Ovarian Cancer Detection Index: Human Epididymis Protein 4 (HE4)

As the most common malignant tumor of female reproductive organs and the first cause of death from gynecological malignancies in China, ovarian cancer has seen a 30% increase in incidence and an 18% increase in mortality over the past 10 years. Because early symptoms are not obvious and early tumors are difficult to detect during pelvic examinations, 70% to 75% of ovarian cancer patients are already in advanced stages when diagnosed, which is why ovarian cancer is called the "silent killer".

Human epididymis protein 4 (HE4) is a new tumor marker that can help in early diagnosis, differential diagnosis, treatment monitoring, and prognosis assessment of ovarian cancer. It is a real benefit for women's health.

1. What is human epididymis protein 4 (HE4)?

HE 4 human epididymis protein 4 belongs to the whey acidic 4-disulfide center (WFDC) protein family, which has suspected trypsin inhibitor properties. Other proteins in this family include SLPI, Elafin, and PS20 (WFDC1). The HE4 gene encodes a segment of 13 kD in length, although, at the time of its mature glycosylation formation, this protein is roughly 20 kD to 25 kD and contains a single chain with two WFDC structural domains.

HE4 was first identified in the epithelium of the distal epididymis and was initially thought to be a protease inhibitor associated with sperm maturation. Immunohistochemical and gene microarray studies confirmed that it is barely expressed in normal human ovarian tissues; in malignant tissues, it is commonly upregulated in ovarian cancer and is one of the most commonly upregulated expressed genes in ovarian cancer; and is not expressed or is lowly expressed in most non-ovarian cancers. In contrast, RT-PCR studies revealed that HE4 was highly expressed in ovarian cancer cell lines, and cell cultures contained a secreted form of HE4.

In a comparative study of ovarian cancer patients with healthy states, Hellstrom et al. found that HE4 was up to 95% specific and 67% sensitive for detecting ovarian cancer. The specificity was significantly higher than that of the cancer antigen 125 marker alone. Combined with CA125, the test was more accurate in predicting ovarian cancer, with a sensitivity and specificity of 76% and 95%, respectively.

2. Application of human epithelial protein 4 (HE4) test in ovarian cancer patients

Ovarian cancer is one of the common malignant tumors threatening women's health. 70% of the patients are already in the advanced stage when diagnosed, and the five-year survival rate of advanced-stage patients is only 20% to 30% despite tumor cytoreductive surgery and chemotherapy. At present, the diagnosis of ovarian cancer mainly relies on clinical symptoms, pelvic examination, vaginal ultrasound, CT/MRI, and serum tumor markers.

The commonly used antigen markers include CA125, HCG, CEA, TPA, etc. Especially CA125 is the most widely used and plays an important role in clinical diagnosis, chemotherapy monitoring, and follow-up; however, due to its low specificity, it has little significance in the early screening of ovarian cancer. Therefore, there is a lack of effective means for early diagnosis of ovarian cancer in clinical practice. And the discovery of HE4 assisted in solving this problem to a great extent.

3. Application of human epithelial protein 4 (HE4) test

(1) The combined test with CA125 is used for risk prediction index (PI) calculation of malignant ovarian cancer to assess the risk of epithelial cell type ovarian cancer in premenopausal and postmenopausal women with pelvic tumors (predicted probability ROMA value).

(2) Disease status monitoring of patients diagnosed with ovarian cancer.

Several studies have demonstrated that changes in HE4 tumour marker concentration levels in ovarian cancer patients are positively correlated with changes in disease progression. Therefore, the progression of ovarian cancer can be assessed by continuous measurement of serum HE4 concentration levels.    

(3) Note on limitations of application:

HE4 test levels may be at normal values in some patients with diagnosed ovarian cancer and may be seen in mucin-type ovarian cancer or germ cell-type ovarian cancer, both of which rarely express human epithelial protein 4 (HE4);

The concentration level of HE4 is not absolute evidence for the presence or absence of malignancy;

The rules of risk assessment for malignant ovarian cancer do not apply to patients undergoing chemotherapy and those younger than 18 years of age.