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Symposium: Genetic Modifiers of Cancer Risk

IL6 variants as modifiers of breast cancer outcome.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA and Pennsylvania Hospital, Philadelphia, PA

Abstract

Currently available clinical and molecular prognostic tools provide some information on the risk of recurrence among poor-prognosis breast cancer patients. Work in this area has primarily focused on somatic tumor characteristics that influence response to treatment and ultimately, clinical outcome. Ovarian hormone receptors, predominantly estrogen and progesterone receptors, as well as ERBB2 overexpression, are well-validated tumor markers that can provide important prognostic information as well as predict response to therapies such as tamoxifen or Herceptin. Many other tumor markers, including proteins involved in cell cycling and angiogenesis are currently being validated in this setting.

The extent of axillary lymph node involvement in breast cancer is one phenotypic marker of recurrence risk. Despite aggressive adjuvant therapy, recurrence rates in patients with four or more involved lymph nodes approaches 50% at 5 years from diagnosis. Markers that can distinguish those patients likely to relapse from those who are likely to be cured are needed to tailor therapy and provide accurate prognostic information. Although most work in this area has focused on tumor characteristics, we hypothesized that the host environment, including germline variants in specific genes, might also play a role in determining risk of relapse. We hypothesized that these host factors may play an important role in determining risk of recurrence by influencing the milieu in which microscopic residual tumor cells are able to proliferate and we approached the search for new prognostic markers by examining associations between clinical outcome and host genetic variants that could affect host response to microscopic residual cancer cells. Immune surveillance is one such host process that may influence recurrence, as several cytokines have been implicated in mediating this process. Interleukin-6 (IL-6) is one such pleiotropic, pro-inflammatory cytokine that may be involved in the host response to cancer. In-vitro data suggest that cytokines such as IL-6 may provide a growth stimulus for breast cancer cells through as-yet unidentified mechanisms. IL-6 was also a good candidate for further investigation as several studies suggest that high serum IL-6 levels have been associated with a greater number of metastatic sites, poor clinical outcome, lack of response to therapy, resistance to chemotherapy and resistance to hormonal therapy in metastatic breast cancer (refs 1–4). Thus we hypothesized that host inflammatory response through production of interleukin-6 (IL-6) may play a role in the control of microscopic residual tumor.

Polymorphisms in the IL-6 gene promoter region may modulate serum levels of the cytokine though regulation of gene transcription. A single nucleotide polymorphism (SNP) involving substitution of cytosine for guanine at position –174 has been associated with reduced transcription and improved outcome in a variety of non-malignant diseases, including coronary artery disease and several autoimmune conditions. TNF-alpha is a pro-inflammatory cytokine that also plays a role in regulating IL-6 transcription. Thus we hypothesized that polymorphisms in IL-6 (–174 G>C) or TNF-alpha (G-238 or G-308) might be associated with prognosis in patients with high-risk breast cancer.

To address this question, genotyping was performed on DNA from stored stem cells of 80 patients diagnosed with breast cancer and at least four positive axillary lymph nodes who underwent anthracycline-based adjuvant chemotherapy followed by high-dose therapy and stem cell rescue. Cox proportional hazards models were used to estimate the effect of genotype and other known prognostic factors on disease-free and overall survival (DFS and OS, respectively).

In this series, the presence of at least one C allele in the IL-6 promoter at position –174 was significantly associated with both disease-free and overall survival compared to G/G homozygotes. After adjustment for ER status, lymph node number and tumor size, those patients carrying the G/G genotype had a 2.1-fold increase in the rate of failure and a 2.6-fold increase in the rate of death over the follow-up period compared to carriers of any C allele (see Table). TNF-alpha –308 and –238 polymorphisms were not associated with disease-free or overall survival in this cohort.

Because of the observed significant association between ER and outcome, as well as our a priori hypothesis that IL-6 may be exerting its effect through hormonally mediated pathways, more closely examined the interaction between ER status and IL-6 polymorphism on both DFS and OS. For DFS, the most favorable outcome was seen in patients who were ER positive and carriers of any C-allele (G/C or C/C). The presence of either G/G genotype or ER negativity increased the hazard for failure (HR=2.6 and HR=3.2, respectively), and the combination of both these factors resulted in a further increase in the hazard ratio (HR=5.4, 4-group comparison p=0.003). Similarly, for OS, either G/G genotype or ER negativity increased the hazard for death (HR=2.0 and HR=2.2, respectively), and the combination of both these factors resulted in a further increase in the hazard ratio (HR=6.2, 4-group comparison p=0.001). These data suggest that ER status and IL-6 promoter polymorphism have a significant combined effect on both DFS and OS, although tests of interaction were not significant (p=0.5 and p=0.65, respectively). In summary, in this cohort of 80 patients with node-positive breast cancer at high risk of recurrence who underwent anthracycline-based adjuvant chemotherapy followed by high-dose chemotherapy and stem cell reinfusion, the presence of at least one C allele in the IL-6 promoter at position –174 was significantly associated with both disease-free and overall survival compared to G/G (WT) homozygotes. After adjustment for ER status, lymph node number and tumor size, those patients carrying the G/G genotype in the IL-6 promoter at position –174 had a 2.1-fold increase in the rate of failure and a 2.6-fold increase in the rate of death over the follow-up period. TNF-alpha –308 and –238 polymorphisms were not associated with disease-free or overall survival in this cohort. These results support the hypothesis that IL-6 may play an important role in the control of micrometastatic disease in breast cancer and add important information to our understanding of IL-6 in breast cancer. This finding that a germline SNP in an immunomodulatory cytokine is significantly associated with recurrence and death from breast cancer provides strong evidence of a mechanistic link between host environment and tumor growth potential in breast cancer. To our knowledge, this is the first study to demonstrate a significant association between a host immune response polymorphism and clinical outcome from breast cancer. Further studies are needed to confirm these results and elucidate the mechanisms responsible for these differences.