Latest Review Date: December 2024

Category: Laboratory

POLICY:

Measurement of human epididymis protein 4 (HE4) for any and all indications is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Human epididymis protein 4 (HE4) is a novel biomarker that has been cleared by the U.S. Food and Drug Administration (FDA) for monitoring individuals with epithelial ovarian cancer. HE4 is proposed as a replacement for or a complement to carbohydrate 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 relative survival rate of 31.4%. In contrast, 19% of women with ovarian cancer were diagnosed when the disease had distant metastases (stage IV), and this was associated with a 5-year relative survival rate of 31.4%. In contrast, 19% of women diagnosed with localized cancer (stage I) had a 5-year survival rate of 91%. 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 outcomes 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 2010 randomized controlled trial in women with 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 two whey acidic proteins with a four disulfide core domain and has been proposed as a biomarker for monitoring patients with epithelial ovarian cancer.

Evaluation of Adnexal Masses

This evidence review 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 U.S. Food and Drug Administration (FDA) for predicting the risk that an adnexal mass is malignant.

KEY POINTS:

This policy was updated with a search of the literature through October 10, 2024.

Summary of Evidence

For individuals who have ovarian cancer who receive a measurement of serum biomarker HE4, the evidence includes seven nonrandomized prospective and retrospective studies comparing the diagnostic accuracy of HE4 with CA 125 for predicting disease progression and/or recurrence. Relevant outcomes are OS, disease-specific survival, test validity, other test performance measures, and change in disease status. Data submitted to the U.S. Food and Drug Administration (FDA) for approval of commercial HE4 tests found that HE4 was not inferior to CA 125 for detecting ovarian cancer recurrence. Although a single prospective observational study found that elevated levels of HE4, but not CA 125, at the time of cancer progression was significantly associated with reduced OS, a direct comparison between biomarkers was not provided. Overall, the superiority of HE4 to CA 125 (alone or in combination), the key question in the evidence review, was not demonstrated in the available literature. In addition, there is no established cutoff in HE4 levels for monitoring disease progression, and cutoffs in studies varied. There is no direct evidence from prospective controlled studies on the impact of HE4 testing on health outcomes, and no clear chain of evidence that changes in management based on HE4 would lead to an improved health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have adnexal masses who receive a measurement of serum biomarker HE4, the evidence includes diagnostic accuracy studies and meta-analyses. Relevant outcomes are OS, disease-specific survival, test validity, and other test performance measures. Meta-analyses have generally found that HE4 and CA 125 have a similar overall diagnostic accuracy (i.e., sensitivity, specificity) and several found that HE4 has significantly higher specificity than CA 125 but not sensitivity. Two meta-analyses had mixed findings on whether the combination of HE4 and CA 125 is superior to CA 125 alone for the initial diagnosis of ovarian cancer. The number of studies evaluating the combined test is relatively low, and publication bias in studies of HE4 has been identified. In addition, studies have not found that HE4 improves diagnostic accuracy beyond that of subjective assessment of transvaginal ultrasound. There is no direct evidence from prospective controlled studies on the impact of HE4 testing on health outcomes, and no clear chain of evidence that changes in management based on HE4 would lead to an improved health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic and not at high-risk of ovarian cancer who receive screening with a serum biomarker HE4 test, the evidence includes several retrospective comparative studies and no prospective studies comparing health outcomes in asymptomatic women managed with and without HE4 screening. Relevant outcomes are OS, disease-specific survival, test validity, and other test performance measures. The retrospective studies found that HE4 levels increased over time in women ultimately diagnosed with ovarian cancer. Prospective comparative studies are needed to determine definitively whether HE4 testing is a useful screening tool. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists

Guidelines from the American College of Obstetricians and Gynecologists (ACOG) on evaluation and management of adnexal masses (2016, reaffirmed 2021) state that measurement of cancer antigen 125 (CA 125) is the most extensively studied serum marker to be used in combination with imaging to determine the likelihood of malignancy. The authors also suggest that measurement of CA 125 is most useful for identification of nonmucinous epithelial cancer in postmenopausal women. Although the guideline mentions that human epididymis protein 4 (HE4) has recently been identified as a biomarker that may be useful for distinguishing between benign and malignant masses, no further recommendations regarding HE4 are provided.

