Longitudinal Dynamics of Blood Microbiome and Circulating Tumor Cell in Metastatic Breast Cancer

About This Grant

PROJECT SUMMARY/ABSTRACT Metastatic breast cancer (mBC) is one of the most devastating diseases. More than 40,000 deaths in the U.S. each year are caused by breast cancer distant metastasis. Triple-negative breast cancer (TNBC) is the most aggressive mBC subtype, with a median overall survival of only 12–18 months. Meanwhile, resistance to treatments occurs in >80% of metastatic TNBC (mTNBC) patients due to the highly dynamic nature of disease progression. These concerning facts underscore the urgent need to enhance understanding of TNBC metastatic mechanisms and identify modifiable factors contributing to the disease burden. One potential key biological contributor and modifiable factor is the microbiome, which has emerged as a potential key player in cancer metastasis. A recent landmark study showed that intratumor microbiota can enter the bloodstream and travel with circulating tumor cells (CTCs) to promote metastasis. Due to the logistical challenges of acquiring repeated tissue and stool samples from cancer patients, studying the blood microbiome alongside CTCs using liquid biopsy samples offers a non-invasive way to assess tumor cells and microbiome features in real-time. However, human blood microbiome studies are extremely limited due to its low-biomass nature and severe interference from host DNA. Recently a novel reduced metagenomic sequencing technique was developed to address these limitations, and we have successfully applied this technique in a preliminary study analyzing longitudinal plasma samples from women with mTNBC. We identified over 15 core microbial species present in plasma, with dynamic changes before and after treatment. Remarkably, we found that low blood microbial diversity was associated with a two-fold increased risk of death, and this risk became even more pronounced when coupled with a high CTC count. Based on these discoveries, we hypothesize that dynamic longitudinal blood microbiome features exist by treatment status, and they can influence mTNBC prognosis directly or through interacting with CTCs. We will characterize the pre-treatment and post-treatment blood microbiome features from the existing ongoing mBC cohort at Thomas Jefferson University (n=200 women, 100 as discovery dataset, 100 as validation dataset). In Aim 1, we will identify baseline blood microbiome features among women with mTNBC and examine the interaction of blood microbiome with CTC in predicting progression-free survival (PFS) across the discovery and validation cohorts. In Aim 2, we will examine the follow-up blood microbiome and CTC signatures and characterize the longitudinal changes of the blood microbiome in predicting mTNBC PFS. We will also compare the profiles between baseline and follow-up signatures and look for changes that are associated with patients’ resistance to their initial treatment. As the first clinical study focusing on blood microbiome in mTNBC, this proposed study will identify longitudinal blood microbial signatures and determine the impact on predicting clinical outcomes with CTC-based liquid biopsy. Successful completion of this study will lead to novel mTNBC disease stratification and the development of microbiome-based strategy for precision treatment and outcome monitoring.