Abstract C64: Iron regulatory gene signature predicts outcome in breast cancer

Abstract

Abstract Extensive experimental and clinical literature attests to the importance of iron in tumor cell growth. For example, high levels of dietary iron have been linked epidemiologically to the increased development of tumors in humans; in animal models, levels of dietary iron affect tumor growth. However, pathways that underlie the apparent demand for iron by tumors remain largely uncharacterized. We recently discovered that an iron efflux pathway plays a role in breast cancer growth and metastasis: expression of the iron efflux pump ferroportin and its regulator hepcidin were predictive of metastasis-free survival in multiple independent breast cancer cohorts. To determine the optimal “iron gene regulatory signature,” we used microarray datasets comprising 674 breast cancer cases to systematically investigate how expression of genes related to iron metabolism is linked to breast cancer prognosis. Of 61 genes involved in iron regulation, 49% were statistically significantly associated with distant metastasis-free survival (DMFS). Optimal risk stratification was achieved with a model comprising 16 genes, which we term the iron regulatory gene signature (IRGS). Multivariable analysis revealed that the IRGS contributes information not captured by conventional prognostic indicators (hazard ratio 1.61; 95% CI 1.16–2.24; p=0.004). The IRGS successfully stratified homogeneously treated patients, including ER+ patients treated with tamoxifen monotherapy, both with (p=0.006) and without (p=0.03) lymph node metastases. To test whether multiple pathways were embedded within the IRGS, we evaluated the performance of two gene dyads with known roles in iron biology in ER+ patients treated with tamoxifen monotherapy (n=371). For both dyads, gene combinations that minimized intracellular iron content (anti-import: TFRCLow/HFEHigh; or pro-export: FPHigh/HAMPLow) were associated with favorable prognosis (p<0.005). Although the clinical utility of the IRGS will require prospective evaluation, its ability to both identify high risk patients within traditionally low risk groups and low risk patients within high risk groups has the potential to affect therapeutic decision-making. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C64.