In 2017 (reaffirmed 2021), a committee opinion document from ACOG and the Society of Gynecologic Oncology stated that tumor markers such as CA 125 and transvaginal ultrasound, alone or in combination, have not improved early detection or survival in women with average risk for ovarian cancer. There is also a potential for harm if surgery is performed in response to a positive test result.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines (v.3.2024) state that, for monitoring and follow-up of patients with stage I to IV ovarian cancer with a complete response to initial treatment, “CA-125 [cancer antigen 125] or other tumor marker” should be used at “every visit if initially elevated”. The guidelines do not specify any marker other than CA 125 for monitoring patients after treatment. The guidelines also recommend "CA-125 or other tumor markers as clinically indicated" for patients referred with newly diagnosed ovarian cancer after recent surgical procedure.

Elsewhere, the NCCN guideline provides the following comment about screening using HE4: "Some evidence suggests that HE4 [human epididymis protein 4] may be a useful prognostic marker in patients with ovarian cancer, decreases during response to treatment, and may improve early detection of recurrence relative to CA-125 alone." The NCCN guidelines currently do not recommend routine HE4 as part of preoperative workup because results vary across studies.

Several biomarker combination tests have received Food and Drug Administration approval for estimating the risk of ovarian cancer in patients with adnexal masses and planned surgery. The Risk of Ovarian Malignancy Algorithm (ROMA) test includes HE4 plus CA-125 plus menopausal status, the OVA1 test includes five markers including CA-125 (but not HE4), and the OVERA test includes 5 markers including both CA-125 and HE4. The NCCN guidelines state the following about using these biomarker tests. Currently, the NCCN Panel does not recommend the use of these biomarker tests for determining the status of an undiagnosed adnexal/pelvic mass.”

The NCCN guidelines state the following on screening for ovarian cancer: "Very few biomarkers have been tested prospectively to determine whether they can detect ovarian cancer or predict development of ovarian cancer in women who have no other signs or symptoms of cancer. Data show that several markers (including CA-125, HE4, mesothelin, B7-H4, decoy receptor 3 [DcR3], and spondin-2) do not increase early enough to be useful in detecting early-stage ovarian cancer."

National Institute for Health and Care Excellence

In 2011, NICE recommended using CA 125 to test for ovarian cancer in patients presenting to primary care providers with symptoms of ovarian cancer. No other biomarker tests are mentioned in the NICE guidance.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (USPSTF) updated its recommendations for screening for ovarian cancer in February 2018.  USPSTF recommended against screening for ovarian cancer in asymptomatic women (D recommendation).  HE4 was not specifically discussed.

KEY WORDS:

Human epididymis protein 4, HE4, HE4 EIA test, ARCHITECT HE4

APPROVED BY GOVERNING BODIES:

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.

Table 1. Serum Human Epididymis 4 Tests Cleared by the Food and Drug Administration

CMIA: chemoluminescent microparticle immunoassay; HE4: human epididymis protein 4; EIA: enzymatic immunoassay

FDA product code: OIU.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING: 

CPT Codes:

REFERENCES:

