Diet-driven gut microbiome and outcome in patients with early-stage triple-negative breast cancer undergoing neoadjuvant chemotherapy and immunotherapy

Plain English summary of protocol

Background and study aims
Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast cancers. TNBC is associated with shorter overall survival than other breast cancer subtypes, despite the use of curative-intent anthracycline- and taxane–based systemic chemotherapy. Neoadjuvant chemotherapy (NACT) is the current standard of care for patients with early disease. The addition of the immune checkpoint inhibitor (ICI) pembrolizumab to NACT regimens has recently been shown to substantially improve the outcome of patients with stage II or III TNBC. The gut microbiome (GM) refers to the genetic makeup of all microbes that exist within the human gastrointestinal tract. Constituents of the GM have been shown to interact with one another and the host immune system in ways that influence physiological homeostasis and the development of diseases. Multiple translational studies suggest the potential influence of the GM in modulating the efficacy of ICI-based therapies. The role of the GM appears far more complex than previously thought, extending beyond specific species and functions present in responders and non-responders, and suggests the existence of a unique, multi-mechanistic interplay of biological factors, which may be reflected in the faecal microbiome signatures, offering the potential for therapeutic and diagnostic exploitation. An exciting prospect of researching the role of the GM is the therapeutic potential to improve patient outcomes by manipulating the GM. It is well recognised that a change in diet can alter the composition of the GM, with evidence showing significant microbial shifts as early as 5 days of commencing dietary interventions. Dietary interventions, therefore, have the potential to affect outcomes of patients undergoing ICI therapy and might be utilised as a safe, cost-efficient, and readily accessible therapeutic intervention. It remains to be shown whether the association between specific microbiota and improved outcomes with ICI therapies is merely a reflection of a pre-existing immune response that is amplified by ICI or could instead be the result of a more complex and dynamic interaction between different systems. This prospective longitudinal study aims to investigate the complex interactions between the GM, the tumour biology of early-stage TNBCs, the efficacy and tolerability of NACT/ICI therapy (including the possible impact on cognitive function), and the long-term outcome. A specific focus will be to study the association of the GM and the risk of breast cancer recurrence in the high-risk group of patients with residual disease after NACT. The study will furthermore assess dynamic changes in both the GM and the tumour biology, and their association with long-term outcome. Furthermore, the association of nutritional input and the GM will be studied. Results of this trial might be the basis for future interventional studies that might stratify treatment modalities based on the GM or attempt to modulate treatment outcomes through targeting the GM.

Who can participate?
Female Patients ≥ 18 years of age undergoing either neoadjuvant chemotherapy plus immunotherapy or neoadjuvant chemotherapy alone will be recruited from within the NHS setting.

What does the study involve?
As part of the trial, stool samples for the analysis of the GM will be collected before the start of neoadjuvant treatment and at the end of the neoadjuvant treatment. Formalin-fixed paraffin-embedded (FFPE) core tumour biopsies will be collected at baseline. In patients with residual invasive cancer, a FFPE sample of the residual tumour will also be collected. In a subset of patients (optional), additional snap-frozen tumour samples may be collected at baseline and at the time of surgery. Nutritional input and cognitive function will be assessed at baseline, end of chemotherapy and during follow-up, using validated questionnaires. All data will be correlated with clinical outcome data.

What are the possible benefits and risks of participating?
The tests performed on patient samples are not established medical tests, and results will not be used to direct their medical care. The analysis performed in this study is for research purposes only, and as such, it is unlikely that patients will directly benefit from taking part in the study. However, we hope that the information we gain in the study will benefit individuals who may develop cancer in the future.

The study poses very little risk for research participants; blood samples and faecal samples are routinely performed in hospitals.
Blood sampling: Risk associated with drawing blood from the participants, including mild discomfort, bruising, light-headedness and on rare occasions infection. When participants are approached regarding the study, especially during a visit to an outpatient clinic, they may feel obliged to take part in the study. To address this issue, we emphasise that participation is voluntary. Participants are provided with ample time to consider participation and provide informed consent. It is also emphasised that declining to take part in the study will have no impact on their future care.

Where is the study run from?
Sampling, treatment and follow-up visits will all be conducted at selected NHS Hospital sites. The study will be coordinated at the Coordinating Centre, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, UK.

When is the study starting and how long is it expected to run for?
October 2025 to November 2032

Who is the Funder?
Barts Charity, UK

Who is the main contact?
Coordinating Team and study PI: Dr Melissa Phillips, bci-captivate@qmul.ac.uk

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• United Kingdom
• England
• Northern Ireland
• Scotland

Study participating centres

Results and Publications

Study outputs

Editorial Notes

04/11/2025: Study's existence confirmed by the Breast Center Management of the Breast Center at LMU University Hospital, Germany.