Serial measurements of serum human epididymal protein 4 in patients at risk for ovarian cancer

Objective: Patients with a BRCA1 or BRCA2 gene mutation have an increased lifetime risk of developing epithelial ovarian cancer (EOC). Screening with CA125 and ultrasound is ineffective for detection of EOC at an early stage and does not reduce the mortality rate of EOC. Therefore, women at risk of developing ovarian cancer are recommended to have risk-reducing salpingo-oophorectomy (RRSO). The benefit of the serum marker human epididymis protein 4 (HE4) in screening programmes is still unknown. Therefore, the authors evaluated serial serum HE4 measurements in patients at high risk of developing EOC based on a familiar or genetic predisposition. Materials and Methods: Patients with BRCA1 or BRCA2 mutation or familiar predisposition that developed EOC during screening were selected from the hospital based cancer registry. HE4 was measured in consecutive serum samples. Results: Cross-linking the hospital-based cancer registry with the serum bank resulted in 182 patients who had developed EOC between 1994 and 2013. More than one serum sample was available of 52 patients but of these only seven patients underwent regular screening. HE4 demonstrated a rapid increase in serum levels just before or at time of diagnosis instead of a longer lead time before diagnosis. This is comparable to the concentrations of serum CA125 in consecutive samples. Conclusion: This is the first study showing that serum HE4 values suddenly increase just before diagnosis and do not precede the development of symptoms. This does not support the use of HE4 with a fixed cut-off value for screening in patients at high risk for EOC.

Biomarker; HE4; Screening; BRCA; Epithelial ovarian cancer.

[1] “Dutch Cancer Registration [Internet]”. Available at: www.iknl.nl

[2] Chen S.: “Meta-analysis of BRCA1 and BRCA2 penetrance”. J. Clin. Oncol., 2007, 25, 1329.

[3] Buys S.S., Partridge E., Black A., Johnson C.C., Lamerato L., Isaacs C., et al.: “Effect of screening on ovarian cancer mortality”. JAMA, 2011, 305, 2295.

[4] Marchetti C., De Felice F., Palaia I., Perniola G., Musella A., Musio D., et al.: “Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers”. BMC Womens Health, 2014, 14, 1.

[5] Hermsen B.B.J., Olivier R.I., Verheijen R.H.M., van Beurden M., de Hullu J.A., Massuger L.F., et al.: “No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study”. Br. J. Cancer, 2007, 96, 1335.

[6] Antoniou A., Pharoah P.D.P., Narod S., Risch H.A., Eyfjord J.E., Hopper J.L., et al.: “Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies”. Am. J. Hum. Genet., 2003, 72, 1117.

[7] Menon U., Ryan A., Kalsi J., Gentry-Maharaj A., Dawnay A., Habib M., et al.: “Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening”. J. Clin. Oncol., 2015, 33, 2062.

[8] Macedo A.C.L., da Rosa M.I., Lumertz S., Medeiros L.R.: “Accuracy of serum human epididymis protein 4 in ovarian cancer diagnosis: a systematic review and meta-analysis”. Int. J. Gynecol. Cancer, 2014, 24, 1222.

[9] Ferraro S., Braga F., Lanzoni M., Boracchi P., Biganzoli E.M., Panteghini M.: “Serum human epididymis protein 4 vs. carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review”. Biochim. Clin., 2013, 37, 179.

[10] Bonfrer J.M.G., Korse C.M., Verstraeten R.A., van Kamp G.J., Hart G.A.M., Kenemans P.: “Clinical evaluation of the Byk LIA-mat CA125 II assay: Discussion of a reference value”. Clin. Chem., 1997, 43, 491.

[11] Moore R.G., Miller M.C., Eklund E.E., Lu K.H., Bast R.C., Lambert- Messerlian G.: “Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age”. Am. J. Obstet. Gynecol., 2012, 206, 1.

[12] Partridge E., Kreimer A.R., Greenlee R.T., Williams C., Xu J.L., Church T.R., et al.: “Results from four rounds of ovarian cancer screening in a randomized trial”. Obstet. Gynecol., 2009, 113, 775.

[13] Drescher C.W., Shah C., Thorpe J., O’Briant K., Anderson G.L., Berg C.D., et al.: “Longitudinal screening algorithm that incorporates change over time in CA125 levels identifies ovarian cancer earlier than a single-threshold rule”. J. Clin. Oncol., 2013, 31, 387.

[14] Urban N., Thorpe J.D., Bergan L.A., Forrest R.M., Kampani A.V., Scholler N., et al.: “Potential role of HE4 in multimodal screening for epithelial ovarian cancer”. J. Natl. Cancer Inst., 2011, 103, 1630.

[15] Palmer C., Duan X., Hawley S., Scholler N., Thorpe J.D., Sahota R.A., et al.: “Systematic evaluation of candidate blood markers for detecting ovarian cancer”. PLoS One, 2008, 3, 1.

[16] Olivier R.I., Lubsen-Brandsma M.A.C., Verhoef S., van Beurden M.: “CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer”. Gynecol. Oncol., 2006, 100, 20.

[17] Skates S.J., Xu F.J., Yu Y.H., Sjovall K., Einhorn N., Chang Y.C., et al.: “Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers”. Cancer, 1995, 76, 2004.

[18] Ferraro S., Schiumarini D., Panteghini M.: “Human epididymis protein 4: Factors of variation”. Clin. Chim. Acta, 2015, 438, 171.