LAUSR

Background: Early adverse skin reactions (EASRs) are common side effects of postoperative adjuvant radiotherapy (RT) that significantly impact the quality of life (QOL) of breast cancer patients. This study used global metabolomics profiles of breast cancer populations to identify metabolic pathways and biomarkers that are significantly associated with RT-induced EASRs to identify potential targets for precision interventions. Methods: Using a frequency-matched study design, pre-RT urine samples from 60 female breast cancer patients receiving RT after breast-conserving surgery were metabolically profiled. Patients were recruited from the University of Miami Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital. Using MetaboAnalyst 3.0, we performed metabolomic data analysis, visualization, and interpretation on 84 candidate metabolites from a dataset of 478 total compounds. Student’s t-tests, correlation analyses, pathway enrichment, and topology analyses were conducted sequentially to identify metabolite biomarkers and pathways associated with RT-induced EASRs. Results: The study population consisted of 24 African American (40%), 18 non-Hispanic white (30%), 14 Hispanic white (24%), and 4 “other” (7%) patients with frequency matched by race/ethnicity and body mass index (BMI) categories (i.e., normal, overweight, and obesity) to have an equal number of high (n=30) and low (n=30) EASRs. Seven metabolic pathways were significantly associated with RT-induced EASRs, including alanine, aspartate, and glutamate metabolism; caffeine metabolism; pentose and glucuronate interconversions; glycine, serine, and threonine metabolism; beta-alanine metabolism; pantothenate and CoA biosynthesis; and glutathione metabolism. The alanine, aspartate, and glutamate metabolism pathway had the lowest false discovery rate (FDR)-adjusted p-value (p=0.0028) and the highest pathway impact value (0.60) of all enriched metabolic pathways. Thirteen metabolite biomarkers were significantly associated with RT-induced EASRs, including the principal compound of interest glutamate. Conclusions: In our study of breast cancer patients receiving adjuvant RT, alanine, aspartate, and glutamate metabolism had the highest impact value and significant FDR-adjusted p-value in predicting RT-induced EASRs. Our findings suggest that glutaminase inhibitors may have broader clinical applications in preventing RT-induced EASRs in addition to their potential enhancement of chemotherapy by triggering metabolic crises in tumor cells. Keywords: breast cancer, metabolomics, radiation therapy, and early adverse skin reactions. Citation Format: Alexandra N. McMahon, Cristiane Takita, Jean L. Wright, Eunkyung Lee, Joshua J. Kleinman, Isildinha M. Reis, Jennifer J. Hu. Metabolomics in radiotherapy-induced early adverse skin reactions in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2824.