A Biomarker Panel Increases the Diagnostic Performance for Epithelial Ovarian Cancer Type I and II in Young Women

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Results

The preoperative plasma levels of B7-H4 were higher in patients with EOC II tumors than in those with benign tumors (p<0.001) (Figure 1 and Table III) but no significant differences were found between EOC I or borderline tumors compared with benign tumors. The suPAR(II-III) levels were significantly lower in benign tumors compared to borderline, EOC I and EOC II tumors. HE4 and CA125 levels were significantly different in all comparisons between benign, borderline, EOC I and EOC II (Figure 1 and Table III).

Conclusion: The biomarker panel suPAR(II-III), HE4, CA125 and age in premenopausal women improved discrimination of malignant and benign ovarian tumors. The plasma levels of B7-H4 were increased in patients with EOC II compared to those with benign ovarian tumors. 

Predicting whether pelvic masses are benign or malignant has become more important as benign tumors now undergo laparoscopic surgery or conservative management. The suspected malignant tumors are referred to gynecological oncology centers for further evaluation and extensive ovarian cancer surgery, if needed to achieve macroscopic radical tumor reduction, improving survival. Subjective ultrasound evaluation of gray-scale and color Doppler images of pelvic masses, with pattern recognition, in the hands of expert ultra-sonographers have shown good prediction of discrimination between benign and malignant adnexal masses (1-3), but the general gynecologist or sonographer does not have that capability, not even after teaching sessions using the International Ovarian Tumour Analysis (IOTA) group scoring system (4) or IOTA simple rules (5).

In suspicion of malignancy, the most commonly used tumor marker, cancer antigen 125 (CA125), is not reliable due to low sensitivity in patients with early-stage ovarian cancer (6). CA125 also has a low specificity since it is often found increased in patients with benign endometriosis. The biomarker human epididymis protein 4 (HE4), alone and in combination with CA125 in the Risk of Ovarian Malignancy Algorithm (ROMA) algorithm, increases sensitivity in the distinction of ovarian carcinoma from benign disease. HE4 is approved by the United States Food and Drug Administration for monitoring recurrence or progressive disease in patients with epithelial ovarian cancer (EOC). We have shown that HE4 is an independent preoperative marker of poor prognosis in serous ovarian cancer (7). Although its physiological functions have not been fully identified, overexpression of the HE4 protein has been found mainly in serous and endometroid ovarian carcinomas (8).....

 A novel (new) ovarian tumor type and grading system has been proposed based on morphological and molecular genetics, which divides EOC into type I and type II tumors (11, 12). Low-grade serous, and endometrial carcinoma, clear cell cancer and mucinous carcinoma are classified as EOC type I (11). Generally, EOC type I carcinomas behave in an indolent manner and are more often confined to the ovary at diagnosis, with a stable genome and without TP53 mutations. EOC type II tumors are high-grade serous carcinomas which are more aggressive and genetically highly unstable, and the majority of carcinomas have TP53 mutations, hypermethylation, or dysfunction of breast cancer gene 1/2. The aggressive EOC type II tumors account for 75% of all EOCs and are responsible for 90% of deaths from the disease. It has also been suggested that type II EOCs develop in the fallopian tube at the conjunction to the ovary or the peritoneum (13).