Camille V. Trinidad

Reducing Ovarian Cancer Mortality Through Early Detection: Approaches Using Circulating Biomarkers

Abstract More than two-thirds of all women diagnosed with epithelial ovarian cancer (EOC) will die from the disease (>14,000 deaths annually), a fact that has not changed considerably in the last three decades. Although the 5-year survival rates for most other solid tumors have improved steadily, ovarian cancer remains an exception, making it the deadliest of all gynecologic cancers and five times deadlier than breast cancer. When diagnosed early, treatment is more effective, with a 5-year survival rate of up to 90%. Unfortunately, most cases are not detected until after the cancer has spread, resulting in a dismal 5-year survival rate of less than 30%. Current screening methods for ovarian cancer typically use a combination of a pelvic examination, transvaginal ultrasonography, and serum cancer antigen 125 (CA125), but these have made minimal impact on improving mortality. Thus, there is a compelling unmet need to develop new molecular tools that can be used to diagnose early-stage EOC and/or assist in the clinical management of the disease after a diagnosis, given that more than 220,000 women are living with ovarian cancer in the United States and are at risk of recurrence. Here, we discuss the state of advancing liquid-based approaches for improving the early detection of ovarian cancer. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention

Lineage specific extracellular vesicle-associated protein biomarkers for the early detection of high grade serous ovarian cancer

Abstract High grade serous ovarian carcinoma (HGSOC) accounts for ~ 70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85 to 98% in a case–control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by a linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% with 99.8% specificity and a positive predictive value of 13.8%. Importantly, these exo-proteins also can accurately discriminate between ovarian and 12 types of cancers commonly diagnosed in women. Our studies demonstrate that these lineage-associated exo-biomarkers can detect ovarian cancer with high specificity and sensitivity early and potentially while localized to the FT when patient outcomes are more favorable.