Abstract LB149: Predicted gut microbial metabolites and chemotherapy induced toxicity among breast cancer patients

Abstract Gut microbial metabolites may be the key hubs connecting the gut microbiota and chemotherapy responses. Little research has investigated the associations between gut microbial metabolites and chemotherapy-induced toxicity, particularly among breast cancer patients. In a prospective study involving 300 chemotherapy-treated breast cancer patients, shotgun metagenomic sequencing was carried out for pre-chemotherapy stool samples. A gut bioactive metabolite profile of 79 gut metabolites was predicted using MelonnPan, a machine-learning approach with proven reliability. Chemotherapy-induced toxicities and date of onset toxicities during the first-line treatment were captured via medical chart reviews. Associations of predicted gut microbial metabolites with onset severe toxicities were evaluated via Cox proportional hazard regression analyses, with the day since chemotherapy to event/censoring as a time metric. The Benjamini-Hochberg (BH) corrected p-value < 0.05 was considered significant. A correlation network analysis was performed for metabolites significantly associated with toxicities.A substantial proportion of study participants experienced severe hematological toxicity (39.3%), especially neutropenia (30.7%), after receiving chemotherapy. Approximately 13.0% and 10.7% of participants experienced moderate hepatoxicity and occurrent nephrotoxicity, respectively. We identified 46 and 38 predicted metabolites significantly associated with severe hematological toxicity and neutropenia (PBH<0.05). The latter included 18 microbial metabolites positively associated with severe neutropenia, such as diacetylspermine, malonate, and creatine (p range: 0.021-7.457x10-4) that have a strong correlation with phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A which were previously significantly linked to an increased risk of severe neutropenia (p<0.05). The 20 microbial metabolites inversely associated with severe neutropenia include chenodeoxycholate, deoxycholate, glutamate, and methylbutyric aid (p range: 0.024-8.283x10-5) that were significantly correlated with a high abundance of phylum Synergistota and class Synergistia which were significantly associated with a reduced risk of severe neutropenia (p<0.05). Correlation network analysis revealed that the relationship of microbial metabolite-metabolite differed significantly between patients with severe and without severe neutropenia groups. Gut microbial metabolites were not significantly associated with liver or renal toxicity.Our study suggests that gut microbiome may affect chemotherapy-induced toxicity, especially neutropenia, via metabolites. These findings, if confirmed, could lead to the development of novel preventive strategies to reduce the toxicity of chemotherapeutic drugs and improve the efficacy of cancer treatment. Citation Format: Sang Minh Nguyen, Huong T. Tran, Danxia Yu, Giang H. Nguyen, Jie Wu, Qiuyin Cai, Thuan V. Tran, Xiao-Ou Shu. Predicted gut microbial metabolites and chemotherapy induced toxicity among breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB149.