Patient Test Information

Human Epididymis Protein 4 (HE4)

Also known as:

HE4

Formal name:

Human Epididymis Protein 4

Related tests:

CA-125, Tumor Markers

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Why Get Tested?

To help monitor epithelial ovarian cancer after treatment; to detect recurrence or disease progression; not recommended for screening asymptomatic women

When to Get Tested?

Before starting therapy for epithelial ovarian cancer and at intervals after treatment

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

How is it used?

Human epididymis protein 4 (HE4) is a relatively new test that 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.

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. In the meantime, regular physicals, pelvic exams, and an awareness of family history and other risk factors are important. (For more information, see the article on Ovarian Cancer.)

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.

HE4 is not recommended as a screening test for asymptomatic women because it is non-specific. Small quantities of HE4 are produced by normal tissues throughout the body and mild elevations may be seen with a variety of non-cancerous conditions.

The HE4 test is not intended to be used to monitor mucinous epithelial ovarian cancers 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. It may sometimes be ordered 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 monitor for cancer recurrence or disease progression.

Occasionally, a healthcare practitioner may order HE4 and CA-125 as part of a ROMA calculation when a woman has a pelvic mass and will be having surgery to help determine whether the mass is likely to be malignant.

What does the test result mean?

If HE4 and CA-125 levels fall after treatment, this generally indicates 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.

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. In this case, the ovarian cancer may not be producing HE4 so it is not a good marker of disease progression.

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.

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 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.

Currently, less than 20% of ovarian cancers are found in the early stages before they have spread outside the ovary. The primary 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.

HE4 is not recommended as a screening test for asymptomatic women because it is non-specific. Small quantities of HE4 are produced by normal tissues throughout the body and mild elevations may be seen with a variety of non-cancerous conditions.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in the arm.

NOTE: If undergoing medical tests makes you or someone you care for anxious, embarrassed, or even difficult to manage, you might consider reading one or more of the following articles: Coping with Test Pain, Discomfort, and Anxiety, Tips on Blood Testing, Tips to Help Children through Their Medical Tests, and Tips to Help the Elderly through Their Medical Tests.

Another article, Follow That Sample, provides a glimpse at the collection and processing of a blood sample and throat culture.

Is any test preparation needed to ensure the quality of the sample?

No test preparation is needed.

  1. Can this test be performed at my healthcare 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.

  2. Should all women have an HE4 test?

    No, it is only indicated when a woman has been diagnosed with epithelial ovarian cancer. It is not intended to be used for general screening, for other ovarian cancers, or for other cancers.

  3. 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.

  4. Why would my healthcare 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 healthcare practitioner may be waiting for more data on the test to become available before adopting it.