Abstract 4719: Associations between IL-6 genotype and IL-6-related tumor alterations in ER+ breast cancer: results from ECOG2190/Int0121
Authors: Demichele Angela M. , Donelson Michelle , Komrokian Sara , Colameco Christopher , Chen Jinbo , Chen Lu , Gray Robert , Nnoli Jennifer , Vaughan William , Anderson Karen , Bromberg Jacqueline 
Published: May 2015

Abstract
Background: Despite overall favorable prognosis, a subset of patients with ER+ breast cancer will subsequently relapse, and there is a need to identify mechanisms associated with recurrence. Interleukin-6 (IL-6) is a cytokine that has been implicated in progression and metastatic behavior in breast cancer. We previously demonstrated that genotypic variants in the IL-6 promotor associated with high IL-6 production are associated with poor prognosis in a subset of non-metastatic, ER+ breast cancers (Cancer Res, 2009). In the current study, we sought to determine whether patients with these “high-producer” (HP) genotypes (GT) had tumors that were enriched for IL-6 related alterations in membrane receptors, signaling pathways and cell cycle control.
Methods: We identified patients with tumor blocks available from the ECOG 2190/INT0121 trial subjects in which we previously had obtained germline DNA and performed GT/haplotype (HT) analysis, and tumor microarrays (TMAs) were prepared. Expression of IL-6/gp130 membrane receptors, tumoral IL-6 content, cytoplasmic signaling through expression of phosphorylated signaling proteins (p-STAT3, p-AKT and p-ERK) and alterations in nuclear cell cycle marker expression (cyclin D, cyclin E and p27) were assessed by immunohistochemistry. Patients had previously been GT for IL-6-174, -572, -597 and the -373 variable repeat as well as assigned HT combining the HP alleles. Chi2 and Fishers exact tests were used to compare proportions. All tests were 2-sided.
Results: From the previously GT ER+ patients in E2190 (n=205), we recovered assessable tumor in 84 (41%) patients. Those with tumor did not differ from the overall or ER+ GT cohorts by any tumor/patient characteristics, genotype frequencies or recurrence rate at 10 years (63% with tumor vs. 60% overall). Gp130 membrane receptor positivity was significantly associated with all IL-6 HP GT (-174GG p=0.012; -572GG p=0.01; -597GG p=0.007 and -373non8A12T p=0.008), though IL-6 receptor or IL-6 tumor content were not, and none were associated with HT. Tumor expression of p-STAT3 was seen exclusively in tumors of patients with any of the four IL-6 HP genotypes (rate 10 - 14% for HP GT vs. 0% for all other GT) and within those with the intermediate and HP HT (p=0.03), and p-AKT expression was significantly higher among those with IL6-174GG (p=0.06) and -373non8A12T (p=0.04) GT. Tumor cyclin D levels were significantly higher in those with IL6-174GG (p=0.02), -597GG (p=0.02) and HT (p=0.04). No associations were seen with p-ERK, cyclin E or p27 expression.
Conclusions: These data suggest that patients with ER+ breast cancer who have “high-producer” IL-6 genotypes and poor prognosis have tumors enriched for the IL-6 gp130 receptor, JAK/STAT signaling and cyclin D overexpression, suggesting targets for intervention in these patients.
Citation Format: Angela M. Demichele, Michelle Donelson, Sara Komrokian, Christopher Colameco, Jinbo Chen, Lu Chen, Robert Gray, Jennifer Nnoli, William Vaughan, Karen Anderson, Jacqueline Bromberg. Associations between IL-6 genotype and IL-6-related tumor alterations in ER+ breast cancer: results from ECOG2190/Int0121. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4719. doi:10.1158/1538-7445.AM2014-4719