Abstract #2444: A model to predict the proliferation index of ductal carcinoma in situ
Authors: Anup Kumar Kasi Loknath Kumar, Yao-Li Chuang, Paul Macklin, Sandeep Sanga, Jahun Kim, Giovanna Tamaiuolo, Vittorio Cristini, Mary Edgerton
Journal: Cancer Research (2009)

Background and Objective: Ductal carcinoma in situ (DCIS) is the most prevalent precursor to invasive breast cancer, the second leading cause of death in women in the United States. In 2007, there were over 60,000 cases of DCIS alone. More importantly, 80% of the nearly 180,000 cases of invasive breast cancer in 2007 had co-existing DCIS. While DCIS itself is not a life-threatening disease,DCIS is the most important known precursor to invasive breast cancer.Our laboratory has developed a mathematical framework to describe the growth of DCIS at the cell and tissue scale. We now seek to parameterize the model with sub cellular information. We have used the fraction of ki-67 positive tumor cells in biopsy material to represent the proliferative index (PI). However, low PI suffers from a lack of sufficient sample to accurately quantify the ki-67-positive fraction. We seek to identify another marker related to ki-67 positivity but that can be more accurately measured in small samples of DCIS. The three most important prognostic markers for invasive breast cancer are Estrogen receptor (ER), Progesterone receptor (PR) and HER2/neu. All the three markers are known to have a role as a signal to increase proliferation of cells in invasive breast cancer. However, they have not been well studied in DCIS. We hypothesize that the PI, defined as the fraction of ki-67 positive cells, is determined by interplay between ER, PR and HER2/neu receptors. We seek a mathematical relationship between PI and ER, PR and HER2/neu expression. Materials and Methods: Using immunohistochemistry, we have measured ki-67, ER, PR and HER2/neu positivity for a series of cases of DCIS without invasion. Results: If HER2/neu is not expressed (negative staining), then PI has a linear relationship with the average of the ER and PR fraction of positive cells. However, if HER2/neu is positive, then ER/PR positivity makes a negligible contribution to PI. Most of the HER2/neu positive cases are almost completely 100% positive. Conclusion: The results of the above experiment demonstrate that PI of DCIS is a function of the interplay between ER, PR and HER2/neu activity. If Her2/neu is negative, then we can predict PI from the fraction of ER and PR positive cells. This fraction is an order of magnitude higher than the ki-67 positive fraction, enabling us to estimate PI more accurately when the ki-67 positive fraction is small and the sample is limited (e.g. a core biopsy). If the Her2/neu pathway is activated, it appears to overwhelm the effects of ER and PR even if these are also positive. These findings will be discussed not only in terms of their importance to measuring input parameters to mathematical models of DCIS, but also for their implications for understanding the interactions of these sub cellular molecular networks in the control of proliferation in DCIS.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2444.