P4-01-13: Biology of Aggressiveness and Tamoxifen Resistance in Hormone Receptor-Positive Very Young Age Breast Cancer.

Abstract

Abstract It has been known that young breast cancer patients have worse outcomes compared with older premenopausal or postmenopausal patients. Survival difference between young and older breast cancer patients is evident only in hormone receptor positive breast cancer regardless of tamoxifen treatment according to our previous report. However, the biology of aggressiveness and endocrine resistance of breast cancer in very young women is largely unknown. The purpose of this study is to find molecular characteristics of hormone receptor positive breast cancers of very young age women (<35) compared with those of older premenopausal women. We extracted mRNA from fresh frozen hormone receptor positive primary breast cancer tissues of 24 young age breast cancer patients (<35 years) and 31 older premenopausal women (40 to 49 years) by standard method. All tumor specimens analyzed contained more than 50% tumor cells. Hormone receptor status was determined by immunohistochemistry (IHC). Gene expression microarray experiment was done in the 55 samples using Illumina HumanRef-8 v3 Expression BeadChip (Illumina, Inc., San Diego, CA). Functional and pathway analysis of differentially expressed genes were done using DAVID (http://david.abcc.ncifcrf.gov/home.jsp) and Ingenuity pathway analysis (IPA, http://www.ingenuity.com). Ki-67 assay was done using IHC in 4,957 ER+ breast cancer patients of Seoul National University cohort and 1,863 ER+ patients from National Cancer Center, Korea. 355 genes were upregulated (>1.5 fold) and 209 genes were down-regulated in breast cancer tissues of young age patients (<35) compared with those of older patients. In pathway analysis of the highly expressed genes in young patients, cell cycle function and pathway was significantly activated. The genes of central role in this pathway were MYC and CCND1. In IHC assay for 4,957 ER+ Seoul National University dataset, the proportion of high Ki-67 expression (>=10%) was positively correlated with decreasing age: 26.4%, 24.0%, 21.3%, 14.8%, 12.0% of women aged <30, 30–34, 35–39, 40–49, 50–59, respectively (p<0.001). The same correlation pattern between younger age and high Ki-67 expression was also seen in another 1,863 patient cohort. In conclusion, we showed that genes involved in cell cycle pathway were upregulated in very young age (<35) ER+ breast cancer using microarray study. It was validated in large data set using Ki-67 IHC assay. High proliferation and fast cell cycle could be a mechanism of worse outcome and tamoxifen resistance of ER+ very young age breast cancer patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-13.