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Serum Biomarker Human Epididymis Protein 4 (HE4)

Policy Number: MP-445

Latest Review Date: December 2019

Category: Laboratory

Policy Grade: B

POLICY:

Measurement of human epididymis protein 4 (HE4) for any and all indications is considered not medically necessary and 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 patients 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 in U.S. women. According to Surveillance Epidemiology and End Results (SEER) data, in 2013, an estimated 22,440 women will be diagnosed with ovarian cancer and 14,080 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. According to Surveillance Epidemiology and End Results (SEER) data, for the period 1999-2006, 62% of women with ovarian cancer were diagnosed when the disease had distant metastases (Stage IV) and this was associated with a 28.9% five-year survival rate. In contrast, 14.8% of women diagnosed with localized cancer (Stage 1) had a 92.5% five-year survival rate. Epithelial ovarian tumors account for 85 to 90% of ovarian cancers.

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 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 measurement of the biomarker carbohydrate 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 (RCT) with women in ovarian cancer that was in complete remission did not find a significant difference in overall survival when treatment for remission was initiated when 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 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 in whom surgery is indicated, further evaluation may be warranted to determine if surgical referral to a specialist with expertise in ovarian cancer is warranted. The Risk of Ovarian Malignancy Algorithm (ROMA) combines HE4, CA-125 and menopausal status into a numeric score. ROMA has been cleared by the FDA for predicting risk that an adnexal mass is malignant; this test is considered separately in policy #426, Multi-marker Serum-Testing Related to Ovarian Cancer.

KEY POINTS:

This policy was updated with a search of the literature through October 14, 2019.

Summary of Evidence

For individuals who have ovarian cancer who receive measurement of serum biomarker human epididymis protein 4, the evidence includes a prospective study and several retrospective studies comparing the diagnostic accuracy of HE4 and CA-125 for predicting disease progression and/or recurrence. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, other test performance measures, and change in disease status. Data submitted to the U.S. Food and Drug Administration for approval of commercial HE4 tests found that HE4 was not inferior to CA-125 for detecting ovarian cancer recurrence. However, 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 not a clear chain of indirect evidence that changes in management based on HE4 would lead to improved health outcome and no direct evidence from prospective controlled studies on the impact of HE4 testing on health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have adnexal masses who receive measurement of serum biomarker human epididymis protein 4, the evidence includes diagnostic accuracy studies and meta-analyses. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and other test performance measures. Meta-analyses have generally found that HE4 and CA-125 have 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 not a clear chain of indirect evidence that changes in management based on HE4 would lead to improved health outcome and no direct evidence from prospective controlled studies on the impact of HE4 testing on health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and not at high risk of ovarian cancer who receive screening with serum biomarker HE4, 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 overall survival, disease-specific survival, test accuracy and validity, and other test performance measures. The retrospective studies found that levels of HE4 increased over time in women ultimately diagnosed with ovarian cancer. Prospective comparative studies are needed to definitively determine whether HE4 is a useful screening tool. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines (v.2.2019) states that, for monitoring/follow-up of patients with Stage I-IV ovarian cancer with a complete response to initial treatment, “CA-125 or other tumor marker” should be used at “every visit if initially elevated”. The guideline does not specify any marker other than CA-125 for monitoring patients after treatment.

The NCCN guidelines state the following on evaluating undiagnosed pelvic masses: “The FDA has approved the use of HE4 and CA-125 for estimating the risk for ovarian cancer in women with a pelvic mass. Currently the NCCN Panel does not recommend the use of these biomarkers for determining the status of an undiagnosed pelvic mass.”

The NCCN guidelines state the following on screening for ovarian cancer: “The literature does not support routine screening for ovarian cancer in the general population, and routine screening is not currently recommended by any professional society. Some physicians follow women with high-risk factors (e.g., those with BRCA mutations, those with a family history) using CA-125 monitoring and endovaginal ultrasound; however, prospective validation of these tests remains elusive.”

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (NICE) issued guidance in 2011 on the recognition and initial management of ovarian cancer. The guideline includes the following recommendations:

  • Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer.
  • If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.
  • If the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation.
  • For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound:
    • assess her carefully for other clinical causes of her symptoms and investigate if appropriate
    • If no other clinical cause is apparent, advise to return to her GP if her symptoms become more frequent and/or persistent.

Malignancy indices

  • Calculate a risk of malignancy index I (RMI I) score (after performing an ultrasound). (The RMI 1 combines CA-125, menopausal status and the ultrasound score).

The NICE guidance did not mention HE4.

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. Serum HE4 Tests Cleared by FDA

Test

Manufacturer

Location

Date Cleared

510(k) No.

HE4 EIA Kit

Fujirebio Diagnostics

Malvern, PA

06/09/2008

K072939

ARCHITECT HE4 assay (CMIA)

Fujirebio Diagnostics

Malvern, PA

03/18/2010

K093957

ELECSYS HE4 (CMIA)

Roche Diagnostics

Indianapolis, IN

09/10/2012

K112624

Lumipulse G HE4 Immunoreaction Cartridges

Fujirebio Diagnostics

Malvern, PA

11/24/2015

K151378

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

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.  Defer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

86305

Human epididymis protein 4 (HE4)

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. Braicu EI, Fotopoulou C, Van Gorp T et al. Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: results from the OVCAD study. Gynecol Oncol 2013; 128(2):245-51.
  3. 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.
  4. Dewan R, Dewan A, Jindal M, et al. NA. Asian Pac. J. Cancer Prev., 2019 Apr 30; 20(4).
  5. FDA. 510(k) substantial equivalence determination decision summary: assay only (K072939). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K072939.pdf. Last accessed January 2014.
  6. FDA. 510(k) substantial equivalence determination decision summary: assay only (K093957). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K093957.pdf.
  7. 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.
  8. 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.
  9. 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.
  10. Lycke M, Kristjansdottir B, Sundfeldt K. A multicenter clinical trial validating the performance of HE4, CA 125, risk of ovarian malignancyalgorithm and risk of malignancy index. Gynecol. Oncol., 2018 Aug 29; 151(1).
  11. 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.
  12. 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.
  13. 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.
  14. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed October 14, 2019.
  15. National Institute for Health and Care Excellence (NICE). Ovarian cancer: recognition and initial management [CG122]. 2011;https://www.nice.org.uk/guidance/cg122. Accessed October 14, 2019.
  16. 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.
  17. Plotti F, Capriglione S, Terranova C et al. Does HE4 have a role as biomarker in the recurrence of ovarian cancer? Tumour Biol 2012; 33(6):2117-23.
  18. 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.
  19. SEER. SEER Stat Fact Sheets: Ovary. Available online at: seer.cancer.gov/statfacts/html/ovary.html.
  20. Steffensen KD, Waldstrom M, Brandslund I, et al. Identification of high-risk patients by human epididymis protein 4 levels during follow-up of ovarian cancer. Oncol Lett. Jun 2016; 11(6):3967-3974.
  21. Surveillance Epidemiology and End Results Program (SEER). SEER Stat Fact: Ovarian Cancer. n.d.; seer.cancer.gov/statfacts/html/ovary.html. Accessed November 8, 2017.
  22. 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.
  23. U.S. Preventive Services Task Force. Recommendation Statement: Screening for Ovarian Cancer. 2018;file:///C:/Users/alt/Downloads/ovarian-cancer-final-rec-statement.pdf. Accessed October 14, 2019.
  24. 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.
  25. 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.
  26. 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.
  27. Wu L, Dai ZY, Qian YH et al. Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. Int J Gynecol Cancer 2012; 22(7):1106-12.
  28. 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.
  29. 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.
  30. 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.


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.