Abstract P1-12-02: Transcriptional Changes Induced by Anastrozole and Fulvestrant Treatment in ER-Positive Breast Cancers
Authors: Z Ghazoui, H Anderson, A Dunbier, E Anderson, J Lindemann, B Wellings, J Walker, I Kuter, M. Dowsett
Journal: Cancer Research (2010)

Abstract Aim: To compare changes in whole genome transcription elicited by anastrozole (ANA) and fulvestrant (FUL) in estrogen receptor positive (ER+) breast cancer. Background: Aromatase inhibitors (AIs), such as ANA, and the selective estrogen receptor down-regulator, FUL, are both effective in the treatment of ER+ breast cancer. AIs reduce stimulation of ER by suppressing estrogen synthesis while FUL acts as an antagonist and receptor down-regulator. Better understanding of their mechanism of action may lead to a more rational clinical application of these two drugs. Methods: Pre-and post-treatment core-cut tumor biopsies were obtained from 105 postmenopausal women with ER+ early breast cancer who received neoadjuvant FUL[1]. Genome-wide expression data were available from 22 matched baseline and post-treatment pairs from the patients who received 500mg of FUL every 28 days and 500mg on day 14 of the first month (FUL500), also, from 16 patients who received 250mg of FUL every 28 days (FUL250). In addition, microarray data were obtained from 81 matched pre-and post-treatment pairs of tumor biopsies from postmenopausal women with ER+ breast cancer who received single agent neoadjuvant ANA[2]. Results: At a false discovery rate (FDR) of 5%, expression of 1875 genes changed with FUL500 but no genes changed with FUL250. Each of 4 index proliferation genes (TOP2A,AURKA, CCNB2, CDC20) and 4 index estrogen responsive genes (ERGs) (TFF1, PGR, PDZK1, GREB1) showed greater suppression with FUL500 than FUL250. Further study of FUL was conducted only in the FUL500 group. At 5% FDR, 1457 genes decreased in expression and 1064 increased with ANA while 1083 decreased and 792 increased with FUL500. Most genes that showed significant changes with ANA also showed changes of a similar magnitude with FUL500 but there were some individual striking differences. There was more commonality in the genes that decreased in expression than those that increased. The reduction in a proliferation metagene was similar with ANA and FUL500 (geometric mean suppression, 23.1% and 23.2% respectively). Each of the 4 proliferation index genes showed a very similar degree of change using the 2 drugs as did the 4 ERGs. However, while IQ motif containing GTPase activating protein 3 was among the 5 most significantly changed genes with ANA (mean 52% suppression, FDR &amp;lt;10-5 %) it showed no significant change with FUL500 (mean 1% suppression, FDR 70%). Kinesin family member C1, on the other hand, was among the top 15 genes significantly down-regulated by FUL500 (mean 47% suppression, FDR 0.06%) but showed no significant change with ANA (mean 2% suppression, FDR 57%). Conclusions: Gene expression changes with FUL250 were modest but with FUL500 were similar in extent to those observed with ANA. Evaluation of the substantial differences in individual gene responses between the two drugs may allow their more rational clinical use. Kuter I, et al; Breast Cancer Res Treat 2008; 109: 589 Smith I.E, et al ; J Clin Oncol 2007; 25:3816 Supported by AstraZeneca, the Mary-Jean Mitchell Green Foundation and Breakthrough Breast Cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-02.