Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer.
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(n)T(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).
DeMichele
Angela
A
Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Angela.Demichele@uphs.upenn.edu
Gray
Robert
R
Horn
Michelle
M
Chen
Jinbo
J
Aplenc
Richard
R
Vaughan
William P
WP
Tallman
Martin S
MS
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002455:Cell Division; D018572:Disease-Free Survival; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis; D012189:Retrospective Studies; D016019:Survival Analysis; D017741:Survivors
D015850:Interleukin-6; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone