Abstract
This study was designed to analyze urinary proteins associated with ovarian cancer (OC) and investigate the potential urinary biomarker panel to predict malignancy in women with pelvic masses. We analyzed 23 biomarkers in urine samples obtained from 295 patients with pelvic masses scheduled for surgery. The concentration of urinary biomarkers was quantitatively assessed by the xMAP bead-based multiplexed immunoassay. To identify the performance of each biomarker in predicting cancer over benign tumors, we used a repeated leave-group-out cross-validation strategy. The prediction models using multimarkers were evaluated to develop a urinary ovarian cancer panel. After the exclusion of 12 borderline tumors, the urinary concentration of 17 biomarkers exhibited significant differences between 158 OCs and 125 benign tumors. Human epididymis protein 4 (HE4), vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were the top three biomarkers representing a higher concentration in OC. HE4 demonstrated the highest performance in all samples with OC (mean area under the receiver operating characteristic curve (AUC) 0.822, 95% CI: 0.772–0.869), whereas TTR showed the highest efficacy in early-stage OC (AUC 0.789, 95% CI: 0.714–0.856). Overall, HE4 was the most informative biomarker, followed by creatinine, carcinoembryonic antigen (CEA), neural cell adhesion molecule (NCAM), and TTR using the least absolute shrinkage and selection operator (LASSO) regression models. A multimarker panel consisting of HE4, creatinine, CEA, and TTR presented the best performance with 93.7% sensitivity (SN) at 70.6% specificity (SP) to predict OC over the benign tumor. This panel performed well regardless of disease status and demonstrated an improved performance by including menopausal status. In conclusion, the urinary biomarker panel with HE4, creatinine, CEA, and TTR provided promising efficacy in predicting OC over benign tumors in women with pelvic masses. It was also a non-invasive and easily available diagnostic tool.
Highlights
Ovarian cancer (OC) is the seventh most common malignancy among women worldwide, accounting for 3.6% of cancers in women [1]. It is the most lethal of all gynecological malignancies, with more than 70% of women presenting with the advanced-stage disease [2], and the primary treatment for advanced-stage disease involves both cytoreductive surgery and chemotherapy
Due to the low prevalence of OC [1], the required minimum SP of the serum test should be 98% when combined with transvaginal sonography (TVS) as a second-line test [25,26], and accurate assessment of such high SP require at least 1000 healthy participants
The present results are comparable to other differential diagnostic techniques using blood samples: (1) the urinary protein panel offered 93% SN at 75% SP, (2) the Risk of Malignancy Index (RMI) showed 85–96% SN at 75% SP [27,28], (3) the Risk of Malignancy Algorithm (ROMA) provided 94% SN at 75% SP [27,28,29], and (4) the OVA1 test revealed 92–97% SN at a low SP of approximately 54% [29,30] (Table 4)
Summary
Ovarian cancer (OC) is the seventh most common malignancy among women worldwide, accounting for 3.6% of cancers in women [1]. It is the most lethal of all gynecological malignancies, with more than 70% of women presenting with the advanced-stage disease [2], and the primary treatment for advanced-stage disease involves both cytoreductive surgery and chemotherapy. Long-term survival has not significantly improved in the past 30 years, with the five-year survival rate remaining between 30% and 45% [3]. The management of OC with complete cytoreductive surgery by a gynecologic oncologist enables a favorable prognosis [5]; the decision of an appropriate referral is important. It has been reported that 65% of patients with malignant adnexal masses are inappropriately referred to gynecologic oncologists in the United States of America [6]
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