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    Awarded Grants
    Value of molecular markers in predicting long-term outcome in ductal carcinoma in situ of the breast.

    Scientific Abstract:
    a) Background: The majority of ductal carcinomas in situ (DCIS) never become invasive. Identifying lesions that are most likely to progress would therefore have a major clinical impact. Many studies investigate the correlations of molecular markers with breast cancer progression, but predictive information requires a longitudinal study design. A handful of such studies in the last decade have been limited by inadequate power and study designs such as analyzing concurrent DCIS and invasive cancer, or classifying recurrent DCIS as disease progression. We have carefully selected two cohorts of DCIS patients with well documented and clearly diverging outcomes: cases that progress to invasive disease after a minimum interval of one year, vs. cases that have shown no recurrence of disease within a minimum of five years. We have developed several breast-specific genetic markers that can be detected in a subset of DCIS lesions, and may therefore be of prognostic or predictive significance. We are also identifying additional DCIS-specific markers to complement our current breast cancer markers. b) Objective/Hypothesis is that there are identifiable differences between DCIS with and without the potential to become invasive cancer. c) Specific Aim 1: Analyze 7 hypermethylation and 7 immunohistochemical markers in patients with DCIS for their ability to predict progression. Specific Aim 2: Analyze markers identified by large-scale gene discovery of breast cancer precursor lesions for prediction of long-term outcome in DCIS patients. d) Study Design: For specific aim 1, we will study archival tissue from 50 patients with DCIS with poor outcomes and a matched control group without disease with median follow-up of 10 years. Laser-capture microdissection (LCM) will be used for quantitative methylation-specific PCR. Judging from the variance of individual markers in preliminary results, we estimate that a single informative assay will provide an 80% power to detect a 20% difference in outcomes. For specific aim 2, we will screen 20 cases of DCIS, 10 of which have already progressed to invasive cancer, by RT-PCR in order to identify markers showing some correlation with disease progression. Assays suited to formalin-fixed archival material will then be developed for promising markers and tested for predictive value on our longitudinal cohorts as well. e) Potential Outcomes and Benefits of the Research. Identifying predictive markers allows improved estimates of invasive breast cancer risk in patients with DCIS, with improved stratification of treatment strategies.

    Lay Abstract:
    a) Background: The majority of ductal carcinomas in situ (DCIS) never become invasive. Identifying lesions that are most likely to progress would therefore have a major clinical impact. Many studies investigate the correlations of molecular markers with breast cancer progression, but predictive information requires a longitudinal study design. A handful of such studies in the last decade have been limited by inadequate study designs such as analyzing concurrent DCIS and invasive cancer, or classifying recurrent DCIS as disease progression. We have carefully selected two cohorts of DCIS patients with well documented and clearly diverging outcomes: cases that progress to invasive disease after a minimum interval of one year, vs. cases that have shown no recurrence of disease within a minimum of five years. We have developed several breast-specific genetic markers that can be detected in a subset of DCIS lesions, and may therefore be of prognostic or predictive significance. We are also identifying additional DCIS-specific markers to complement our current breast cancer markers. b) Objective/Hypothesis is that there are identifiable differences between DCIS with and without the potential to become invasive cancer. c) Specific Aim 1: Analyze 7 established DNA markers and 7 established protein markers in patients with DCIS for their ability to predict progression. Specific Aim 2: Analyze markers identified by large-scale gene discovery of breast cancer precursor lesions for prediction of long-term outcome in DCIS patients. d) Study Design: For specific aim 1, we will study archival tissue from 50 patients with DCIS with poor outcomes and a matched control group without disease with median follow-up of 10 years. Laser-capture microdissection (LCM) will be used for quantitating the DNA markers. Judging from the results of individual markers in preliminary results, we estimate that a single informative assay will provide an 80% power to detect a 20% difference in outcomes. For specific aim 2, we will screen 20 cases of DCIS, 10 of which have already progressed to invasive cancer, by measuring specific genes in order to identify markers showing some correlation with disease progression. Assays suited to formalin-fixed archival material will then be developed for promising markers and tested for predictive value on our longitudinal cohorts as well. e) Potential Outcomes and Benefits of the Research. Identifying predictive markers allows improved estimates of invasive breast cancer risk in patients with DCIS, with improved stratification of treatment strategies.