The widespread adoption of screening mammography has led to an increase in the diagnoses ofductal carcinoma in situ (DCIS) of the breast. While it is estimated that 62,000 women will be diagnosed withDCIS in 2006, only a small fraction of these women (~10-20%) will subsequently develop invasive breastcancer or die of the disease. However, most women with DCIS are treated similarly, i.e. the DCIS issurgically excised during lumpectomy and additional radiation or tamoxifen is often offered. This means thatmany women are receiving unnecessary adjuvant radiation, adjuvant hormonal therapy, or mastectomy toprevent invasive cancers that will not occur. Additionally, a minority of women is not receiving adequateintervention because they subsequently develop a tumor after local excision alone. Identifying molecularmarkers that can accurately predict subsequent DCIS and/or invasive cancer events could aid in stratifyingan individual's risk for subsequent disease and response to therapy. Thus, to avoid over- and undertreatment of these women, there is a critical need for studies with complete pathology review, molecularmarker measurements and long term follow-up to determine prognostic factors can be accurately andreproduciblv measured and are consistently associated with subsequent tumor events among women withDCIS. Exciting preliminary data have demonstrated that expression of specific markers is associated withincreased probability of subsequent tumor events following lumpectomy alone. Using a large, establishedand well-characterized population-based cohort of women with DCIS treated by lumpectomy alone with 8.1years of follow-up, we will examine the role of these and additional markers in signaling subsequent diseaseevents. To accomplish this, we will: 1) Validate assays and correlation of biomarkers with outcomeretrospectively (a) using a large number of specimens (b) in different labs and (c) determine if it isstatistically robust. (2) Refine clinical biomarker assay reagents using multiplex methodology. (3)Validate correlation of biomarker with outcome in a prospective human study. (4) Develop a riskassessment model to assist women and physicians with clinical decision-making about treatment forDCIS. (5) Evaluate vHMEC biomarkers as potential diagnostic targets. The risk assessment tool willestimate the risk of subsequent DCIS and invasive events for an individual woman as a function of herclinical (e.g., age at diagnosis) and histopathology (e.g., nuclear grade, margin width) information, andmolecular markers (e.g., Ki67, p16, COX-2). This decision-making tool could be applied to women entering arandomized controlled trial to determine if our risk assessment tool consistently predicts subsequent diseaseand type of disease. The evaluation of biomarkers as potential diagnostic targets may provide the basis inthe future for developing a targeted imaging and preventive agents for clinical use.
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