Prognostic Significance of Oncogenic Markers in Ductal Carcinoma In Situ of the Breast: A Clinicopathologic Study

Abstract

Ductal carcinoma in situ (DCIS) is a heterogeneous malignant condition of the breast with an excellent prognosis. Until recently mastectomy was the standard treatment. As the results of the National Surgical Adjuvant Breast and Bowel Project-17 trial and the introduction of the Van Nuys Prognostic Index (VNPI) less radical therapies are used. Objectives are to identify clinicopathologic and biologic factors that may predict outcome. Cases of DCIS diagnosed in two Belgian University Centers were included. Paraffin-embedded material and Hematoxylin and Eosin stained slides of DCIS cases were reviewed and tumor size, margin width, nuclear grade, and comedo necrosis were assessed. Molecular markers (estrogen receptor, progesterone receptor, HER1-4, Ki67, and c-myc) were assayed immunohistochemically. Applied treatment strategies were correlated with the prospective use of the VNPI score. Kaplan-Meier survival plots were generated with log-rank significance and multiple regression analysis was carried out using Cox proportional hazards regression analysis; 159 patients were included with a median age of 54 years (range 29-78); 141 had DCIS and 18 DCIS with microinvasion. The median time of follow-up was 54 months (range 5-253). Twenty-three patients developed a recurrence (14.5%). The median time to recurrence was 46 months (range 5-253). Before the introduction of the VNPI, 37.5% of the DCIS patients showed a recurrence while thereafter 6.7% recurred (p < 0.005). Two recurrences occurred in the VNPI group I (7.1%); seven in the VNPI group II (8.5%) (median time to recurrence 66.3 months) and 14 in the VNPI group III (28.5%) (median time to recurrence 40.2 months) (disease-free survival [DFS]: p < 0.05). A Cox proportional hazards regression analysis indicated that tumor size, margin width, pathologic class, and age were independent predictors of recurrence, but none of the studied molecular markers showed this. Overexpression of HER4 in the presence of HER3 was found to be associated with a better DFS (p < 0.05). This study confirms the value of the VNPI score and questions the benefit of an aggressive approach in the low-risk DCIS lesions. Independent predictors for recurrence included size, margin width, pathologic class, and age, but none of the molecular markers were part of it. Overexpression of HER4 in the presence of HER3 was associated with a better DFS.

Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone

“…9,10,24,28 Additionally, Kepple et al 29 and Kerlikowske et al 30 found Her-2 positivity to be significantly associated with an increased risk of recurrence in DCIS. This correlates with findings in the previous study, in which Her-2 status was inversely related to bcl-2 status, a marker of low-grade breast neoplasms.…”

“…Estrogen receptor (ER) and progesterone receptor (PR) were among the first markers studied in breast cancer and have been evaluated in DCIS. 9,16,17 Research on marker status in DCIS has shown hormone receptor status to be more effective as a predictor of response to treatment than as a predictor of time to recurrence. 9, 10 Balleine et al 10 established a binary molecular grading scheme for DCIS in 2008 based on nuclear grade and Ki-67 score.…”

“…Recent research has focused on overexpression of Her-2 in both invasive and in situ ductal carcinoma of the breast. 9,10,18 Her-2 overexpression is reported in 0%-50% of low-grade DCIS and 50%-100% of high-grade DCIS, whereas it is only found in 20%-25% of invasive breast cancer. 9, 10 Altintas et al 9 found that Her-2 overexpression was significantly associated with high nuclear grade in DCIS, although nuclear grade alone was found to be an independent risk factor for recurrence.…”

Factors Predicting Microinvasion in Ductal Carcinoma in situ

“…Nevertheless, it is known that some women treated for DCIS subsequently develop invasive breast cancer, which is associated with a poorer prognosis. Moreover, in rare cases, DCIS may behave as an aggressive breast cancer, whereby a woman may die from metastatic disease without any evidence of invasive cancer at the time of being treated for DCIS (Altintas et al, 2009).…”

Targeting Molecular Pathways for Prevention of High Risk Breast Cancer: A Model for Cancer Prevention

“…Specifically, for the past 6 years we have routinely stained all of the tumors from our DCIS patients for the over-expression of HER-2. Other biologic markers that are may have prognostic significance include HER 1-4, Ki67, p21, bcl-2, p16 and COX-2, c-myc and survivin [10,13,49].…”