miRNA as biomarkers in early detection and personalized treatment in ovarian cancer

Epithelial ovarian cancer has poor survival. There are no effective early detection strategies, and early disease symptoms are not specific to the disease (for example, bloating and frequent urination). The best available blood-based early detection biomarker for ovarian cancer is CA125, but this marker has limited ability to distinguish between women with the disease and those who are free of cancer. This study will provide the necessary validation of a panel of microRNAs for EOC early detection. We will use serum samples from prospective cohorts and clinical studies. The objective is to validate a serologic miRNA panel that, together with CA125, would have sufficient diagnostic discrimination to be used as a tool that, together with imaging, would allow early diagnosis and direction of patients with suspected malignancy to personalized specialist care. We will: • Validate serum miRNA profiles as biomarkers for early detection in samples collected from cases <=3 years prior to EOC diagnosis and matched controls, and characterize sources of variation in miRNA profiles. • Evaluate miRNA profiles in the clinical setting and the discrimination between EOC cases and women with (i) benign ovarian tumors and (ii) underlying comorbidities (including other cancer types). Further, we will evaluate serum miRNA profiles as predictors of recurrence and will compare tumor tissue and serum miRNA profiles. • Develop and optimize protocols for data integration and methods for algorithm development. • Address Ethical, Legal and Social Aspects (ELSA), including activities in key stakeholder groups. Challenges in health data privacy and sharing, including for development of an artificial intelligence model, will be addressed, as will the definition of a “healthy” population with respect to miRNA profiles for EOC. In the first grant year, we have completed the following project tasks: • Initiated the project with a kick-off meeting in Oslo, including all project partners, together with user representatives. • Finalized the consortium agreement across the participating institutions. • Finalized the project Data Management Plan. • Obtained the required ethical approvals for access to the required samples and data linkages. • Finalized the selection of samples and data from the prospective and clinical biobanks. • Optimized the assay methods for the miRNA assays using digital PCR (dPCR), with sample analysis to be completed throughout project year 2. This required special consideration given the unique characteristics of biobanked study samples, including those which have been in long-term storage. • Presented the design and concept of the miRPOC project with a poster “microRNA as biomarkers in early detection and personalized treatment in ovarian cancer: Development of the miRPOC consortium” at the American Association for Cancer Research Ovarian Cancer Symposium (Boston, USA; October 2023). • Initiated ELSA activities. Challenges in cross-border data sharing were addressed to facilitate sample and data transfer between collaborators. Further ELSA-related activities included user-oriented outreach: o Dr. Hilde Langseth and Dr. Renée Fortner were featured in Afrodite, the magazine of the Gynecological Cancer Society, describing their studies on ovarian cancer earlier detection (Edition 1/2024). o Dr. Langseth presented “Biomarkers for early detection of cancer - examples from ongoing research in the Janus biobank” for the Gynecological Cancer Society (Oslo; January 2024). o Dr. Fortner presented “MicroRNA as biomarkers in early detection and personalized treatment in ovarian cancer: Development of a personalized prevention consortium” at the Nordic Conference on Future Health (Trondheim, September 2024) The project will move forward with sample preparation and dPCR assays on study samples, implement the data integrating and methods development component of the project, and with multiple ELSA-related activities in preparation.

Epithelial ovarian cancer (EOC) is a lethal malignancy with poor survival. There are no effective early detection strategies, and early symptoms are vague. This study will provide validation of a miRNA panel for EOC early detection in serum samples from prospective cohorts, paired with clinical data and biospecimens. The project is organized as a consortium, where the collaborators are leading the Prospective Early Detection Consortium for Ovarian Cancer. We have used next generation sequencing to identify and validate a miRNA panel. The panel was developed and validated in patients with benign and malignant pelvic masses; and was further validated on a subset of patients and in silico. We have shown that the expression of circulating RNAs varies between healthy individuals and by age, sex, and lifestyle factors. Sources of variation in miRNA levels and the impact of confounders on discrimination between cases and non-cases must be evaluated. We plan to validate a serologic miRNA panel that, together with CA125, would have sufficient diagnostic discrimination for early-stage disease to be used clinically together with imaging, would allow early diagnosis and streaming of patients with suspected malignancy to personalized care. Toward that objective we will: -Validate serum miRNA profiles as biomarkers for EOC early detection in samples collected <=3 years before diagnosis and controls and characterize sources of variation in miRNA profiles. -Evaluate miRNA profiles in the clinical setting and the discrimination between EOC cases and (i) women with benign ovarian tumors in blood samples and (ii) women with underlying comorbidities. We will also evaluate miRNA profiles as predictors of recurrence and compare tumor tissue and serum miRNA profiles. -Develop and optimize protocols for data integration and methods for algorithm development and direct in silico validation. -Evaluate Ethical, Legal and Social Aspects (ELSA) of implementation in key stakeholder groups.