Diagnosing Ovarian Cysts - the DOC Study

Background:

Ovarian cysts are commonly found in women with an estimated prevalence up to 35 % in premenopausal women and 17 % in postmenopausal women. The majority are of benign character and sometimes self-limiting; however, malignancy occurs as ovarian cancer (OC). More than 500 women are diagnosed with OC every year in Denmark, and Denmark has the highest OC incidence rate in the Nordic countries. Today, more than 70% of women with OC are diagnosed with advanced stage disease, where the five-year overall survival rate is 16-29% compared to 70-88% in early stages. Symptoms are often present months prior to diagnosis, however, they are vague and un-specific of character leading to delay of diagnosis. Attempts to improve patient awareness and correct symptom interpretation are encouraged. OC rates the fifth most deadly cancer among women and causes more deaths than any other cancer of the female reproductive system in more developed countries. Centralized treatment of OC9, OC guidelines10, fast-track OC programs, and a gynecologic cancer database (Danish Gynecological Cancer Database (DCGD)) are all national approaches that has contributed to a decreased mortality rate in Denmark during the past decades.

Yet further approaches to improve OC survival are highly needed. Given that OC survival is considerably better in early stage disease, methods to correctly differentiate benign ovarian tumors from OC at an early stage is a high research priority. In Denmark, gynecologists currently use the Risk of Malignancy Index (RMI) to detect women at high risk of OC. RMI calculation is based on transvaginal ultrasound findings, serum Cancer Antigen 125 (CA125) level, and menopausal status. Women in high risk of OC (RMI ≥ 200) are referred in the national fast-track cancer program for further diagnostics at a tertiary center specialized in gynecologic malignancies, whereas women in low risk of OC (RMI < 200) can be observed or treated at a local department of gynecology or in a gynecology practice. However, RMI is not optimal to distinguish between benign and malignant tumors with a sensitivity of 92 %, specificity of 82 %, negative predictive value of 97 %, and a positive predictive value of 62 % in a Danish population.

Considering the high prevalence of benign ovarian cysts in comparison to OC, it is of utmost importance, that efforts to detect OC at an early stage is not accompanied by an unintended increase of false positive tests, resulting in overdiagnosis and overtreatment. New promising studies suggest an improvement in the diagnostics and risk assessment models by adding the serum biomarker Human Epididymis protein 4 (HE4) and systemized ultrasound imaging in accordance to the International Ovarian Tumor Analysis (IOTA).

The biomarker HE4 is a secretory gluco-protein that is highly elevated especially in serum from women with OC. The diagnostic performance of HE4 is equal to CA125 and improves further when HE4 and CA125 is combined In the newly developed diagnostic Copenhagen Index (CPH-I), HE4 is combined with age and CA125. On tertiary center data, CPH-I has shown to distinguish benign gynecologic disease from OC significantly better than RMI in the international, multicenter, validating cohort demonstrating an area-under-curve (AUC) at 0.951 and 0.935, respectively.