Added value of cell-free DNA over clinical and ultrasound information for diagnosing ovarian cancer

Background: We previously proposed two cfDNA-based scores (genome-wide z-score and nucleosome score) as candidate non-invasive biomarkers to further improve pre-surgical diagnosis of ovarian malignancy. We aimed to investigate the added value of these cfDNA-based scores to the predictors of the ADNEX model (Assessment of Different NEoplasias in the adnexa) to estimate the risk of ovarian malignancy. Methods: 526 patients with an adnexal mass scheduled for surgery were consecutively recruited in three oncology referral centers. cfDNA-based scores were calculated in pre-operative plasma samples. Logistic regression models were fitted for ADNEX predictors alone and after adding cfDNA scores. We reported likelihood ratio tests, the area under the Receiver Operating Characteristic curve (AUC), sensitivity, specificity, and Net Benefit for thresholds between 5% and 40%. Results: The study included 272 benign, 86 borderline, 36 stage I invasive, 113 stage II-IV invasive, and 19 secondary metastatic tumors. The likelihood ratio tests for adding the cfDNA variables to the ADNEX model were statistically significant (p<0.001 for ADNEX without CA125, p=0.001 for ADNEX with CA125). The accompanying increases in AUC were 0.013 and 0.003. Net Benefit, sensitivity and specificity were similar for all models. The increase in Net Benefit at the recommended 10% threshold estimated risk of malignancy was 0.0017 and 0.0020, respectively. According to these results, adding cfDNA markers required at least 453 patients per additional true positive. Conclusion: Although statistically significant, the addition of the cfDNA scores to the ADNEX model do not improve the ADNEX model in a clinically meaningful way.