mp-445 - mp-445 - Medical Policies
Serum Biomarker Human Epididymis Protein 4 (HE4)
Policy Number: MP-445
Latest Review Date: December 2020
Policy Grade: B
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 is the fifth most common cause of cancer mortality in U.S. women. According to Surveillance Epidemiology and End Results (SEER) data, in 2020, an estimated 21,750 women would be diagnosed with ovarian cancer and 13,940 women would 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.
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.
This policy was updated with a search of the literature through October 28, 2020.
Summary of Evidence
For individuals who have ovarian cancer who receive measurement of serum biomarker human epididymis protein 4, the evidence includes four nonrandomized prospective and 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. Although a single prospective observational study found elevated levels of HE4, but not CA 125, at the time of cancer progression to be significantly associated with reduced overall survival, 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 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
American College of Obstetricians and Gynecologists
Guidelines from the American College of Obstetricians and Gynecologists on evaluation and management of adnexal masses (2016) state that measurement of 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 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.
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines (v.1.2020) 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.”
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.
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 Human Epididymis 4 Tests Cleared by the Food and Drug Administration
HE4 EIA Kit
ARCHITECT HE4 assay (CMIA)
ELECSYS HE4 (CMIA)
Lumipulse G HE4 Immunoreaction Cartridges
CMIA: chemoluminescent microparticle immunoassay; HE4: human epididymis protein 4; EIA: enzymatic immunoassay
FDA product code: OIU.
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.
Human epididymis protein 4 (HE4)
- 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.
- 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.
- 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.
- 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.
- Dewan R, Dewan A, Jindal M, et al. NA. Asian Pac. J. Cancer Prev., 2019 Apr 30; 20(4).
- Eskander R, Berman M, Keder L. Practice Bulletin No. 174: Evaluation and Management of Adnexal Masses. Obstet Gynecol. Nov 2016; 128(5): e210-e226.
- FDA. 510(k) substantial equivalence determination decision summary: assay only (K072939). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K072939.pdf. Accessed November 5, 2020.
- FDA. 510(k) substantial equivalence determination decision summary: assay only (K093957). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K093957.pdf. Accessed November 5, 2020.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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 28, 2020.
- 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.
- 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.
- 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.
- 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.
- 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.
- Surveillance Epidemiology and End Results Program (SEER). SEER Stat Fact: Ovarian Cancer. n.d.; http://seer.cancer.gov/statfacts/html/ovary.html. Accessed November 5, 2020.
- 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.
- 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.
- 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.
- 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 28, 2020.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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.
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