Molecular & Genetic Determinants of Outcome in Breast Ca

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DESCRIPTION (provided by applicant): Breast cancer remains a major public health problem, with over 190,000 new cases in the U.S. annually. Approximately 1/3 of these cases comprise women with disease limited to the breast and axillary lymph nodes. In these patients, aggressive multi-modality treatment can be curative in just over 50% of cases. However, current prognostic markers are unable to discriminate between those who will be cured with therapy, those who are cured without aggressive therapy and those who are destined to recur regardless of therapy. In order to improve survival and appropriately target therapies, better markers and improved understanding of the biology of recurrence is clearly needed. The proposed study seeks to expand our knowledge of breast cancer recurrence and prognosis by examining the role of host genetic characteristics on treatment outcome, and examining links between these host factors and tumor molecular characteristics. The host genetic factor of interest in this study is Interleukin-6 (IL-6), a pleiotropic cytokine involved in the host immune response to cancer. High serum levels of IL-6 are characteristic in breast cancer patients, and increased level is associated with aggressive disease, including more metastatic sites and resistance to standard therapies. Genetic polymorphisms in the promoter region of the IL-6 gene confer functional significance in transcription rates of the cytokine. We propose to examine the impact of these polymorphisms, individually and in combination, on disease-free survival (DFS) and overall survival (OS) in node-positive breast cancer patients. We propose to study this issue in the context of a large, multi-institution clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG). This study, a randomized trial comparing standard anthracycline-based adjuvant chemotherapy to high dose chemotherapy with autologous stem cell rescue in 540 women with at least 10 positive lymph nodes, will provide germ-line DNA (from stored stem cells), tumor specimens and substantial follow-up (5.7 years) to address four main hypotheses: (1) that IL-6 promoter polymorphisms are associated with DFS and OS in patients with node-positive breast cancer, (2) that this relationship is modified by estrogen receptor status of the tumor and menopausal status of the patient (3) that these polymorphisms are associated with specific alterations in tumor receptors and/or signaling that mediate the clinical outcomes and (4) that these polymorphisms are related to the toxicity of the treatments administered. We will utilize PCR-based genotyping techniques to identify the following polymorphism in the IL-6 promoter: -174G/C, -597G/A, -572G/C and -373AnTn. We will utilize immunohistochemical staining to identify alterations in tumor receptors (IL-6R, gp130, Her2/neu, EGFR), apoptosis (via TUNEL, STAT-1, STAT-3, bcl-2), cell cycle control (via MIB-1, AKT, p27) and cyclooxygenase-2 enzyme activity (COX-2), all of which have been shown to interact with IL-6 in vitro. Kaplan-Meier and Cox proportional hazards techniques will be used to investigate the associations of interest. This study will provide important information on interactions between genetic determinants of the host environment and tumor behavior, and will provide much-needed mechanistic data that will be important in utilizing this information for the development of targeted therapies for this devastating disease.