Abstract PD7-04: Metabolic syndrome increases risk of recurrence and impacts immune pathways in invasive lobular carcinoma
Authors: Robinson P , Treece T , Osipo C , Uygun S , Kling H , Qamar R , Zon R , Levine E , Budway R , Mavromatis B , Untch S , Bernards R , Audeh W , Soliman H , IMPACt Investigators Group 
Published: May 2019

Background: Invasive lobular carcinoma (ILC) of the breast has been shown to be more strongly associated with risk factors that modulate hormone levels, including obesity, as compared with invasive ductal carcinoma (IDC). Our previous study indicated the biology of disease engages disparately for ILC and IDC. This study further evaluated the effect of metabolic syndrome (MS) in patients with ILC histopathological tumor types using whole transcriptome gene expression (GEA) and pathway analyses.

Methods: This analysis included 76 patients with ILC from the PROMIS and IMPACt studies for whom metabolic characteristics were captured with informed consent. To be classified as having MS, the patient had to exhibit any 3 of the 5 metabolic factors (obesity, hypertension, hypercholesterolemia, hypertriglyceridemia, diabetes mellitus). Risk of recurrence was established using the 70-gene signature (70-GS). Pathway enrichment analysis was performed in DAVID v 6.8 (https://david.ncifcrf.gov/). Benjamini-Hochberg corrected P&lt; 0.05 was considered significant.

Results: Thirty-four percent (26/76) of patients with ILC had MS. Significantly more ILC patients with MS than without MS were 70-GS high risk (42% vs. 12%, respectively, [P=0.007]). GEA identified 486 significant differentially expressed genes between MS and non-MS ILC patients. These differentially expressed genes indicated that the immune pathways were affected rather than growth factor pathways. The significantly enriched pathways were driven by genes upregulated on average across all MS ILC patients, and represented in the immune response (P&lt; 0.001), adaptive immune response (P=0.001), B cell signaling (P&lt; 0.001), inflammatory response (P&lt;0.05), chemokine-mediated signaling (P&lt;0.05), T cell co-stimulation (P&lt;0.05), and intracellular signal transduction processes (P&lt;0.05); as well as enriched in systemic lupus erythematosus (largely overlapping with nucleosome assembly, P=0.001) and osteoclast differentiation (P&lt;0.05) pathways. While early infiltration of cytolytic T-lymphocytes may protect against tumor development, humoral-mediated immunity and a sustained state of chronic inflammation may result in polarization toward a pro-tumor microenvironment.

ILC MS Status by 70-GS Risk ClassificationILC MS Status70-GS High Risk70-GS Low RiskP-valueTotalNo6 (12%)44 (88%)0.00750Yes11 (42%)15 (58%) 26

Conclusions: ILC is generally considered to have a low risk of recurrence, but with poorer long- term prognosis. We show that ILC patients with MS have a significantly higher 70-GS risk of recurrence than their non-metabolic counterparts. Our gene expression analysis suggests that ILC in the setting of metabolic syndrome, likely results in chronic immune activation and has distinct drivers of disease progression and metastasis, specifically to bone. The current study underscores the complex interplay between inflammation and immune suppression. Studies are needed to further characterize differences in enriched pathways as it relates to optimizing targeted therapeutics.

Citation Format: Robinson P, Treece T, Osipo C, Uygun S, Kling H, Qamar R, Zon R, Levine E, Budway R, Mavromatis B, Untch S, Bernards R, Audeh W, Soliman H, IMPACt Investigators Group. Metabolic syndrome increases risk of recurrence and impacts immune pathways in invasive lobular carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-04.