Abstract 3327: Metabolomics: Potential molecular mechanisms of radiotherapy (RT)-related normal tissue toxicities in breast cancer

Abstract

Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in American women. Clinical guidelines recommend that when breast-conserving surgery is provided as a primary therapy for early-stage breast cancer, RT should follow to improve clinical outcome. Although well tolerated by most patients, even with improved RT technology, breast cancer patients experience moist desquamation as early adverse skin reactions. To elucidate the molecular mechanisms involved in RT-related normal tissure toxicity, global metabolomic profiles were determined in urine samples comparing across paired pre-RT and post-RT samples from 60 breast cancer patients exhibiting low (n = 30) or high (n = 30) skin toxicity in response to RT. The extracted samples were split into equal parts for analysis on the GC/MS and LC/MS platforms. The dataset comprises a total of 478 compounds of known identity. Preliminary data suggest that pre-RT glucose and a variety of derivatives linked to the pentose phosphate pathway, such as ribulose, or the consumption of pyruvate in the mitochondrial tricarboxylic acid cycle, including citrate and succinate, were significantly elevated in the high toxicity group. Multiple metabolites derived from the oxidation of aromatic compounds such as amino acids and dietary polyphenolics - vanillate, 3-hydromandelate, tyramine, 3-methoxy-4-hydroxyphenylglycol, and 2-hydroxyphenylacetate - were elevated in a trending or significant fashion at the pre-RT baseline in the high toxicity relative to the low toxicity group. Pre-RT ascorbate depletion and accumulation of tobacco metabolites were associated with radiation sensitivity. Ascorbate was significantly decreased at baseline in the high toxicity group and its pre-RT levels were negatively correlated with post-RT skin toxicity. Nicotine derivatives were only detected in 12% of the pre- and post-RT samples but their presence seemed to be a risk factor that could predispose smokers to unfavorable outcomes during radiation therapy. Histamine breakdown markers provided an indication of a heightened inflammatory activity in individuals who experienced toxicity as suggested that anti-histamines might be useful to prevent sensitivity. Our preliminary data suggest the potential application of metabolomics in predicting and monitoring RT-related normal tissue toxicities; future larger studies are warranted to confirm out promising findings and identify targeted metabolic pathways for effective intervention. Citation Format: Jennifer J. Hu, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Omar L. Nelson. Metabolomics: Potential molecular mechanisms of radiotherapy (RT)-related normal tissue toxicities in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3327. doi:10.1158/1538-7445.AM2015-3327