SURVEY-CNS: A Feasibility Study of Randomising Women and Men With HER2-Positive Metastatic Breast Cancer to Central Nervous System Surveillance Versus No Surveillance

HER2-positive metastatic breast cancer is associated with a high cumulative incidence of central nervous system metastases. Advances in systemic HER2-targeted therapies have improved extracranial disease control and overall survival; however, CNS progression remains a major cause of morbidity and mortality.

Current standard practice does not include routine CNS surveillance imaging in asymptomatic patients. Brain imaging is typically performed only following the onset of neurological symptoms. Observational registry data suggest that detection of asymptomatic brain metastases may be associated with improved survival compared with symptomatic presentation. Whether a structured surveillance approach is feasible and acceptable to patients has not been prospectively evaluated.

SURVEY-CNS is a non-CTIMP, randomised, parallel-group feasibility study conducted in Ireland in collaboration with UK centres running a parallel study under the same protocol.

All registered participants will undergo a baseline contrast-enhanced MRI of the brain. Participants with radiologically evident CNS metastases at baseline will not proceed to randomisation and will be managed according to standard clinical practice. Participants without CNS metastases will be randomised in a 1:1 ratio to:

Surveillance arm: Brain MRI at 6 months and 12 months Standard-of-care arm: No routine surveillance imaging

Randomisation will be stratified by:

Oestrogen receptor (ER) status (positive vs negative) Line of metastatic therapy (first line vs second or later)

Participants will be followed for 14 months from baseline for:

Development of radiologically detected CNS metastases Development of symptomatic CNS disease CNS-directed local therapy (surgery, stereotactic radiosurgery, whole brain radiotherapy) Changes in systemic anti-cancer therapy Survival status

The primary endpoint is feasibility, defined as the proportion of eligible patients who consent to screening and randomisation. A single-stage A'Hern design will be used. The study will halt when either 69 patients have consented or 193 patients have been approached.

Recruitment pathways will be evaluated using a structured screening log and the SEAR (Screened, Eligible, Approached, Randomised) framework to identify barriers to participation and inform planning of a future definitive trial.

This study is designed to determine whether a larger efficacy trial of CNS surveillance in HER2-positive metastatic breast cancer is practicable.

Inclusion criteria

• Age ≥18 years
• Male or female
• Histologically or cytologically confirmed HER2-positive breast cancer
• Evidence of metastatic breast cancer
• Estrogen receptor (ER) positive or negative disease permitted
• Presence of visceral metastatic disease
• Receiving active HER2-directed systemic therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Estimated life expectancy greater than 6 months
• Ability to provide written informed consent
• Willing and able to comply with study procedures and follow-up

Exclusion criteria

• Prior history of brain metastases
• History or evidence of leptomeningeal carcinomatosis
• Symptoms suggestive of brain metastases at screening
• Bone-only metastatic disease
• Inability to undergo MRI scanning
• Known hypersensitivity or contraindication to MRI contrast agents that cannot - be managed per local standard of care
• Significant medical condition or laboratory abnormality that, in the opinion of - the investigator, makes participation inappropriate Inability to provide informed consent
• Deemed unsuitable for participation by the principal investigator due to clinical, mobility, or social circumstances