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

Abstract

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.

Double Trouble: Whole-Genome Doubling Distinguishes Early from Late Ovarian Cancer

“…Cancer detection and minimal residual disease monitoring via circulating tumour DNA has increasing applications across tumor indications. Recently, Braicu and colleagues ( 6 ) provided proof-of-concept evidence to detect HGSC in a prospective cohort ( n = 109) in comparison to healthy controls ( n = 241) by copy-number index score (CNI-Score) from ctDNA. Together with the conclusions of Cheng and colleagues ( 1 ), the need for high-sensitivity detection of chromosomal alterations and WGD will need to be incorporated into ctDNA detection algorithms for HGSC.…”

Ploidy Status of Ovarian Cancer Cell Lines and Their Association with Gene Expression Profiles

“…CNV analysis indicated that hyperploid cells enriched tumor metastasis and chemoresistance in ovarian cancer [21][22][23]. The analysis of cell-free DNA or circulating-tumor DNA supports the value of aneuploidy in the monitoring of tumor progression, therapeutic efficacy and tumor recurrence [24,25]. Overall, as a genetically unstable tumor, aneuploidy and chromosomal instability are prevalent and dynamic in ovarian cancer patients.…”

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

“…Chromosomal instability is a source of a disturbed copy number state, which is detectable in the ctDNA test. The copy number instability score (CNI-score) reached a sensitivity of 91% and a specificity of 95% to detect ovarian cancer in blood samples [237].…”

“…Improved malignancy detection (AUC 0.94) compared to CA125 (AUC 0.78) and RMI index (AUC 0.81) [191] NIPT sequencing Detected 41% of all HGSOC, including 38% of early-stage cases [236] CNI-score A sensitivity of 91% and a specificity of 95% to detect ovarian cancer in blood samples [237]…”