Abstract
Abstract The retinoblastoma (RB) tumor suppressor is functionally inactivated at high frequency in human malignancies including breast cancer. By immunohistochemistry loss of RB function is associated with p16ink4a overexpression and high Ki67 proliferation index.We have previously shown that loss of RB results in dramatic upregulation of genes associated with tumorigenesis and is a key determinant of therapeutic response in invasive breast carcinoma. Recently publish data indicate that RB pathway dysregulation plays an important role in DCIS progression to invasive carcinoma. The aim of this study was to evaluate the expression p16ink4a and Ki67 (indicative of RB loss) in a large cohort of DCIS patients treated at one institution with wide-excision and close follow-up. Material and Methods 149 DCIS patients were included in the study. Expression of p16ink4a and Ki67 was assessed by employing a standard immunoperoxidase method with ani-p16ink4a (MTM Laboratories Westborough, MA) and anti-Ki67 (AbCam Cambridge, MA) antibodies. The p16ink4a staining in DCIS epithelium was scored semi-quantitatively as negative (0; no staining), weak (1;staining in less than 25% of cells), moderate (2; defined as staining in 25-75% of cells) and strong (3; >75% of cells staining). For statistical analysis, the original p16ink4a scores (0, 1, 2, 3) were dichotomized as low (0,1) vs. high (2-3) and original ki67 scores were dichotomized as low (<= 10%) vs. high (> 10%). Stromal p16 staining was scored as absent or present. Association between p16ink4a and Ki67 and nuclear grade, necrosis, hormone receptor and Her2 expression as well as recurrence was assessed using Fisher's exact test. The Cox proportional hazard model was used for analyses of time to recurrence. Results There was a statistically significant association between high p16ink4a and Ki67 expression in DCIS epithelium and triple negative as well as Her2 positive DCIS subtypes. Significant association was detected between high expression of p16 and Ki67 in DCIS epithelium and DCIS recurrence (p=0.005). Stromal expression of p16 was the strongest predictor of DCIS recurrence (p < 0.0001). In multivariate Cox model DCIS cases with high expression of p16 and Ki67 in epithelium and stromal p16 expression had the shortest time to recurrence. Conclusion RB pathway dysregulation in DCIS epithelium as well as stromal expression of p16ink4a indicative of senescence are associated with DCIS recurrence. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-02.
Published Version
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