Abstract 1070: Overcoming deficiencies in the early detection of high grade serous ovarian cancer: Evaluating exosomal proteins as novel biomarkers of disease
Authors: Lightfoot Michelle , Dorayappan Kalpana Deepa Priya , Yu Lianbo , Hisey Colin , Sakaue Takahiko , Anbalagan Muralidharan , Cosgrove Casey M. , Maxwell Larry G. , Thaker Premal , Karlan Beth Y. , O’Malley David , Pollock Raphael E. , Cohn David E. , Gogna Rajan , Karuppaiyah Selvendiran 
Published: March 2024

Abstract
Introduction: High-grade serous ovarian cancer (HGSOC) accounts for over 75% of all epithelial ovarian cancer and has a high mortality rate due to a lack of early detection methods. Many biomarkers have been proposed; however, none have been shown to improve detection at an early stage in this patient population. The purpose of this study is to assess whether there are unique extracellular vesicle (EV) protein signatures of early-stage HGSOC that could serve as early detection biomarkers.
Methods: 250 serum samples were obtained from a multi-institutional retrospective cohort of patients with all stages of HGSOC and healthy controls. LC-MS/MS and PEA of serum samples from patients with early-stage HGSOC identified differentially expressed EVs proteins in HGSOC versus controls. Tob candidate proteins are validated by ELISA.
Results: We have identified the top 10 EVs candidate proteins based on their fold change and statistical significance. When comparing early-stage HGSOC and controls using ELISA, CFH, PCP, and CCNE1 exhibited the highest Area Under the Curve (AUC) values of 0.94, 0.91, and 0.83, respectively. In contrast, MUC16 (also known as CA-125) exhibited an AUC of only 0.42 in whole serum. Furthermore, MUC16 distinguished between controls and both early and advanced-stage HGSOC in EVs, while in whole serum, it was only differentially expressed between controls and advanced-stage disease. Our results demonstrate that the predictive performance of the combined biomarkers surpasses that of any individual biomarker. Further, we integrated the ten aforementioned biomarkers, deriving the optimal combination biomarker by maximizing the corresponding Sum of Harmonic Means (SHUM) function by utilizing data from all 70 patients, results showed the optimal coefficients of the biomarkers, which maximize the diagnostic accuracy for early-stage HGSOC. The overall true positive rate (TPR) of 0.943, false positive rate (FPR) of 0.000, and Mathew's correlation coefficient (MCC) were presented for both the combined biomarker approach and individual biomarkers. The results demonstrated that the predictive performance of the combined biomarkers surpassed that of any individual biomarker.
Conclusion: Expression of EV-based protein biomarkers is significantly different in early-stage HGSOC compared to both control and late-stage HGSOC. This work can be readily translated to clinical use and potentially improve the early detection of HGSOC substantially.
Citation Format: Michelle Lightfoot, Kalpana Deepa Priya Dorayappan, Lianbo Yu, Colin Hisey, Takahiko Sakaue, Muralidharan Anbalagan, Casey M. Cosgrove, Larry G. Maxwell, Premal Thaker, Beth Y. Karlan, David O’Malley, Raphael E. Pollock, David E. Cohn, Rajan Gogna, Selvendiran Karuppaiyah. Overcoming deficiencies in the early detection of high grade serous ovarian cancer: Evaluating exosomal proteins as novel biomarkers of disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1070.