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DESCRIPTIONHuman Epididymis Protein 4 (HE4) is a potential new biomarker for detecting ovarian cancer early and for monitoring disease progression and recurrence. It has been cleared by the FDA for monitoring patients with epithelial ovarian cancer. HE4 is proposed as a replacement for or complement to CA-125, a biomarker with limited specificity.
Ovarian cancer is the fifth most common cause of cancer mortality in U.S. women; in 2010, it is estimated that ovarian cancer will account for approximately 14,000 deaths, 5% of the cancer deaths in women. 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 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.
Several factors contribute to the frequent late-stage diagnosis of ovarian cancer. First, symptoms are non-specific e.g., abdominal pain, persistent indigestion and bloating, urinary urgency, fatigue and weight loss, and many women do not immediately seek medical consultation. When women seek care, doctors frequently do not recognize the implications of the symptoms and diagnosis can be delayed. Furthermore, there is no reliable test to differentiate between benign and malignant pelvic masses. Generally, women are evaluated with a pelvic examination and ultrasound, and if they are found to have a pelvic mass, they are referred for surgery. The standard treatment for epithelial ovarian cancer is surgical staging and primary cytoreductive surgery followed by chemotherapy in most cases. Health outcomes tend to be better for women with ovarian cancer who are treated by gynecologic oncologists. The proteomics-based OVA1 is cleared by the FDA for assessing the likelihood of malignancy in women with adnexal masses. Following treatment for ovarian cancer, women continue to be monitored for disease recurrence.
In addition to the tests and procedure discussed above, there is interest in identifying biomarkers that can be used to manage patients with ovarian cancer. Currently, the most widely used biomarker is CA-125, a high-molecular-weight protein antigen. Testing for CA-125 in women with a pelvic mass suggestive of ovarian cancer is common practice. However, although elevated serum CA-125 levels are highly correlated with epithelial ovarian cancer (elevated in about 80% of cases), levels can also be elevated by benign gynecological and medical conditions such as endometriosis, congestive heart failure and cirrhosis, limiting the specificity for distinguishing between benign and malignant masses. Moreover, CA-125 levels tend to be higher in pre-menopausal women, increasing the likelihood of false-positives when used in this population. After treatment for ovarian cancer, serial measurement of CA-125 has been used to detect early recurrence of disease. A rising CA-125 level has been found to correlate with disease recurrence, although a survival advantage of detecting recurrence early with CA-125 compared to symptomatic detection has not yet been demonstrated.
Another serum biomarker, recently 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 it a candidate to replace or complement CA-125. Tests for HE4 are FDA-approved for monitoring women known to have epithelial ovarian cancer. Although HE4 tests are not FDA-approved for evaluating women with ovarian masses to aid in the identification of malignant tumors, the test has been investigated for this indication and is available outside of the Untied States for evaluating women with pelvic masses.
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 CA125 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. 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.
Refer to the following related medical policies: CA-125, Analysis of Proteomic Patterns in Serum to Identify Cancer, and Proteomics-based Testing for the Evaluation of Ovarian (Adnexal) Masses.
POLICYMeasurement of HE4 is investigational for all indications.
POLICY EXCEPTIONSFederal 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 GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY11/11/2010: 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.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.66
This is not an all-inclusive list of non-covered procedure codes.
All codes billed for this procedure are considered investigational and not eligible for coverage.