Impact of EZH2 and ALDH1 Expression on Ductal Carcinoma In Situ (DCIS) Recurrence.
Agnieszka K Witkiewicz, Jessica Kline, Gordon Schwartz, Kathy Toy, Maria E Gonzalez, Celina G Kleer. Thomas Jefferson University, Philadelphia, PA; University of Michigan, Ann Arbor
Background: There are no biomarkers able to predict which DCIS cases will recur after breast conserving therapy. Polycomb protein enhancer of zeste homologue 2 (EZH2) and stem cell marker ALDH1 have been implicated in breast carcinogenesis. In invasive breast carcinoma EZH2 is an independent predictor of breast cancer recurrence and death. Data on ALDH1 in invasive breast cancer is contradictory but ALDH1 expression was shown to be associated with poor outcome in some studies.
The aim of this study was to evaluate the expression EZH2 and ALDH1 in a large cohort of DCIS patients treated at one institution with wide-excision and close follow-up.
Design: 151 DCIS patients were included in the study. Expression of EZH2 and ALDH1 was assessed by employing a standard immunoperoxidase method with anti-EZH2 (BD Biosciences, Mouse Monoclonal, Clone 11, 1:250) and anti-ALDH1 (BD Biosciences, Mouse Monoclonal, Clone 44, 1:5000, DAB) antibodies. The EZH2 expression was scored as high (>15%) versus low (0-15%). Stromal ALDH1 staining was scored as negative, weak, moderate or strong and epithelial staining was scored as negative or positive (any cell staining). ALDH1 positivity was defined as strong stromal and/or epithelial staining. Association between markers expression and recurrence was assessed using Fisher's exact test.
Results: Of the 151 DCIS cases, 41 recurred (26 as DCIS and 15 as invasive carcinoma). There was a statistically significant association between high EZH2 expression and DCIS recurrence, either as DCIS or invasive carcinoma. Of the cases 41 that recurred, 32 (78%) had high EZH2 and 9 (22%) had low EZH2 (Fisher's exact test, p=0.0036)
Positive ALDH1 showed marginally significant association with recurrence (p=0.07). However, its significance increased when considered in combination with EZH2. High EZH2/positive ALDH1 were seen in 73% of recurrent vs. 35% of not recurrent DCIS. Low EZH2/negative ALDH1 were detected in 26% of recurrent vs. 64% of non recurrent DCIS (Fisher's exact p=0.0075). No association was found between these markers and the type of recurrent disease (DCIS vs. invasive).
Conclusions: High expression of EZH2 and positive ALDH1 in DCIS is associated with increased risk of recurrence either as invasive or in situ carcinoma after wide excision. Our study opens the field to further investigate their utility, alone or in combination, as biomarkers of recurrence in patients with DCIS.
Monday, February 28, 2011 1:00 PM
Poster Session II # 42, Monday Afternoon