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Fragmentation patterns of plasma cell-free DNA (cfDNA) are known to reflect nucleosome positions of cell types contributing to cfDNA. Based on cfDNA fragmentation patterns, the deviation in nucleosome footprints was quantified between diagnosed ovarian cancer patients and healthy individuals. Multinomial modeling was subsequently applied to capture these deviations in a per sample nucleosome footprint score. Validation was performed in 271 cfDNAs pre-surgically collected from women with an adnexal mass. We confirmed that nucleosome scores were elevated in invasive carcinoma patients, but not in patients with benign or borderline disease. Combining nucleosome scores with chromosomal instability scores assessed in the same cfDNA improved prediction of malignancy. Nucleosome scores were, however, more reliable to predict non-high-grade serous ovarian tumors, which are characterized by low chromosomal instability. These data highlight that compared to chromosomal instability, nucleosome footprinting provides a complementary and more generic read-out for pre-surgical diagnosis of invasive disease in women with adnexal masses.

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validated assays to assess HRD are BRCA-mutation (BRCAmut) analysis and genomic instability scores (GIS) designed to detect genomic 'scars' in tumor DNA. However, these tests require large samples and yield non-contributive (NA) in 15% of cases. Bevacizumab and PARPi are approved as maintenance therapy regardless HRD status and the optimal maintenance strategy in case of non-contributive HRD test is a major unmet medical need. We aim to report the clinical characteristics and behavior under chemotherapy of NA HGOC pts. Methodology This is a retrospective analysis of all pts tested for GIS by myChoice HRD Plus assay (Myriad Genetic Laboratories). Pts included presented HGOC with advanced FIGO III/IV diseases and treated according to guidelines. GIS was performed on baseline pretreatment samples, preferably. Platinum-free interval (PFI) was calculated from the date of last platinum-based chemotherapy to the date of relapse. Results 210 patients were recruited: 100 were classified HRD negative (HRD-, score <42), 81 HRD positive (HRD+, score 42) and 29 NA (14%). HRD+ cohort was significantly enriched with BRCAmut pts (21/81 = 27%) compared to HRD-and NA. In the NA cohort, median age was 64 years, 86% had an high-grade serous tumor and 10% presented germinal BRCAmut. With a median follow-up of 39 months, median PFI in the overall population was 19.8 months (95% CI 16.7-24.4). In the HRD+, HRD-and NA cohorts (excluding BRCAmut), median PFI were 34.0 (95%CI 16.7-64.4), 14.6 (95%CI 12.0-20.9) and 37.3 months (95%CI 21.0-NA) respectively (P=0.004). Conclusion Our results suggest that patients with NA GIS results behave like HRD+ tumors harboring high platinumsensitivity and therefore may benefit from PARPi maintenance. The reason for non-contributivity in the first place is unknown and may explain these observations.