Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer-Impact for Diagnosis and Treatment Monitoring

Braicu, Elena Ioana; du Bois, Andreas; Sehouli, Jalid; Beck, Julia; Prader, Sonia; Kulbe, Hagen; Eiben, Bernd; Harter, Philipp; Traut, Alexander; Pietzner, Klaus; Glaubitz, Ralf; Ataseven, Beyhan; Chekerov, Radoslav; Keck, Christoph; Winkler, Thomas; Heikaus, Sebastian; Gellendin, Peggy; Schuetz, Ekkehard und Heitz, Florian (2022): Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer-Impact for Diagnosis and Treatment Monitoring. In: Cancers, Bd. 14, Nr. 1, 168

Abstract

Simple Summary The prognosis of ovarian cancer is dependent on the tumor stage and the development of chemotherapy resistance. Using low-coverage cell-free tumor DNA sequencing, we were able to determine the chromosomal instability (CI) of tumors that are frequently found in patients with primary advanced and recurrent high-grade ovarian cancer from a blood sample. We were able to show that the CI could be used for the reliable detection of ovarian cancer in comparison to healthy controls. Moreover, we showed that the CI was significantly associated with the prognostic and predictive clinical measures in primary and recurrent ovarian cancer. The high diagnostic accuracy of the tumor CI derived from cfDNA analysis might lead to the optimization of main prognostic determinants in patients with ovarian cancer. As the CI is a characteristic feature in high-grade ovarian cancer, no upfront tumor tissue analysis is required to identify genomic alterations for targeted sequencing of cfDNA, if the herein described low-coverage sequencing and CNI-Score determination is used. Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment. Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set. Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively. Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch