Role of Transcription Factors [FOXA1,GATA-3] in Predicting Outcomes in Recurrent Ductal Carcinoma-In-Situ (DCIS) or Invasive Carcinoma (IC) in DCIS Patients on Core Needle Biopsies of Breast.
Authors: Picarsic J. , Brufsky A. , Ahrendt G. , Tseng G. , Chivukula M. 
Published: December 2010

Background: Estrogen receptor (ER) plays a key role in the development and treatment outcome in breast cancer patients. The two broad groups of invasive carcinoma (IC), namely ER(+) and ER(-), are yet to be well understood in DCIS. Absence of ER was shown to be one significant predictor of IC recurrence in DCIS patients. Recently functional interaction between FOXA1 transcription factor and ER has shown to play a critical role in suppressing ER-dependent breast cancer cell growth and tumorigenesis in vivo. This suggests that FOXA1 may be novel marker that can inhibit tumor proliferation and development of IC. Similarly the GATA-3 transcription factor, highly expressed in the mammary luminal epithelial cells, has emerged as a strong predictor of tumor differentiation, ER status, and clinical outcome. The specific aim of this study is to analyze the expression of novel biological transcription markers FOXA1, GATA-3, and established markers MIB-1 (Ki-67) and HER2/neu in ER(+) and ER(-) DCIS patients.Materials and Methods: Cases of DCIS (N=225) diagnosed on core needle biopsy were retrieved from our Pathology database, with average follow-up from 1995-2009. Cases with recurrence (N=21) and without (N=204) were evaluated, with current data of 153 cases thus far. Recurrence was defined in terms of DCIS or IC. FOXA1, GATA3, ER, PR were evaluated with a cumulative “H score” based on proportionality (PS) and intensity scores (IS) [0-negative, 1-150-low, 151-250-intermediate, 250-300-high]. A 10% or more “nuclear” staining of the tumor cells was considered “positive.” MIB-1 was given a nuclear proliferation index (1-10%-low, 11-25%-intermediate, 26-50%-high, &gt;51%-very high); HER2, a membrane stain, was interpreted as per routine guidelines for IC (0/1+ negative, 2+ weakly positive, 3+ strongly positive]. Pathologic as well as clinical variables were also evaluated.Statistical analysis: Fisher's exact test for testing the dependence between clinical outcome (non-recurrence, recurrent-IDC and recurrent-DCIS) for each biomarker and calculation of p-value.Results: Currently, data on 153 cases is presented. Entire results will be available at time of meeting. No recurrence was seen in 92% (141/153) cases, while 8% (12/153) had recurrence (7 cases with IC, 5 cases with recurrent DCIS). We are reporting the initial results of biological marker expression in terms of recurrence. A high recurrence is seen with expression of low GATA-3 (p=0.78), high/intermediate MIB-1 (p=0.9), and low/absent PR (p=0.07). FOXA1 and GATA-3 expression is maintained in 94% of ER(-) cases.Conclusions: Our study is on-going in comparing the initial biomarker data to other important clinical variables and response to therapy, for clinical predictors of outcome in a novel prediction model. Our initial observation is that a strong expression of FOXA1, GATA-3, low MIB-1 index, and absent Her2 expression are characteristically seen in the ER(+) DCIS group, similar to previously described in IC. However, nearly all of the ER(-) cases expressed FOXA1 and GATA-3, which needs be evaluated further, as these transcription factors may offer new promising targets for therapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2115.