Discovery and Validation of Breast Cancer Early Detection Biomarkers in Preclinical Samples

Abstract

Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of blood-based biomarkers useful for the early detection of breast cancer could have a major impact on reducing breast cancer disease burden by identifying cancers early when they are most treatable. We conducted a series of large-scale proteomic discovery and validation studies using preclinical samples from the Women's Health Initiative Observational Study prospective cohort. Of the 503 proteins quantified in experiments conducted on samples from ER(+) breast cancer patients and matched controls, 57 differentiated cases from controls. The seven candidates were assessed in an independent validation set with a commercially available ELISA assay. We confirmed that one of these candidates, epidermal growth factor receptor (EGFR), was elevated in cases versus controls. Compared to women in the lowest EGFR quartile, those in the highest quartile has a 2.90-fold (p = 0.0005) increased risk of developing breast cancer. An interaction with use of menopausal hormone therapy was observed such that among current estrogen plus progestin users, those in the highest EGFR quartile had a 9.04-fold (p = 0.0004) increased risk of developing breast cancer. While the performance of EGFR in terms of sensitivity and specificity is insufficient for it to be used on its own clinically, the formal validation of EGFR suggests that there may indeed be changes in the plasma proteome prior to the clinical diagnosis of breast cancer that are detectable and of potential clinical utility.