BlueCross BlueShield of Tennessee Medical Policy Manual

Serum Biomarker Human Epididymis Protein 4 (HE4)


Human epididymis protein 4 (HE4) is a novel biomarker that has been proposed as a replacement for or a complement to carbohydrate antigen 125 (CA-125) for monitoring ovarian cancer progression and recurrence. HE4 is also proposed as a test to evaluate women with ovarian masses and to screen for ovarian cancer in asymptomatic women.

There are limited data on the diagnostic test performance of the HE4 test used to monitor disease progression and recurrence in women after initial treatment for epithelial ovarian cancer. There is no established cutoff for determining when an HE4 test is positive or for identifying disease progression or recurrence. Moreover, a survival advantage of early detection of ovarian cancer recurrence using HE4 levels has not been established.




Studies have not found that HE4 improves diagnostic accuracy beyond that of subjective assessment of transvaginal ultrasound. The evidence is insufficient to conclude that HE4 alone or in combination with CA-125 has better diagnostic performance than CA-125 alone. No published studies were identified evaluating use of the HE4 test to screen asymptomatic women for ovarian cancer.


BlueCross BlueShield Association. Medical Policy Reference Manual. (12:2017). Serum biomarker human epididymis protein 4 (2.04.66). Retrieved July 24, 2018 from BlueWeb. (24 articles and / or guidelines reviewed)

Chudecka-Glaz, A., Cymbaluk-Ploska, A., Menkiszka, J., Sompolska-Rzechula, A., Byra, E., & Rzepka-Gorska, I. (2014). HE4 tumor marker concentration in neoplastic peritoneal effusion and in peritoneal fluid associated with benign gynecological diseases. Journal of Ovarian Cancer Research, 7 (22), 1-10. (Level 3 evidence)

Karlsen, N., Karlsen, M., Høgdall, C., and Høgdall, E.(2014) HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: a systematic review. Cancer Epidemiology Biomarkers and Prevention, 23 (11), 2285–95. (Level 1 evidence)

Macedo, A.C., da Rosa, M.I., Lumertz, S., & Medeiros, L.R. (2014). Accuracy of serum human epididymis protein 4 in ovarian cancer diagnosis: a systematic review and meta-analysis. International Journal of Gynecological Cancer, 24 (7), 1222-1231. Abstract retrieved August 14, 2017 from PubMed database.

Nassir, M., Guan, J., Luketina, H., Siepmann, T., Rohr, I., Richter, R., et al. (2016). The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study. Tumour Biology, 37 (3), 3009-3016. Abstract retrieved August 14, 2017 from PubMed database.

National Comprehensive Cancer Network. (2017). NCCN clinical practice guidelines in oncology (NCCN guidelines®)  Ovarian cancer - V.2.2018. Retrieved July 24, 2018 from

Scaletta, G., Plotti, F., Luvero, D., Capriglione, S., Montera, R., Miranda, A., et al. (2017). The role of novel biomarker HE4 in the diagnosis, prognosis and follow-up of ovarian cancer: a systematic review. Expert Review of Anticancer Therapy, 17 (9), 827-839. Abstract retrieved August 14, 2017 from PubMed database.

Steffensen, K., Waldstrøm, M., Brandslund, I., Lund, B., Sørensen, S., Petzold, M., & Jakobsen, A. (2016). Identification of high-risk patients by human epididymis protein 4 levels during follow-up of ovarian cancer. Oncology Letters, 11, 3967-3974. (Level 3 evidence)

U. S. Food and Drug Administration. (2008, June). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K072939. Retrieved August 14, 2017 from

U. S. Food and Drug Administration. (2010, March). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K093957. Retrieved March 18, 2014 from

U.S. Preventive Services Task Force. (2018). Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Journal of the American Medical Association, 319 (6), 588-594.

Zhen, S., Bian, L., Chang, L., & Gao, X. (2014). Comparison or serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer: a meta-analysis. Molecular and Clinical Oncology, 2, 559-566. (Level 1 evidence)




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