HE4 – a new tumour marker for ovarian cancer

Ovarian cancer, with an incidence of 15 / 100,000 women, is the sixth most common form of cancer in Germany and the second most common genital tumour in women. Ovarian cancer is the fourth most common cause of cancer death in women around the world. The 5-year survival rate of patients with ovarian cancer is 45%, and the 10-year survival rate is 35 %. Over 90 % of ovarian cancers are epithelial tumours. Of the epithelial tumours, serous and endometrial tumours are by far the most frequently found.

To date, CA 125 has proven to be the most important tumour marker for serous ovarian cancer and is regarded as the gold standard. CA 125 is used with success for therapy monitoring and detection of tumour recurrence. It is not, however, suitable for use as a screening test for the detection of very early tumour stages because of its minimal diagnostic sensitivity in this case. In the early tumour stages, false negative values are often found.
False positive values are found when there are cysts and benign tumours of the ovaries. Hence, 70 % of cases of ovarian cancer today are not diagnosed until it has reached the advanced tumour stages III and IV, with invasive growth that is often no longer local in scope. The prognosis for the early stages of the tumour is considerably more favourable. The early detection of ovarian cancer using a biomarker with high diagnostic sensitivity and specificity in stages I and II is therefore of great clinical relevance.

The epididymal protein HE4 has proven itself to be a new biochemical marker with, in comparison to CA 125, a greater potential for detecting the early tumour stages.

The HE4 gene is greatly amplified on the cellular level in serous and endometrioid ovarian cancer. An overexpression of the gene has been demonstrated in 93 % of serous and 100 % of endometrioid ovarian cancers in the early stages. In contrast, its expression in normal tissues and benign tumours, as well as in mucinous ovarian cancer, is minimal. The marked differences in the gene expression at the cellular level are reflected in significant differences in the serum concentrations. The result is, compared to CA 125, a significantly greater diagnostic sensitivity for detecting the earlier stages of serous and endometrioid ovarian cancer.
Through using the combination of the HE4 and CA 125 markers, diagnostic sensitivity and specificity for the evaluation of epithelial ovarian cancer, especially for detecting the early tumour stages (I and II), can be improved significantly. Both biomarkers also complement one another with respect to the correlation to the clinical status.

Using a mathematical algorithm (ROMA = Risk of Ovarian Malignancy Algorithm), the results of HE4 and CA 125 determination can be combined to produce a predictive index.
This predictive index makes it possible to assess the risk of the presence of epithelial ovarian cancer in patients with an adnexal tumour of unknown malignancy — even before surgery.

Method
Chemiluminescence micro-particle immunoassay

Test material

1 ml of serum

Reference values

< 70 pmol/l (96 %) premenopausal women
< 140 pmol/l (95 %) postmenopausal women
ROMA Value > 7.4 % high risk (premenopausal)
  < 7.4 % low risk
ROMA Value > 25.3 % high risk (postmenopausal)
  < 25.3 % low risk

Please note: Determining HE4 is currently not part of the service catalogue of statutory health insurance.

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