1. Anderson GL, McIntosh M, Wu L et al. Assessing lead time of selected ovarian cancer biomarkers: a nested case-control study. J Natl Cancer Inst 2010; 102(1):26-38.
2. Carreras-Dieguez N, Glickman A, Munmany M, et al. Comparison of HE4, CA125, ROMA and CPH-I for Preoperative Assessment of Adnexal Tumors. Diagnostics (Basel). Jan 17 2022; 12(1).
3. Committee Opinion No. 716: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer in Women at Average Risk. Obstet Gynecol. Sep 2017; 130(3): e146-e149.
4. Dayyani F, Uhlig S, Colson B, et al. Diagnostic performance of risk of ovarian malignancy algorithm against CA125 and HE4 in connection with ovarian cancer: a meta-analysis. Int J Gynecol Cancer. Nov 2016; 26(9):1586-1593.
5. Eskander R, Berman M, Keder L. Practice Bulletin No. 174: Evaluation and Management of Adnexal Masses. Obstet Gynecol. Nov 2016; 128(5): e210-e226.
6. FDA. 510(k) substantial equivalence determination decision summary: assay only (K072939). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K072939.pdf.
7. FDA. 510(k) substantial equivalence determination decision summary: assay only (K093957). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K093957.pdf.
8. Ferraro S, Braga F, Lanzoni M et al. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol 2013; 66(4):273-81.
9. Gentry-Maharaj A, Burnell M, Dilley J, et al. Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses. Am J Obstet Gynecol. Jan 2020; 222(1): 56.e1-56.e17.
10. Han Y, Jiang L, Liu K, et al. Predictive Value of HE4 in Platinum-Based Chemotherapy for Ovarian Cancer: A Systematic Review. Front Oncol. 2021; 11: 703949. 
11. Harris HR, Guertin KA, Camacho TF, et al. Racial disparities in epithelial ovarian cancer survival: An examination of contributing factors in the Ovarian Cancer in Women of African Ancestry consortium. Int J Cancer. Oct 15 2022; 151(8): 1228-1239.
12. Huang J, Chen J, Huang Q. Diagnostic value of HE4 in ovarian cancer: A meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol., 2018 Oct15; 231:35-42.
13. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
14. Kaijser J, Van Gorp T, Smet ME et al. Are serum HE4 or ROMA scores useful to experienced examiners for improving characterization of adnexal masses after transvaginal ultrasonography? Ultrasound Obstet Gynecol 2013.
15. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. Oct 2013; 24 Suppl 6: vi24-32.
16. Lof P, van de Vrie R, Korse CM, et al. Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?. Gynecol Oncol. Aug 2022; 166(2): 284-291. 
17. Macedo AC, da Rosa MI, Lumertz S, et al. Accuracy of serum human epididymis protein 4 in ovarian cancer diagnosis: a systematic review and meta-analysis. Int J Gynecol Cancer. Sep 2014; 24(7):1222-1231.
18. Moszynski R, Szubert S, Szpurek D et al. Usefulness of the HE4 biomarker as a second-line test in the assessment of suspicious ovarian tumors. Arch Gynecol Obstet 2013; 288(6):1377-83.
19. Nassir M, Guan J, Luketina H, et al. The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study. Tumour Biol. Sep 29 2015.
20. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 3.2024. www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.
21. National Institute for Health and Care Excellence (NICE). Ovarian cancer: recognition and initial management [CG122]. 2011. Updated October 2, 2023; www.nice.org.uk/guidance/cg122.
22. Nikolova T, Zivadinovic R, Evtimovska N, et al. Diagnostic performance of human epididymis protein 4 compared to a combination of biophysical and biochemical markers to differentiate ovarian endometriosis from epithelial ovarian cancer in premenopausal women. J Obstet Gynaecol Res. Dec 2017; 43(12):1870-1879.
23. Olsen M, Lof P, Stiekema A, et al. The diagnostic accuracy of human epididymis protein 4 (HE4) for discriminating between benign and malignant pelvic masses: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. Oct 2021; 100(10): 1788-1799. 
24. Potenza E, Parpinel G, Laudani ME, et al. Prognostic and predictive value of combined HE-4 and CA-125 biomarkers during chemotherapy in patients with epithelial ovarian cancer. Int J Biol Markers. Dec 2020; 35(4): 20-27. 
25. Rong Y, Li L. Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer. J Ovarian Res. Jan 04 2021; 14(1): 2. 
26. Rustin GJ, van der Burg ME, Griffin CL et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 2010; 376(9747):1155-63.
27. Salminen L, Gidwani K, Grenman S, et al. HE4 in the evaluation of tumor load and prognostic stratification of high grade serous ovarian carcinoma. Acta Oncol. Dec 2020; 59(12): 1461-1468.
28. Samborski A, Miller MC, Blackman A, et al. HE4 and CA125 serum biomarker monitoring in women with epithelial ovarian cancer. Tumour Biol. 2022; 44(1): 205-213.
29. Suri A, Perumal V, Ammalli P, et al. Diagnostic measures comparison for ovarian malignancy risk in Epithelial ovarian cancer patients: a meta-analysis. Sci Rep. Aug 27 2021; 11(1): 17308.
30. Surveillance Epidemiology and End Results Program (SEER). SEER Stat Fact: Ovarian Cancer. n.d.; seer.cancer.gov/statfacts/html/ovary.html.
31. Terry KL, Schock H, Fortner RT, et al. A prospective evaluation of early detection biomarkers for ovarian cancer in the European EPIC cohort. Clin Cancer Res. Sep 15 2016; 22(18):4664-4675.
32. U.S. Preventive Services Task Force. Recommendation Statement: Screening for Ovarian Cancer. 2018; file:///C:/Users/alt/Downloads/ovarian-cancer-final-rec-statement.pdf.
33. Urban N, Thorpe JD, Bergan LA et al. Potential role of HE4 in multimodal screening for epithelial ovarian cancer. J Natl Cancer Inst 2011; 103(21):1630-4.
34. Vallius T, Hynninen J, Auranen A, et al. Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer. Tumour Biol. Feb 2017; 39(2):1010428317691189.
35. Wang J, Gao J, Yao H, et al. Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol. Jun 2014; 35(6):6127-6138.
36. Yang Z, Wei C, Luo Z et al. Clinical value of serum human epididymis protein 4 assay in the diagnosis of ovarian cancer: a meta-analysis. Onco Targets Ther 2013; 6:957-66.
37. Yu S, Yang HJ, Xie SQ et al. Diagnostic value of HE4 for ovarian cancer: a meta-analysis. Clin Chem Lab Med 2012; 50(8):1439-46.
38. Zhen S, Bian LH, Chang LL, et al. Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer: A meta-analysis. Mol Clin Oncol. Jul 2014; 2(4):559-566.

