Host Genetic Variants in the Interleukin-6 Promoter Predict Poor Outcome in Patients with Estrogen Receptor-Positive, Node-Positive Breast Cancer

Departments of ¹Medicine (Hematology/Oncology) and ²Biostatistics and Epidemiology, University of Pennsylvania School of Medicine; ³Abramson Cancer Center, University of Pennsylvania; ⁴Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁵Eastern Cooperative Oncology Group, Boston, Massachusetts; ⁶University of Alabama at Birmingham, Birmingham, Alabama; and ⁷Northwestern University Feinberg School of Medicine; ⁸Robert Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois

^* To whom correspondence should be addressed. E-mail: Angela.Demichele{at}uphs.upenn.edu.

	Abstract

Interleukin-6 modulates immune response, estrogen production, and growth pathways in breast cancer. We evaluated the effect of several common, functional interleukin-6 promoter variants in node-positive breast cancer patients enrolled on a multicenter, cooperative group, adjuvant chemotherapy trial to determine whether these variants were associated with clinical outcome overall and by estrogen receptor tumor phenotype. Genomic DNA and clinical data were collected from a clinical trial of adjuvant anthracycline-based chemotherapy followed by randomization to high-dose cyclophosphamide/thiotepa or observation (Intergroup Trial 0121). Genotyping for -174G>C (rs1800795), -597G>A (rs1800797), and -572G>C (rs1800796) was done by site-specific PCR and PyroSequencing, whereas the -373A_nT_n repeat was directly sequenced. Log-rank tests and Cox modeling were used to compare outcomes by genotype/haplotype and other factors. Three hundred forty-six patients (64% of trial) had corresponding genotype/clinical data available and did not differ from overall trial participants. After adjustment, patients with estrogen receptor-positive tumors and genotypes 597 GG or 174 GG had significantly worse disease-free survival [hazard ratio (HR), 1.6; P = 0.02 and HR, 1.71; P = 0.007, respectively], whereas the 373 8A12T repeat appeared to be protective (HR, 0.62; P = 0.02). The presence of at least one copy of the haplotype ([-597G, -572G, -373[10A/11T], -174G]) was associated with worse disease-free survival (HR, 1.46; P = 0.04). Kaplan-Meier plots show that all patients in this group relapsed by 24 months from diagnosis. This poor-risk haplotype was quite common overall (estimated frequency, 0.20) and twice as frequent among Blacks (estimated frequency, 0.41). [Cancer Res 2009;69(10):4184–91]

Key Words: Breast Cancer, Polymorphism, Cytokines, Interleukin-6