A Bard1 Autoimmune Antibodies Test For Early Detection Of Ovarian Cancer

Ovarian cancer is a rare and most deadly cancer of women, as it has no symptoms and there is no screening for early detection in place. The CA125 biomarker has been used for decades but it is not recommended for screening due to insufficient specificity and sensitivity. We aimed to develop a blood test for early detection of all types of ovarian cancer based on the immunogenicity of aberrant oncogenic splice isoforms of BARD1 that are specifically upregulated in ovarian cancer. While the BARD1 protein acts with BRCA1 as tumour suppressors in DNA repair and cell cycle control[1], expression of high levels of deletion-bearing isoformswas correlated with tumour aggressiveness and progression in breast, ovarian, and lung cancer[2],[3]. The different structures of tumour-associated BARD1 isoforms cause an immune response in cancer patients, that can be used as a tell-tale of cancer. Hence, we have developed an autoimmune antibody test for early detection of breast and ovarian cancer. ELISA assays were performed on a panel of short synthetic peptides presenting epitopes of BARD1 isoforms to measure serum levels of antibodies against BARD1 epitopes. We tested 721 blood samples from ovarian cancer patients and healthy controls on multiplex ELISA plates.These data were analyzed using Lasso logistic regression, and an optimal combination of BARD1 antigens that showed maximal discrimination of ovarian cancer from controls was determined. This algorithm was validated in cross validation. This BARD1 ovarian cancer (BARD1 OC) test was validated by cross validations to determine its accuracy in out of sample test data sets.Finally, CA125 values were measured for each sample and integrated in the algorithm. The BARD1 OC test reached high accuracy with an average AUC[4]0.92 in training sets, and an average AUC 0.88, 82% sensitivity, and 79% specificity in test sets. It was further improved by combining the BARD1 OC test values with values for the currently in use ovarian cancer biomarker CA125. The combined BARD1 OC-CA125 test, showed an average AUC 0.98 in training sets, and an average AUC 0.95, 88% sensitivity and 93% specificity in test sets. The BARD1 OC test, as well as the BARD1 OC-CA125 test, are equally highly sensitive and specific for early stage 1 and 2 ovarian cancer and all types of ovarian cancer. The BARD1 OC test can detect ovarian cancer equally well or with higher accuracy in women who are carriers of predisposing mutations in BRCA1/2 genes or part of the HBOC (hereditary breast and ovarian cancer) group. We therefore believe that the BARD1 OC test could be developed further to become a diagnostic aid for women with suspicious symptoms of ovarian cancer or a screening and monitoring tool for genetically predisposed or HBOC type women. [1]Irminger-Finger and Jefford, Nature Reviews Cancer, 2006; Irminger-Finger et al, IJBCB 2017. [2]Li et al, Cancer Research 2007. [3]Pilyugin et al, Oncotarget 2016. [4]Area under the curve Citation Format: Maxim Pilyugin, Magda Ratajska, Marie Cohen, Irmgard Irminger-Finger. A BARD1 autoimmune antibodies test for early detection of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1101.