Abstract P4-04-03: A microgenomic approach using LCM procured breast cancer cells to identify clinically relevant gene signatures that underlie favorable response of ILC to aromatase inhibitors

Abstract

Abstract Based on CGH analyses, invasive lobular carcinoma (ILC) is closely related to low grade invasive ductal carcinoma (IDC), and is genetically unrelated to intermediate and high grade invasive carcinomas (Pathol Res Pract 2005; 201:713). Results from the BIG 1-98 trial, showed that patients with ILC and luminal B (intermediate/high grade) IDC treated with Letrozole, an aromatase inhibitor (AI), had a significant improvement in overall survival, whereas patients with luminal A (low grade) IDC did not (Cancer Res 2012; 72(24 Suppl):Abstract nr S1-1). Despite genetic evidence suggesting a close relationship between ILC and low grade IDC, and disparity between ILC and intermediate and high grade IDC, a clinically relevant gene set underlying a tumor's biologic responsiveness to AIs likely exists. We are deciphering a gene subset that would differ in expression between low grade IDC and ILC, and would be shared by ILC and luminal B IDC. Identification of such a gene set should lead to a more robust marker for identifying AI responsive tumors rather than relying solely on histomorphology and/or immunohistochemistry for the pathologic diagnosis of ILC, since the distinction between ILC and IDC is not always straight forward in pathology practice. Using 247 de-identified human breast carcinoma biopsies collected under standardized, stringent conditions, total RNA was extracted from carcinoma cells procured by laser capture microdissection to perform microarray analyses of approximately 22,000 genes to identify expression signatures associated with breast cancer characteristics. Of the 247 samples, 169 samples were used for the analysis and included 16 ILCs, 13 low grade IDCs, 55 intermediate grade IDCs and 85 high grade IDCs. Preliminary analyses identified 1267 genes that were differentially expressed (p<0.01) between cell samples from patients with IDC compared to those with ILC. Gene expression levels in breast cancer cells from patients with low grade IDC compared to those with ILC yielded 200 genes that were statistically differentially expressed (p<0.01). When comparing high grade IDC to ILC, 149 of these genes were not differentially expressed indicating that this gene set may serve as a panel of candidate genes for identifying cancers responsive to AIs. Pathway analysis software (Ingenuity®) identified that these genes were associated with key molecular and cellular functions, e.g., cell-to-cell signaling, cell morphology, cell death and survival, cellular assembly and organization and carbohydrate metabolism. qPCR analyses are used to validate and refine the gene subset distinguishing ILC from low grade IDC. Our approach is revealing subtle molecular features that discriminate these lesions based on clinical behavior. Supported in part by a grant from the Phi Beta Psi Charity Trust. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-03.