Abstract 391: Serum ferritin predicts response to trastuzumab and is a biomarker for breast and pancreatic cancers: A potential novel inflammatory effector mechanism (2012)

Abstract Inflammation plays a critical role in cancer. However, it is still unclear what inflammatory effector mechanisms, if any, are directly responsible for enhancing tumorigenesis. Serum ferritin is an acute-phase protein that is elevated in multiple cancer types including breast cancer. However due to the prevailing paradigm on ferritin as a ‘house-keeping’ iron storage protein, no further investigation of the functional significance of serum ferritin or its clinical utility in cancer has been made thus far. In light of recent advances in iron and ferritin biology, we hypothesized that the elevation in serum ferritin represents an inflammatory effector mechanism that is actively and directly enhancing tumorigenesis, and thus it can be used to predict clinical outcome. Herein we provide data that extracellular ferritin stimulates proliferation of breast cancer cells and activates AKT signaling through an iron-independent mechanism - a novel function for this traditional iron storage protein. With this novel mechanism in mind, we made clinical predictions about the ability of serum ferritin to predict response to the anti-HER2/neu antibody trastuzumab. Higher pretreatment serum ferritin was significant on a continuous basis for predicting reduced Overall Survival (OS, p&amp;lt;0.0001) and Progression Free Survival (PFS, p&amp;lt;0.0001) in a patient cohort (n=66) receiving first-line trastuzumab-containing therapy. When analyzed as dichotomous categorical groups using the median pretreatment serum ferritin level as a cutoff point, patients with elevated serum ferritin had significantly reduced PFS (p &amp;lt;0.004, median 8.30 vs. 23.90 months) and OS (p &amp;lt;0.0001, median 12.73 vs. 69.57 months). Because several reports have suggested the elevation in serum ferritin is due to localized secretion within breast tumors, we examined the ability of breast caner cells to secrete ferritin. Breast cancer cell lines did not secrete detectable levels of ferritin. However, macrophages (a prominent cell type in the breast tumor microenvironment) were capable of ferritin secretion, and this secretion was potentiated in response to pro-inflammatory cytokines. We also expanded our analysis of the prognostic value of serum ferritin to include pancreatic cancer. Serum ferritin was significant in predicting overall survival (P=0.003) in a metastatic pancreatic cancer cohort (n=164). Collectively, these data suggest that the elevation in serum ferritin may represent an inflammatory effector mechanism involving tumor-associated macrophages in which ferritin serves as a pro-tumor factor. Therapeutic strategies targeting ferritin functionality or secretion may have potential usefulness in multiple cancer types, and its cancer-associated elevation may have clinical value as a prognostic factor or a predictor of response to established therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 391. doi:1538-7445.AM2012-391