Abstract 77: Genetic variations in the stem cell pathway predict for toxicity following radiotherapy in lung cancer.

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Abstract Lung cancer is a devastating malignancy leading to over 150,000 deaths in the US annually. One primary modality in the treatment of locally advanced lung cancer is radiotherapy in combination with chemotherapy. However, this treatment can lead to significant local toxicity in as many as 50% of all patients and, in some cases, is fatal. Though post-radiation toxicity significantly affects adherence to treatment, quality of life and clinical outcome, it is difficult to predict. Further, no genetic markers have yet been found to be useful in a clinical setting. Because stem cell recruitment is part of the post-radiation tissue repair response, we hypothesize that alterations in stem cell signaling may predict for toxicity following radiotherapy. To investigate this question we examined 441 SNPs related to stem cell signaling in the peripheral blood lymphocytes in 159 patients with stage III-IV lung cancer treated with chemoradiotherapy. After adjusting for treatment-related and demographic factors, we found 47 SNPs significantly associated with symptomatic radiation pneumonitis (p<0.05) and 51 SNPs associated with symptomatic esophagitis (p<0.05). For example, patients with at least one risk allele for WNT9Brs:2165846 had a 46% risk of symptomatic pneumonitis, compared to 31% in those who did not, for a 2.23 fold increase in risk (CI: 1.05-4.07, p=0.04). On analysis of a 141 patient validation set with similar characteristics, variant WNT9Brs:2165846 was confirmed to be associated with symptomatic radiation pneumonitis (OR 2.6, CI: 1.1-6.16, p=0.03). Analysis on this confirmation set is ongoing; however, the preliminary results are indicative of the importance of stem cell signaling in modulating repair following radiotherapy and, in combination with clinical factors, may allow for better management of these patients. Citation Format: Heath D. Skinner, Xia Pu, Joe Chang, Charles Lu, Ritsuko Komaki, Xifeng Wu. Genetic variations in the stem cell pathway predict for toxicity following radiotherapy in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 77. doi:10.1158/1538-7445.AM2013-77