Development and validation of a panel of breast cancer autoantigens for the early diagnosis of breast cancer Abstract Detection of the early stages of breast cancer is one of the pillars of successful therapy and the identification of cancer risk is paramount in cancer prevention. Meta-analyses of data from clinical trials support the conclusion that annual screening mammography reduces breast cancer mortality. Although there is support for its use as a screening tool for breast cancer, mammography has known limitations, mainly false negative and false positive results. On this basis, we propose a new method which will complement and improve the accuracy of screening mammography to detect breast cancer early and accurately. Many studies have shown that autoantibodies appear in cancer sera before the disease becomes clinically evident, suggesting that they have the potential of detecting early disease, i.e., when the treatment has the best chance to influence tumor behavior and ideally to achieve a cure. In response to the need of accurate biomarkers predictive of early diagnosis of breast cancer, we developed an autoantigen panel based on autoantibody recognition of phage-encoded human antigens for the diagnosis of breast cancer. The primary objective of this proposal is to improve the accuracy of this diagnostic panel. The accuracy of the panel will be improved by identifying a larger pool of breast cancer-associated autoantigens with potential diagnostic value. This will be accomplished by using sera from women with ductal carcinoma in situ (DCIS) of the breast for cloning the new antigens, and by selecting cloning sera containing antibodies not previously used for immunoscreening. The performance of the expanded antigen panel will be tested by probing the microarray with an existing collection of sera from women with biopsy-proven diagnosis of DCIS and, infiltrating ductal carcinoma (IDC) of the breast and complete follow up, including mammography findings and outcome measures obtained from the Tissue Procurement Facility at the Henry Ford Health System (HFHS). Control sera will be obtained prospectively from women undergoing mammography screening at HFHS with final assessment of BI-RADS 4 and benign diagnosis at breast biopsy. We propose to validate the performance of the expanded panel constructed with phage inserts in a racially diverse group of women with mammography BI-RADS 4 final assessment, who are members of a large health maintenance organization and regular participants in mammography screening. Finally, we will develop a specific ELISA using the identified phage antigens as substrates which will be reacted with the same case and control sera used to validate the microarray. The outcome of this project will be the development of a new diagnostic test based on serum reactivity to an autoantigen panel, which will prove to be an accurate, relatively inexpensive, accessible, rapid and easy test to perform, which may effectively improve the accuracy of screening mammography for the early diagnosis of breast cancer with potential for the identification of breast cancer risk.
This project is based on a reported case-control investigation of a phage-coded autoantigen panel that could distinguish breast cancer sera from normal controls without cancer and appeared to be a promising test for the early diagnosis of breast cancer. Here we propose to improve the accuracy of the reported panel by concentrating our efforts on DCIS of the breast, the first clinically recognizable form of breast cancer, by expanding the diagnostic panel through the identification of new breast cancer- associated phage-coded autoantigens and to validate this array in an independent group of women from the Henry Ford Health System with BI-RADS 4 final assessment at mammography. A portable ELISA constructed with the antigens identified will be probed with the case and control sera used to externally validate the panel to assess the potential value of this platform in a clinical setting. The outcome of this project will be the development of a new diagnostic instrument, based on serum reactivity to an autoantigen panel constructed with phage-coded antigens which may prove to be an accurate, relatively inexpensive, accessible, rapid and easy to administer blood test for the early diagnosis of breast cancer. We propose that this test used in conjunction with mammography has the potential to complement and increase the accuracy of the screening process.
| Madrid, Félix Fernández; Maroun, Marie-Claire; Olivero, Ofelia A et al. (2015) Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis. BMC Cancer 15:407 |
| Maroun, Marie-Claire; Olivero, Ofelia; Lipovich, Leonard et al. (2014) Anti-centrosome antibodies in breast cancer are the expression of autoimmunity. Immunol Res 60:339-47 |
| Madrid, Félix Fernández; Maroun, Marie-Claire (2011) Serologic laboratory findings in malignancy. Rheum Dis Clin North Am 37:507-25 |
