A multiplex biomarker assay improves the diagnostic performance of HE4 and CA125 in ovarian tumor patients

• Published in: PloS one Vol. 15; no. 10; p. e0240418
• Main Authors: Leandersson, Pia, Åkesson, Anna, Hedenfalk, Ingrid, Malander, Susanne, Borgfeldt, Christer
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.10.2020; Public Library of Science (PLoS)
• Subjects: Adult; Age; Aged; Aged, 80 and over; Algorithms; Benign; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - blood; CA-125 Antigen - blood; Cancer; Cancer and Oncology; Cancer och onkologi; Carcinogenesis; Carcinogens; Carcinoma, Ovarian Epithelial - blood; Carcinoma, Ovarian Epithelial - diagnosis; Carcinoma, Ovarian Epithelial - pathology; Case-Control Studies; CD66 antigen; CEACAM1 protein; Clinical Medicine; Colorectal cancer; Deoxyribonucleic acid; Diagnosis; Diagnostic systems; Discrimination; DNA; Early Detection of Cancer; Evaluation; Female; Gynecology; Hospitals; Humans; Klinisk medicin; Medical and Health Sciences; Medical diagnosis; Medical prognosis; Medicin och hälsovetenskap; Medicine and Health Sciences; Membrane Proteins - blood; Menopause; Middle Aged; Multiplexing; Neoplasm Staging; Obstetrics; Oncology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - blood; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - pathology; Patients; Principal components analysis; Protein expression; Proteins; Proteomics; Regression Analysis; Risk factors; ROC Curve; Sensitivity and Specificity; Statistical analysis; Statistical methods; Survival; Tumor markers; Tumors; Ultrasonic imaging; WAP Four-Disulfide Core Domain Protein 2 - metabolism; Womens health; Sweden
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0240418

Survival in epithelial ovarian cancer (EOC) remains poor. Most patients are diagnosed in late stages. Early diagnosis increases the chance of survival. We used the proximity extension assay from Olink Proteomics to search for new protein biomarkers with the potential to improve the diagnostic performance of CA125 and HE4 in patients with ovarian tumors. Plasma samples were obtained from 180 women with ovarian tumors; 30 cases of benign tumor, 28 cases with borderline tumors, 25 early EOC cases (FIGO stage I) and 97 advanced EOC cases (FIGO stages II-IV). Proteins were measured using the Olink® Oncology II and Inflammation panels. For statistical analyses, patients were categorized into benign tumors versus cancer and benign tumors versus borderline + cancer, respectively. We analyzed 177 biomarkers. Thirty-four proteins had ROC AUC > 0.7 for discrimination between benign tumors and cancer. Fifteen proteins had ROC AUC > 0.7 for discrimination between benign tumors and borderline tumors + cancer. HE4 ranked highest for both comparisons. A reference model with HE4, CA125 and age (AUC 0.838 for benign tumors vs. cancer and AUC 0.770 for benign tumors vs. borderline tumors + cancer) was compared to the reference model with the addition of each of the remaining proteins with AUC > 0.7. ITGAV was the only individual biomarker found to improve diagnostic performance of the reference model, to AUC 0.874 for benign tumors vs. cancer and AUC 0.818 for benign tumors vs. borderline tumors + cancer (p < 0.05). Cross-validation and LASSO regression was combined to select multiple biomarker combinations. The best performing model for discrimination between benign tumors and borderline tumors + cancer was a 6-biomarker combination (HE4, CA125, ITGAV, CXCL1, CEACAM1, IL-10RB) and age (AUC 0.868, sensitivity 0.86 and specificity 0.82, p = 0.016 for comparison with the reference model). HE4 was the best performing individual biomarker for discrimination between benign ovarian tumors and EOC including borderline tumors. The addition of other carcinogenesis-related biomarkers in a multiplex biomarker panel can improve the diagnostic performance of the established biomarkers HE4 and CA125.