Biological Markers Predictive of Invasive Recurrence in DCIS

Abstract

DCIS is a heterogeneous group of non-invasive cancers of the breast characterized by various degrees of differentiation and unpredictable propensity for transformation into invasive carcinoma. We examined the expression and prognostic value of 9 biological markers with a potential role in tumor progression in 133 patients with pure DCIS treated with breast conserving surgery alone, between 1982-2000. Histology was reviewed and immunohistochemical staining was performed. Pearson correlation coefficient was used to determine the associations between markers and histopathological features. Univariate and multivariate analysis examined associations between time to recurrence and clinicopathologic features and biological markers.Median age at diagnosis was 55 years (25-85). With a median follow up of 8.91 years, 41/133 patients recurred (21 as invasive recurrence). In this cohort 13.5% had low, 43% intermediate and 42% high nuclear grade. Comedo necrosis was found in 65% of cases. Expression of ER (62.4%), PR (55.6%), HER2/neu (31.6%), MIB1 (39.8%), p53 (22.6%), p21 (39.8%), Cyclin D1 (95.5%) calgranulin (20.5%), psoriasin (12%), was found in DCIS. HER2/neu was overexpressed in 45% that recurred as DCIS and 42.9% that recurred as invasive cancer, and only in 26.1% in cases that never recurred. On univariate analysis, HER2/neu overexpression was the only marker associated with an increased risk for any recurrence (p = 0.044). The hazard ratio for recurrence for HER2/neu positive DCIS was 1.927 (confidence interval 1.016-3.653) compared to HER2 negative DCIS. On multivariate analysis, HER2/neu overexpression remained the only independent variable significantly associated with any recurrence (p = 0.014) and with invasive recurrence (p = 0.044).This data suggest that HER2/neu testing may become an important parameter in the management of DCIS and the treatment of cases with positive HER2/neu status could be modified accordingly, similar to the current approach for HER2/neu positive invasive disease.

Keywords: HER2/neu; biological markers; breast cancer; ductal carcinoma in situ; molecular markers; prognosis; recurrence; tumour invasion.

Figure 1

The distribution of positive DCIS cases according to the percentage of positive cells for each of the biological markers.

Figure 2

2A- Positive membranous immunostain for HER2/neu oncoprotein in high grade DCIS (clone: CB11, X200) 2B- Positive nuclear immunostain for p21in 50% of the cells in intermediate grade DCIS. Note the variable intensity of stains. (x100) 2C- Positive nuclear immunostain for MIB1 in 30% of the cells in high grade DCIS. (x100) 2D- Positive nuclear immunostain for cyclin D1 in 100% of the cells in low grade, cribriform DCIS. (x50) 2E- Positive nuclear and/or cytoplasmic immunostain for psoriasin (S100A7). The staining is heterogeneous, with negative and positive areas of DCIS. (x50) 2F- Positive nuclear and/or cytoplasmic immunostain for calgranulin (S100A9). The staining is heterogeneous with some negative and some strongly positive cells within the same focus of DCIS. Note the positive reaction in the granulocytes (arrow, x200).

Figure 3

The proportion of Her2/neu overexpressed cases was significantly higher in patients with invasive or in situ recurrence compared with those that never recurred. The difference in ER and PR expression was not significant.