況統(tǒng)計臨床動態(tài)監(jiān)測符合率臨床動態(tài)監(jiān)測符合率: 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療效監(jiān)測。癌的療效監(jiān)測。32例患者術(shù)前例患者術(shù)前/ /術(shù)后術(shù)后HE4HE4濃度變化圖濃度變化圖 備注：備注：HE4HE4濃度變化值濃度變化值= =（手術(shù)后（手術(shù)后HE4HE4濃度濃度- -手術(shù)前手術(shù)前HE4HE4濃度）濃度）/ /手術(shù)前手術(shù)前HE4HE4濃度濃度100%100% 其中其中1-251-25號為陰轉(zhuǎn)樣本，號為陰轉(zhuǎn)樣本，26-3226-32號為非陰轉(zhuǎn)樣本。號為非陰轉(zhuǎn)樣本。 -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濃度變化值（%）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由婦科腫瘤?？漆t(yī)生施行手術(shù)將改善卵巢癌的預(yù)后由婦科腫瘤?？漆t(yī)生施行手術(shù)將改善卵巢癌的預(yù)后問題是：問題是：How do we identify malignant pelvic masses from benign masses?術(shù)前確診可改善卵巢癌預(yù)后術(shù)前確診可改善卵巢癌預(yù)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 Proportions p=0.0129CI: Confidence IntervalPre & PostMenopausalBenign (n=315) vs Stage I-II EOC (n=35)Sensitivity* (95% CI)Specificity (95% CI)RMI66%