Human Epididymis Protein 4 (HE4)
At a Glance
Why Get Tested?
To help monitor epithelial ovarian cancer after treatment; to detect recurrence or disease progression; not recommended for screening asymptomatic women for ovarian cancer
When To Get Tested?
Before starting therapy for epithelial ovarian cancer and at intervals after treatment
A blood sample drawn from a vein in your arm
Test Preparation Needed?
What is being tested?
Human epididymis protein 4 (HE4) is a protein that is produced by most, but not all, epithelial ovarian cancer cells. This makes the test useful as a tumor marker in specific circumstances. The HE4 test measures the amount of human epididymis protein 4 in the blood.
Significantly elevated concentrations of HE4 are frequently present in the blood of a woman who has epithelial ovarian cancer. When HE4 is increased, the HE4 test may be used to monitor the effectiveness of treatment and/or for recurrence or progression of the cancer.
Ovarian cancer is the fifth most common cause of cancer death in women. According to the American Cancer Society (ACS), the lifetime risk of a woman developing ovarian cancer is about 1 in 75 and the lifetime risk of death is 1 in 100. ACS estimates that about 22,000 new cases are diagnosed each year in the U.S. and about 14,000 women die of it.
Epithelial ovarian cancer is the most common type of ovarian cancer. It originates in cells that cover the outside of the ovaries and accounts for 85% to 90% of ovarian cancers.
There are several different subtypes of epithelial ovarian cancer, including: serous, endometrioid, mucinous, and clear cell, with serous being the most common. Some studies have shown that HE4 is elevated in more than 90% of serous and endometrioid epithelial ovarian cancers and about 50% of clear cell tumors, but it is not usually elevated in mucinous cancers. Therefore, HE4 is not used for monitoring of patients with other types of ovarian cancer, such as mucinous or germ cell tumors.
Currently, there is no reliable method for early detection of ovarian cancer among asymptomatic women. Less than 20% of ovarian cancers are found in the early stages before they have spread outside the ovary. One reason they go undetected is that the symptoms of ovarian cancer are fairly non-specific. The need for a reliable method for early detection of ovarian cancer among asymptomatic women continues to drive ongoing research. In the meantime, regular physicals, pelvic exams, and an awareness of family history and symptoms are important.
How is the test used?
Human epididymis protein 4 (HE4) is used along with CA-125 to monitor women who have been treated for epithelial ovarian cancer. In order for HE4 to be useful as a tumor marker, it must be elevated prior to treatment. CA-125 has been the primary tool used to monitor ovarian cancers, but it is not elevated in all cancers, may not be significantly increased with early cancer, and can be elevated in non-cancerous conditions. For these reasons, the medical community continues to search for tumor markers that are more sensitive and specific.
Ordering HE4 and CA-125 together provides complementary information and creates a better monitoring system to detect whether treatment has been effective and whether epithelial ovarian cancer has come back. These tests are ordered prior to treatment to establish a baseline and then periodically after treatment. A series of HE4 and CA-125 tests that show rising or falling concentrations is often more useful than a single sample set. Serial testing for HE4 should be used in conjunction with other clinical findings for monitoring ovarian cancer. HE4 test results by different instruments/methods cannot be compared with one another.
HE4 is not recommended as a screening test for asymptomatic women because it is non-specific. Small amounts of HE4 can be produced by normal tissues throughout the body and mild elevations may be seen in individuals with a variety of non-cancerous conditions.
The HE4 test is not intended to be used to monitor mucinous epithelial ovarian cancers or germ cell tumors because it is rarely elevated in these cancers.
An additional use of HE4 is as part of a Risk of Ovarian Malignancy Algorithm (ROMA). This calculation combines the results of HE4, CA-125, and a woman’s menopausal status into a numerical score. The ROMA score can be used by a healthcare practitioner prior to surgery to help determine whether a lump in the pelvis (pelvic mass) is likely to be malignant or not.
When is it ordered?
