Serum Biomarker Human Epididymis Protein 4 (HE4)

POLICY NUMBER

A.2.04.66

DESCRIPTION

Human epididymis protein 4 (HE4) is a novel biomarker that has been cleared by the U.S. Food and Drug Administration for monitoring individuals with epithelial ovarian cancer. HE4 is proposed as a replacement for or a complement to cancer antigen 125 (CA 125) for monitoring disease progression and recurrence. HE4 has also been proposed as a test to evaluate women with ovarian masses and to screen for ovarian cancer in asymptomatic women.

Ovarian Cancer

Ovarian cancer is the fifth most common cause of cancer mortality among U.S. women. According to Surveillance Epidemiology and End Results data, in 2024, an estimated 19,680 women will be diagnosed with ovarian cancer and 12,740 women will die of the disease. The stage at diagnosis is an important predictor of survival; however, most women are not diagnosed until the disease has spread. For the period of 2014 to 2020, 55% of women with ovarian cancer were diagnosed when the disease had distant metastases (Stage IV), and this was associated with a 5-year survival rate of 31.4%. In contrast, 19% of women diagnosed with localized cancer (Stage 1) had a 5-year survival rate of 91.9%. Epithelial ovarian tumors account for 85% to 90% of ovarian cancers.

Research from the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium reports that Black women with ovarian cancer have worse survival than White women. Contributors to this disparity may include education level, nulliparity, smoking status, body mass index, diabetes, and postmenopausal hormone therapy duration.

Treatment

The standard treatment for epithelial ovarian cancer is surgical staging and primary cytoreductive surgery followed by chemotherapy in most cases. There is a lack of consensus about an optimal approach to the follow-up of patients with ovarian cancer after or during primary treatment. Patients undergo regular physical examinations and may have imaging studies. In addition, managing patients with serial measurements of the biomarker cancer antigen 125 (CA 125) to detect early recurrence of disease is common. A rising CA 125 level has been found to correlate with disease recurrence and has been found to detect recurrent ovarian cancer earlier than clinical detection. However, a survival advantage of initiating treatment based on early detection with CA 125 has not been demonstrated to date. For example, a randomized controlled trial in women having ovarian cancer that was in complete remission did not find a significant difference in overall survival when treatment for remission was initiated after CA 125 concentration exceeded twice the limit of normal compared to delaying treatment initiation until symptom onset.

Human epididymis protein 4 (HE4) is a protein that circulates in the serum and has been found to be overexpressed in epithelial ovarian cancer, lung adenocarcinoma, breast cancer, pancreatic cancer, endometrial cancer, and bladder cancer. HE4 is made up of 2 whey acidic proteins with a 4 disulfide core domain and has been proposed as a biomarker for monitoring patients with epithelial ovarian cancer.

Evaluation of Adnexal Masses

This policy also addresses the use of the HE4 as a stand-alone test for evaluating women with ovarian masses who have not been diagnosed with ovarian cancer. Such patients undergo a diagnostic workup to determine whether the risk of malignancy is sufficiently high to warrant surgical removal. In patients for whom surgery is indicated, further evaluation may be warranted to determine if a surgical referral to a specialist with expertise in ovarian cancer is warranted. The Risk of Ovarian Malignancy Algorithm (ROMA) test combines HE4, CA 125, and menopausal status into a numeric score. The ROMA test has been cleared by the U.S. FDA for predicting the risk that an adnexal mass is malignant; this test and other combination biomarker tests are considered separately in the Multimarker Serum Testing Related to Ovarian Cancer medical policy.

Multiple HE4 test kits have been cleared by the Food and Drug Administration through the 510(k) process and summarized in the table below. The FDA determined that this device was substantially equivalent to a CA 125 assay kit for use as an aid in monitoring disease progression or recurrence in patients with epithelial ovarian cancer. The FDA-approved indication states that serial testing for HE4 should be done in conjunction with other clinical methods used for monitoring ovarian cancer and that the HE4 test is not intended to assess the risk of disease outcomes.

Serum HE4 Tests Cleared by the FDA

CMIA: chemoluminescent microparticle immunoassay; HE4: human epididymis protein 4; EIA: enzymatic immunoassay; FDA: Food and Drug Administration.

Refer to the following related medical policies:  CA-125 ,  Analysis of Proteomic Patterns for Early Detection of Cancer , and Multimarker Serum Testing Related to Ovarian Cancer .

POLICY

Measurement of HE4 is investigational for all indications.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

11/11/2010: Approved by Medical Policy Advisory Committee.

09/23/2011: Policy reviewed; no changes.

09/25/2012: Policy statement revised to delete the bullet points; intent unchanged. Measurement of HE4 is investigational for all indications. 

11/15/2013: Policy reviewed; no changes.

05/02/2014: Policy reviewed; description section revised. Policy statement unchanged.

04/02/2015: Policy reviewed; description updated. Policy statement unchanged. Policy guidelines updated to revise definition of investigative.

07/23/2015: Code Reference section updated for ICD-10.

01/15/2016: Policy reviewed; no changes.

06/06/2016: Policy number A.2.04.66 added.

01/20/2017: Policy description updated regarding HE4 as a stand-alone test. Policy statement unchanged.

01/18/2018: Policy description updated regarding ovarian cancer data. Policy statement unchanged.

01/15/2019: Policy description updated regarding HE4 and HE4 test kits. Policy statement unchanged.

01/16/2019: Policy reviewed; no changes.

02/03/2021: Policy description updated regarding 2020 data for ovarian cancer. Policy statement unchanged.

02/07/2022: Policy description updated regarding ovarian cancer in the United States. Policy statement unchanged.

01/26/2023: Policy description updated regarding estimated cases of ovarian cancer and disparities in ovarian cancer. Policy statement unchanged.

01/16/2024: Policy description updated regarding new data for ovarian cancer. Policy statement unchanged.

02/10/2025: Policy description updated regarding new data for ovarian cancer. Policy statement unchanged.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.66

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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