IRELAND Trial: A Translational Biomarker and Exercise Study During Neoadjuvant Breast Cancer Therapy

Investigating Molecular and Clinical pREdictors of Outcome foLlowing neoadjuvAnt Therapy in Breast caNcer Dynamics (IRELAND Trial): A Translational Study With an Embedded Physiotherapist-Led Exercise Randomised Controlled Trial

The goal of this clinical trial is to learn whether a physiotherapy-led exercise programme delivered during treatment before surgery (neoadjuvant therapy) for breast cancer can improve physical fitness, quality of life, and how well people cope with treatment. The study will also investigate whether blood and tumour markers, including microRNAs (small molecules that help regulate gene activity), together with information about the participant and the cancer itself (clinical information), can help predict how well patients respond to treatment.

The main questions this study aims to answer are:

• Does a structured physiotherapy-led exercise programme improve physical fitness, muscle strength, quality of life, and the ability to complete treatment?
• Can blood and tumour markers, together with clinical information, help predict which patients will have the best response to treatment?

Researchers will compare participants who receive the physiotherapy-led exercise programme with participants who receive standard care to determine whether the exercise programme improves physical and patient-reported outcomes.

Participants will:

• Receive standard treatment before surgery for breast cancer.
• Be randomly assigned to either a 14-week physiotherapy-led personalised exercise programme or standard care.
• Provide blood and tumour tissue samples for research.
• Complete physical assessments and questionnaires about their symptoms, physical function, and quality of life during treatment.
• Be followed throughout treatment, surgery, and follow-up to assess treatment response and other health outcomes.

Breast cancer is a heterogeneous disease with substantial variability in response to neoadjuvant systemic therapy despite advances in systemic treatment. Although pathological complete response (pCR) is an established surrogate marker of treatment efficacy in selected breast cancer subtypes, there remains a need for improved molecular and clinical predictors of treatment response, disease progression, and long-term outcomes. Circulating and tumour-derived microRNAs (miRNAs) have emerged as promising translational biomarkers because of their biological stability and potential to reflect tumour biology and dynamic changes during therapy.

The IRELAND Trial is designed to prospectively integrate molecular, clinical, imaging, physiological, and patient-reported data collected throughout the neoadjuvant treatment pathway. The study aims to develop a comprehensive understanding of factors associated with treatment response and patient outcomes by combining biological specimen analysis with longitudinal clinical assessment. Blood and tumour tissue specimens will be collected at predefined time points for translational analyses, while radiological, pathological, and patient-reported outcome data will be collected prospectively using standardised assessment methods.

Embedded within the translational cohort is a randomised controlled trial (CanReAct Trial) evaluating a structured 14-week physiotherapist-led personalised adaptive exercise programme delivered concurrently with standard-of-care neoadjuvant systemic therapy. Participants will be randomised to receive either the exercise intervention or standard care. The intervention is intended to optimise physical function during treatment and evaluate its effects on functional capacity, treatment tolerance, quality of life, and other patient-centred outcomes without altering oncological management.

By integrating translational biomarker research with a structured supportive care intervention, the IRELAND Trial seeks to generate evidence that may improve prediction of treatment response while informing future personalised management strategies for patients undergoing neoadjuvant therapy for breast cancer.

Inclusion Criteria:

1. Age 18 years or older.
2. Histologically confirmed diagnosis of breast cancer.
3. Planned treatment with standard-of-care neoadjuvant systemic therapy.
4. Ability to provide written informed consent.
5. Ability to partake in 14-week physiotherapist-led personalised adaptive exercise programme.
6. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2.

Exclusion Criteria:

1. Inability to provide informed consent.
2. Inability to complete patient-reported outcome assessments.
3. Pregnancy.
4. Presence of any condition that, in the opinion of the treating clinician, would preclude participation in study procedures.
5. Inability to partake in 14-week physiotherapist-led personalised adaptive exercise programme.