Abstract
BackgroundIn women with duct carcinoma in-situ (DCIS) receiving breast conservation therapy (BCT), in-breast recurrences are seen in approximately 10%, but cannot be accurately predicted using clinical and histological criteria. We performed a case-control study to identify protein markers of local recurrence risk in DCIS.MethodsWomen treated for DCIS with BCT, who later developed in-breast recurrence (cases) were matched by age and year of treatment to women who remained free of recurrence (controls).ResultsA total of 69 women were included in the study, 31 cases and 38 controls. Immunohistochemical evaluation of DCIS tissue arrays was performed for estrogen receptor, progesterone receptor, HER-2/neu, cyclin D1, p53, p21, cycloxygenase-2 (COX-2) and peroxisome proliferator activated receptor γ (PPARγ). Two markers were significantly different between cases and controls on univariate analysis: strong COX-2 expression was associated with increased risk of recurrence, with 67% vs. 24% positivity in cases and controls p = 0.006; and nuclear expression of PPARγ was associated with protection from recurrence with 4% vs. 27% positivity in cases and controls, p = 0.024. In a multivariate model which included size, grade, COX-2 and PPARγ positivity, we found COX-2 positivity to be a strong independent risk factor for recurrence (OR 7.90, 95% CI 1.72–36.23)., whereas size and grade were of borderline significance. PPARγ expression continued to demonstrate a protective trend, (OR 0.14, 95% CI 0.06–1.84).ConclusionOur findings suggest that COX-2 and PPARγ should be investigated further as biologic markers to predict DCIS recurrence, particularly since they are also potential therapeutic targets.
Highlights
In women with duct carcinoma in-situ (DCIS) receiving breast conservation therapy (BCT), in-breast recurrences are seen in approximately 10%, but cannot be accurately predicted using clinical and histological criteria
The proportion of patients receiving radiation therapy was similar between cases (65%) and controls (61%) and was not associated with recurrence risk The use of adjuvant tamoxifen therapy was infrequent between cases (32%) and controls (32%), and was not associated with a decreased risk of recurrence (OR0.99, 95% CI 0.64–1.51)
When we examined the tamoxifen use based on estrogen receptor α (ER) data generated on the tissue microarrays (TMA) produced for this study, we found no differences in the proportion of ER positive cases and controls who received tamoxifen therapy (7/12 ER positive controls vs. 6/10 ER positive cases)
Summary
In women with duct carcinoma in-situ (DCIS) receiving breast conservation therapy (BCT), in-breast recurrences are seen in approximately 10%, but cannot be accurately predicted using clinical and histological criteria. Because of the increasing number of women being diagnosed with DCIS, the identification of those patients at high risk for a recurrence (invasive and non-invasive) is of increasing importance Morphological factors such as grade and the presence of comedo-necrosis have been used far to predict recurrence, but lack sensitivity and are subject to variability of interpretation[5]. Cyclin D1, p53, and p21, are all proteins involved in cell cycle regulation and have prognostic value in invasive breast cancer as well [11,12,13,14] All of these markers have been identified in DCIS recently, but their biologic significance is not fully understood, and long-term data relating these markers to recurrence risk in DCIS are extremely scant[7,1517]. PPARγ expression has been studied in invasive cancers but not in DCIS far
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