The HE4 test may be ordered along with a CA-125 and other clinical evaluations when a woman is diagnosed with epithelial ovarian cancer to see if these proteins are being produced by the cancer and to establish a baseline to compare against future measurements. If the concentrations are elevated prior to treatment, then HE4 and CA-125 may be ordered periodically after treatment to determine the change of the test results and monitor for cancer recurrence or disease progression.
Occasionally, a health care practitioner may order HE4 and CA-125 as part of a ROMA calculation when a woman has a pelvic mass to help determine whether the mass is likely to be malignant.
What does the test result mean?
If a woman who has been diagnosed with epithelial ovarian cancer has a baseline HE4 that is normal, then the test is not useful to monitor her ovarian cancer.
If HE4 and CA-125 levels are initially elevated and then decline after treatment, it generally means that the epithelial ovarian cancer has responded to treatment.
If levels rise or stay the same, then the cancer has likely not responded. Increased and increasing HE4 and CA-125 levels found during periodic monitoring after cancer treatment or surgery may indicate that the cancer has come back.
In a woman with a lump in her pelvis who will be undergoing surgery, an increased ROMA score can predict that the pelvic mass is more likely to be malignant.
Is there anything else I should know?
Different laboratories may use different types of tests to measure HE4, thus results from different labs may not be comparable. When undergoing a series of HE4 tests, it is preferable that all of the tests be performed using the same type of test, usually by the same laboratory. This ensures that results from the series of tests can be compared and interpreted correctly. You may wish to talk to your healthcare provider about where your tests are done.
Can this test be performed at my health practitioner’s office?
No, HE4 testing requires specialized equipment. It is not widely available at this time and your sample may need to be sent to a reference laboratory.
Is it necessary to use both HE4 and CA-125?
At this time, with available data, HE4 is not intended to be used by itself – it is considered an aid in the monitoring of epithelial ovarian cancer. Its use may evolve over time as more data become available.
Why would my health care provider not monitor my ovarian cancer with HE4?
This test would not be indicated if you have a non-epithelial ovarian cancer. It would not be useful as a monitoring tool if your cancer does not produce increased amounts of HE4. Also, since it is a new test, your health care practitioner may be waiting for more data on the test to become available before adopting it.
Sources Used in Current Review
2020 review performed by Qing H. Meng PhD, MD, DABCC, FAACC, Professor and Director of Clinical Chemistry and Special Chemistry Laboratories, Department of Laboratory Medicine.
(April 11, 2018) American Cancer Society. Ovarian Cancer, Tests. Available online at https://www.cancer.org/cancer/ovarian-cancer.html. Accessed on 4/8/2020.
(April 2019) American College of Obstetricians and Gynecologists (ACOG). Ovarian Cancer, Frequently Asked Questions. Available online at https://www.acog.org/patient-resources/faqs/gynecologic-problems/ovarian-cancer. Accessed on 4/8/2020.
(April 2019) American Society of Clinical Oncology (ASCO). Ovarian, Fallopian Tube, and Peritoneal Cancer: Diagnosis. Available online at https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/diagnosis. Accessed 4/8/2020.
(August 19, 2019) Centers for Disease Control and Prevention. Ovarian Cancer. Available online at https://www.cdc.gov/cancer/ovarian/index.htm. Accessed on 4/8/2020.
Yang WL, Lu Z, Bast RC Jr. The role of biomarkers in the management of epithelial ovarian cancer. Expert Rev Mol Diagn. 2017 Jun;17(6):577-591.
Sources Used in Previous Reviews
(2016 February 4 Revised). Ovarian Cancer, Detailed Guide. American Cancer Society [On-line information]. Available online at http://www.cancer.org/cancer/ovariancancer/detailedguide/index. Accessed on 03/04/16.
Ferraro, S. et. al. (2013). Serum Human Epididymis Protein 4 vs Carbohydrate Antigen 125 for Ovarian Cancer Diagnosis. Medscape Multispecialty from J Clin Pathol. 2013;66(4):273-281. [On-line information]. Available online at http://www.medscape.com/viewarticle/781857. Accessed on 03/04/16.
