Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment Original paper

What was studied?

This study investigated how the intestinal microbiome influences clinical outcomes and treatment-related toxicities in early breast cancer, using shotgun metagenomics to define microbial signatures. The analysis compared gut microbiota before and after chemotherapy, linking specific bacteria with prognosis, treatment response, and side effects, creating a microbiome signature relevant to cancer care.

Who was studied?

Seventy-six women enrolled in the CANTO cohort contributed 121 stool samples, with 45 paired before and after chemotherapy. Participants had diverse early-stage breast cancer subtypes and received anthracycline/taxane regimens, with hormonal therapy in many cases. Their microbiome profiles were analyzed alongside 336 healthy controls. A subset underwent plasma metabolomics, and fecal samples were transferred into mouse models to test causal effects.

Most important findings

The gut microbiome strongly associated with tumor characteristics and prognosis. Patients with more aggressive disease—larger tumors, higher grade, nodal involvement, or stage II–III—showed enrichment of unfavorable taxa, notably Clostridium bolteae, Clostridium asparagiforme, Bacteroides uniformis, Eggerthella lenta, Eisenbergiella massiliensis, Veillonella spp., and Streptococcus spp. These species overlapped with microbial signatures previously linked to resistance to immune checkpoint therapy. Favorable profiles featured Akkermansia muciniphila, Collinsella aerofaciens, Coprococcus comes, Coprococcus catus, Eubacterium rectale, Methanobrevibacter smithii, and Ruminococcaceae species. Chemotherapy induced significant shifts, increasing alpha diversity and promoting beneficial taxa such as M. smithii, Dorea formicigenerans, Ruminococcus torques, and in some cases Blautia obeum. Unfavorable species decreased post-treatment in many patients. Metabolomics demonstrated parallel shifts: higher glutamine and ornithine during chemotherapy (especially in node-negative patients), activation of polyamine pathways, and enhanced ketogenesis. Neurological toxicities at 12 months were strongly associated with post-chemotherapy beta diversity. Patients who developed neuropathy, cognitive symptoms, or paresthesia exhibited microbiomes enriched in Clostridiaceae species, including C. symbiosum, C. aldenense, C. citroniae, C. bolteae, and E. ramosum. Those without neurological toxicity more often retained favorable taxa such as C. aerofaciens, C. comes, B. crossotus, R. torques, and D. piger. Functional pathway analysis showed neurotoxicity linked to glycolysis, histidine degradation, fatty acid biosynthesis, and beta-oxidation, while neuroprotective profiles displayed enhanced purine biosynthesis and polyamine pathways. Mouse models confirmed causality: fecal microbiota from breast cancer patients accelerated tumor progression and reduced cyclophosphamide efficacy, while healthy-donor microbiota slowed tumor growth and restored therapeutic response.

Key implications

The study provides compelling evidence that gut microbiota shape breast cancer prognosis, modulate chemotherapy response, and influence long-term neurotoxicity. Certain microbial signatures may serve as biomarkers for risk stratification or treatment planning. Interventions—dietary strategies, probiotics, microbiota-directed therapies, or fecal transplantation—may eventually be leveraged to improve outcomes, enhance chemosensitivity, reduce side effects, and personalize supportive care. The findings support integrating microbiome assessment into future breast cancer clinical pathways.

Citation

Terrisse S, Derosa L, Iebba V, et al. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment. Cell Death & Differentiation. 2021;28:2778-2796. doi:10.1038/s41418-021-00784-1