High-Grade Serous Ovarian Cancer-A Risk Factor Puzzle and Screening Fugitive

Abstract

High-grade serous ovarian cancer (HGSOC) is the most lethal tumor of the female genital tract. Despite extensive studies and the identification of some precursor lesions like serous tubal intraepithelial cancer (STIC) or the deviated mutational status of the patients (BRCA germinal mutation), the pathophysiology of HGSOC and the existence of particular risk factors is still a puzzle. Moreover, a lack of screening programs results in delayed diagnosis, which is accompanied by a secondary chemo-resistance of the tumor and usually results in a high recurrence rate after the primary therapy. Therefore, there is an urgent need to identify the substantial risk factors for both predisposed and low-risk populations of women, as well as to create an economically and clinically justified screening program. This paper reviews the classic and novel risk factors for HGSOC and methods of diagnosis and prediction, including serum biomarkers, the liquid biopsy of circulating tumor cells or circulating tumor DNA, epigenetic markers, exosomes, and genomic and proteomic biomarkers. The novel future complex approach to ovarian cancer diagnosis should be devised based on these findings, and the general outcome of such an approach is proposed and discussed in the paper.

Keywords: biomarkers; circulating tumor DNA; circulating tumor cells; diagnosis; liquid biopsy; ovarian cancer; prediction; risk factors.

Figure 1

“DEPHENCE” system in ovarian cancer diagnosis. The general population of women should be divided into the population with an increased risk (identified based on the higher incidence of cancer in family members, the incidence of ovarian/breast cancer in first/second-degree relatives, and positive familial history of genetic syndromes with increased risk of cancer) and the population with an average risk of ovarian cancer. The higher-risk population should be subjected to the identification of gene mutations and/or SNPs, increasing the risk of ovarian cancer occurrence. In the case of positivity, the risk-reducing salpingo-oophorectomy or serial monitoring should be offered after completing reproduction. According to IOTA rules, the average-risk population should be tested with a serial multimodal combination of serum markers and serial transvaginal ultrasound. In the case of the positivity of either marker levels or the presence of a suspected adnexal tumor, the next step should be performing a liquid biopsy and expert ultrasound, and, when positive, eventual diagnostic laparoscopy. Patients with negative results of marker tests or ultrasound are directed to observation and further screening (once a year?). The multimodal combination of serum markers, as well as targets for the liquid biopsy, should be chosen on the basis of high specificity and sensitivity for early-stage ovarian cancer, as advanced tumors are easily recognizable. TV US—transvaginal ultrasound; IOTA—International Ovarian Tumor Analysis group; ctDNA—circulating tumor DNA.