Hussain, F. et. al. (2015 January 13 Updated). Gynecologic Tumor Markers Tumor Marker Overview. Medscape Drugs & Diseases [On-line information]. Available online at http://emedicine.medscape.com/article/269839-overview#a1. Accessed on 03/04/16.
(© 1995–2016). Human Epididymis Protein 4, Serum. Mayo Clinic Mayo Medical Laboratories. [On-line information]. Available online at http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/62137. Accessed on 03/04/16.
Grenache, D. (2016 February Updated).Ovarian Cancer. ARUP Consult [On-line information]. Available online at https://arupconsult.com/node/2384. Accessed on 03/04/16.
Santotoribio, J. (2016 January 20). What are the tumor markers that best identify the epithelial ovarian cancer? NACB Scientific Shorts. [On-line information]. Available online at https://www.aacc.org/community/national-academy-of-clinical-biochemistry/scientific-shorts/2016/what-are-the-tumor-markers-that-best-identify-the-epithelial-ovarian-cancer. Accessed on 03/04/16.
(2015 November 4 Reviewed). Tumor Markers. National Cancer Institute [On-line information]. Available online at http://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet. Accessed on 03/04/16.
Jinping L. et. al. (2009). HE4 as a Biomarker for Ovarian and Endometrial Cancer Management. Medscape News & Perspective from Expert Rev Mol Diagn. 2009;9(6):555-566 [On-line information]. Available online at http://www.medscape.com/viewarticle/711023. Accessed on 03/04/16.
(2016 March 2). New Report Finds ‘Surprising Gaps’ in Knowledge of Ovarian Cancers; Better Understanding Needed to Make Progress in Prevention, Early Detection, Treatment, and Management of Disease. National Academies of Sciences, Engineering, and Medicine Press Release [On-line information]. Available online at http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=21841. Accessed on 03/04/16.
Algeciras-Schimnich, A. (2013 March 1). Ovarian Cancer, A Review of Current Serum Markers and Their Clinical Applications. Clinical Laboratory News [On-line information]. Available online at https://www.aacc.org/publications/cln/articles/2013/march/ovarian-cancer. Accessed on 03/04/16.
Zhuang, H. et. al. (2014 November 1). Human epididymis protein 4 in association with Annexin II promotes invasion and metastasis of ovarian cancer cells. Molecular Cancer 2014 13:243. [On-line information]. Available online at http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-13-243. Accessed on 03/04/16.
(2012 December Reviewed). HE4, Ovarian Cancer Monitoring. Quest Diagnostics [On-line information]. Available online at http://www.questdiagnostics.com/testcenter/testguide.action?dc=TS_HE4_Ovarian_Cancer_Monitoring. Accessed on 03/04/16.
Chang, X. et. al. (2011 July). Human Epididymis Protein 4 (HE4) as a Serum Tumor Biomarker in Patients With Ovarian Carcinoma. Int J Gynecol Cancer. 2011; 21(5): 852-858. [On-line information]. Available online at http://journals.lww.com/ijgc/Abstract/2011/07000/Human_Epididymis_Protein_4__HE4__as_a_Serum_Tumor.12.aspx. Accessed on 03/04/16.
Macedo, A. et. al. (2014 September). Accuracy of serum human epididymis protein 4 in ovarian cancer diagnosis: a systematic review and meta-analysis. Int J Gynecol Cancer. 2014; 24(7):1222-31. [On-line information]. Available online at http://journals.lww.com/ijgc/Fulltext/2014/09000/Accuracy_of_Serum_Human_Epididymis_Protein_4_in.14.aspx#. Accessed on 03/04/16.
Drapkin, R. et. al. (2005). Human Epididymis Protein 4 (HE4) Is a Secreted Glycoprotein that Is Overexpressed by Serous and Endometrioid Ovarian Carcinomas. Cancer Res, March 15, 2005 65; 2162 [On-line information]. Available online at http://cancerres.aacrjournals.org/content/65/6/2162.full. Accessed on 03/04/16.