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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 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 2013, an estimated 22,240 women will be diagnosed with ovarian cancer and 14,030 women will die of the disease. Stage at diagnosis is an important predictor of survival; however, most women are not diagnosed until the disease has spread. 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 27.6% 5-year survival rate. In contrast, the 15% of women diagnosed with localized cancer (Stage 1) had a 93.5% 5-year survival rate. Epithelial ovarian tumors account for 85-90% 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 follow-up patients with ovarian cancer following primary treatment. Patients undergo regular physical examinations. In addition, managing patients with serial measurement of the biomarker 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 (RCT) with women having 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 with delaying treatment initiation until symptom onset.
Another serum biomarker, cleared by the FDA for monitoring patients with epithelial ovarian cancer, is human epididymis protein 4 (HE4). HE4 is made up of two whey acidic proteins with a four disulfide core domain. It has been found to be over-expressed by epithelial ovarian cancer tumors and to circulate in the serum of patients with epithelial ovarian cancer. Levels of HE4 may be less likely to be elevated due to benign conditions, as is the case with CA-125, which would make HE4 a candidate to replace or complement CA-125. Tests for HE4 are FDA-approved for monitoring women known to have epithelial ovarian cancer. Another possible application of HE4 testing is screening asymptomatic women for ovarian cancer; screening is not an accepted use of the CA-125 test.
The policy 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. The Risk of Ovarian Malignancy Algorithm (ROMA) combines HE4, CA-125 and menopausal status into a numeric score. ROMA has been cleared by FDA for predicting risk that an adnexal mass is malignant; this test is considered separately in the Proteomics-Based Testing Related to Ovarian Cancer medical policy.
In June 2008, the HE4 EIA test kit (Fujirebio Diagnostics) was cleared for marketing by the FDA through the 510(k) process. 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-cleared 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.
In March 2010, the ARCHITECT™ HE4 (Abbott Diagnostics, co-developed with Fujirebio Diagnostics), an automated version of the HE4 EIA test, was cleared by the FDA for the same indications. The ARCHITECT HE4 test is being distributed in the United States by Quest Diagnostics (Madison, NJ).
Refer to the following related medical policies: CA-125, Analysis of Proteomic Patterns in Serum to Identify Cancer, and Proteomics-Based Testing Related to Ovarian Cancer.
Measurement of HE4 is investigational for all indications.
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.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
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.
Blue Cross Blue Shield Association policy # 2.04.66
This may not be a comprehensive list of procedure codes applicable to this policy.