PROJECT SUMMARY While breast cancer prognosis has substantially improved over the last three decades, recurrence remains a significant risk, particularly for African American patients and patients from low- and middle-income countries (LMIC). Novel interventions are needed to prevent cancer recurrence and reduce mortality. Increasing evidence suggests that the gut microbiota may influence the efficacy of cancer therapy, thus impacting cancer prognosis. On the other hand, cancer treatment, particularly chemotherapy, may lead to dysbiosis of the gut microbiota and changes in bacterial metabolic activities. These alterations might persist beyond the time of treatment, resulting in a reduction in beneficial bacteria, thereby influencing long-term breast cancer outcomes. Thus, gut microbiota is a potential target to improve the efficacy of cancer treatment and long-term health outcomes in breast cancer patients. However, the impact of cancer therapy, particularly chemotherapy, on gut microbiota after the completion of therapy, as well as the influence of gut microbiota on long-term breast cancer survival, is largely unknown. To address these knowledge gaps, we propose conducting a pilot study to evaluate the associations of pre- and post-chemotherapy and -radiotherapy gut microbiome profiles with breast cancer recurrence and mortality (Aim 1). We will use the existing pre-systematic treatment gut microbiome data from 364 cases and perform shotgun metagenome sequencing on 110 post-chemotherapy or/and - radiotherapy stool samples in the Vietnam Breast Cancer Study (VBCS). We will also investigate the impact of chemotherapy on the gut microbiome profile (Aim 2). We will examine changes in gut microbial diversity, taxa abundance, microbial metabolic pathways, and microbiome dysbiosis indexes among 110 breast cancer patients with paired pre- and post-chemotherapy stool samples. This proposed study will be the first to evaluate the associations of pre- and post-systemic treatment gut microbiome profiles, as well as their gut microbiome dysbiosis indexes, with the risk of breast cancer recurrence and mortality at 5 years post- diagnosis. Findings from this proposed study will support the launch of a full-scale study to fully understand the role of gut microbiota in breast cancer outcomes, eventually leading to the development of a microbial-based intervention to improve long-term cancer outcomes and quality of life for survivors.

PROJECT NARRATIVE We will investigate whether the pre- and post-systemic treatments gut microbiome affect breast cancer outcomes (recurrence and mortality) and evaluate whether changes in the gut microbiome, particularly cancer treatment-related dysbiosis persist after the completion of cancer therapy. Results from this study will be valuable in developing interventions to optimize the pre-treatment gut microbiota and attenuate dysbiosis during and after cancer treatment with an optimal goal of promoting health and reducing recurrence risk among breast cancer survivors.