Chemotherapy-induced gut microbiota taxonomic deviation and its association with outcomes and toxicities in breast cancer: CANTO microbiota.

Abstract

2589 Background: Gut microbiota (GM) modulates immunotherapy (IT) efficacy and toxicity, but its impact on outcomes in breast cancer (BC) patients (pts) remains unclear. TOPOSCORE is a GM-derived score reflecting the ecosystem structure that classifies pts into SIG1+ or SIG2+ profiles, the latter being enriched in obligate anaerobes with immunostimulatory proprieties and associated with favorable IT outcomes. Methods: CANTO-Microbiota (target N=1000) is an ongoing substudy of the prospective CANTO cohort (NCT01993498). Stool samples were available from 209 pts (202 pre-treatment (Tx) and 94 post-Tx [after surgery, chemotherapy (CT) ±targeted-, and/or radiotherapy]), enrolled 2015-2024. GM was profiled by shotgun metagenomics and assessed as TOPOSCORE (SIG1+ vs. SIG2+) pre- and post-Tx. Associations of GM with invasive (iDFS), distant disease-free (DDFS), and overall survival (OS) (Kaplan–Meier and Cox regression models), and with treatment-related toxicities (multivariable logistic regression). Post-treatment analyses were landmark-based. Results: Median age was 46.6 years, 72% were premenopausal, 79% had stage II-III, 36% HER2+, 34% HR+/HER2-, and 30% TN, 89% received (neo)adjuvant CT, 15% IT and 33% anti-HER2-therapy. Median follow-up was 2.2 years. At baseline, 74% of pts had a SIG2+ profile. This profile was not associated with clinicopathologic features or clinical outcomes; however, SIG2+ was associated with a reduced incidence of post-treatment diarrhea and long-term neuropathy, and remained independently protective against neuropathy (OR 0.25, 95% CI 0.09–0.64; p=0.005). Paired analyses (n=87) revealed a significant shift in TOPOSCORE signatures post-treatment, resulting in an increase in SIG1+ prevalence from 28% to 47% (p=0.004), In univariable landmark Cox analyses, post-treatment SIG1+ was associated with worse iDFS (HR 5.0, 95% CI 1.1–4.2; p=0.04), DDFS (p=0.0053) and OS (p=0.04). In multivariate model adjusted for age, stage, and subtype, post-treatment SIG2+ remained independently protective for iDFS (HR 0.17, 95% CI 0.03–0.88; p=0.035). Assessing longitudinal GM trajectories, worsening patterns (SIG2+→SIG1+ in 28% and persistent SIG1+→SIG1+ in 20% of pts ) were associated with an increased risk of iDFS (HR 5.25, 95% CI 1.11–24.7; p = 0.036). Post-treatment TOPOSCORE associations with outcomes were validated in two independent prospective cohorts outside France. Conclusions: Chemotherapy is associated with measurable shifts in GM composition that correlated with treatment-related long-term toxicity and outcomes. These findings support the evaluation of microbiota centered interventions during treatment in eBC.