Abstract 4815: Elevated plasma levels of epidermal growth factor receptor prior to diagnosis of breast cancer in preclinical specimens from the Women's Health Initiative Observational Study

Abstract

Abstract Background: Applying advanced proteomic technologies to prospectively collected specimens from large studies is one means of identifying preclinical changes in plasma proteins that are potentially relevant to the early detection of diseases such as breast cancer. Methods: We conducted biomarker discovery and validation experiments using pre-clinical samples from a case-control study nested in the Women's Health Initiative (WHI) Observational Study (OS). In the discovery phase of this study we conducted fourteen independent quantitative proteomics experiments comparing pooled plasma samples collected from 420 estrogen receptor positive (ER+) breast cancer patients ≤17 months prior to their diagnosis and matched controls that involved immunodepletion, isotopic labeling with acrylamide, extensive fractionation, and high resolution tandem mass spectrometry. Eight proteins that differentiated between cases and controls, for which quantitative assays were available, were assessed in an independent validation set consisting of 198 ER+ breast cancer case/control sets. Results: Based on the over 3.4 million tandem mass spectra collected in the discovery set, 545 proteins were quantified of which 79 differentiated cases from controls with a p-value<0.05. Eight of these 79 candidates had an available ELISA assay and were assessed in our validation set. Of these eight candidates, epidermal growth factor receptor (EGFR) was validated as a predictor of breast cancer risk in our independent set of preclinical plasma samples among women overall [odds ratio (OR)=1.44, p-value=0.0008], and particularly among current users of estrogen plus progestin (E+P) menopausal hormone therapy (OR=2.41, p-value=0.0001). Among current E+P users EGFR's sensitivity for ER+ breast cancer risk was 31% with 90% specificity, and compared to those in the lowest EGFR quartile those in the highest EGFR quartile had a 9.04-fold (95% CI: 2.78-33.21) increased risk of developing ER+ breast cancer. Conclusions: While EGFR's sensitivity and specificity are insufficient for a clinically useful early detection biomarker, this study is important in two respects. First, no prior studies have validated even a single breast cancer early detection biomarker in preclinical specimens to the degree we have here. This suggests that detectable changes in the plasma proteome may indeed be present preclinically for relatively small tumors such as ER+ breast cancer. Second, consideration of other exposures in biomarker discovery studies is likely critical given that while overall EGFR modestly distinguished cases from controls, among E+P users this relationship was considerably stronger. Further studies are warranted to both examine the role of EGFR and to discover and validate other proteins that could potentially be used for breast cancer early detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4815.