POLICY HISTORY:

Medical Policy Group, September 2009 (2)

Medical Policy Group, August 2010 (2)

Medical Policy Panel, August 2010

Medical Policy Administration Committee, August 2010

Available for comment September 4-October 18, 2010

Medical Policy Group, October 2010

Medical Policy Panel, August 2011

Medical Policy Group, September 2011 (2): Description, Key Points, Reference updated

Medical Policy Panel, August 2012

Medical Policy Group, April 2013 (1): Update to Key Points and References; Material on evaluation of ovarian (adnexal) masses removed as this is addressed in policy 426; no change to policy statement

Medical Policy Panel, August 2013

Medical Policy Group, September 2013 (1): Update to Descriptions, Key Points and References; no change to policy statement

Medical Policy Panel, March 2014

Medical Policy Group, March 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, March 2015

Medical Policy Group, March 2015 (3):  Updates to Key Points and References; no change to policy statement.

Medical Policy Panel, December 2015

Medical Policy Group, January 2016 (3):  2015 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Panel, December 2017

Medical Policy Group, December 2017 (3): 2017 Updates to Description, Key Points & References; no change in policy statement

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2018 Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Panel, December 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, December 2020

Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, December 2021

Medical Policy Group, December 2021 (9): 2021 Updates to Description, Key Points, References. Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Panel, December 2022

Medical Policy Group, December 2022 (9): 2022 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, December 2023

Medical Policy Group, January 2024 (5): Updates to Description, Key Points; Practice Guidelines and Position Statements, Benefit Application, and References. No change to Policy Statement.

Medical Policy Panel, December

Medical Policy Group, December 2024 (5): Updates to Description, Key Points, and References. No change to Policy Statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.