Polymorphisms in estrogen receptor beta, interleukin-8, and interleukin-8 receptor associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5-fluorouracil/oxaliplatin

4130 Background: Many factors contribute to the progression of colorectal cancer and to chemoresistance. Two factors that have recently gained attention are angiogenesis and sex hormones. Interleukin-8 and its receptors play a critical role in angiogenesis, and polymorphisms in these genes have previously been reported to predict clinical outcome and resistance to therapy in a variety of cancer types. In addition, gender and the subsequent varied levels of sex hormones between males and females may also have an impact on colorectal cancer progression. Sex hormones such as estrogen exert their effects on the cell by binding to steroid receptors such as estrogen receptor beta (ER-β). It is known that ER-β is predominantly expressed in the colon, and that differential expression of this gene is predictive of clinical outcome. Therefore, functional polymorphisms within ER-β, IL-8, and the IL-8 receptors may prove to be molecular markers for predicting clinical outcome in colorectal cancer patients. Methods: 173 patients were enrolled in this phase II study. 152 patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. Polymorphisms in estrogen receptor beta, IL-8, and CXCR2 (IL-8 receptor) were tested by PCR. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. IL-8 T251A polymorphism was predictive of time to tumor progression (p=0.04, log-rank test). ER-β CA repeat polymorphism was predictive of tumor response as well as time to tumor progression (p=0.015, p=0.012, respectively). ER-β A730G SNP was also predictive of time to tumor progression (p=0.03). Polymorphism in CXCR2 was predictive of tumor response (p=0.034). Conclusions: Our results suggest that polymorphisms within IL-8, CXCR2, and ER-β may affect the progression of colorectal cancer and subsequent clinical outcome. These results highlight the importance of angiogenesis and hormone levels in colorectal cancer. No significant financial relationships to disclose.