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

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

SURVEY-CNS is a feasibility study evaluating whether women and men with HER2-positive metastatic breast cancer can be successfully recruited and randomised to a strategy of central nervous system (CNS) magnetic resonance imaging (MRI) surveillance versus standard of care (no routine CNS surveillance).

Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Brain metastases can cause significant symptoms, including headache, nausea, seizures, visual disturbance, motor dysfunction, and cognitive or psychological changes. Although new HER2-directed therapies have improved systemic disease control, CNS progression remains common and is associated with reduced quality of life and survival.

Currently, routine brain imaging is not recommended in asymptomatic patients. Brain imaging is typically performed only when neurological symptoms develop. Observational data suggest that patients diagnosed with asymptomatic brain metastases may have better outcomes than those diagnosed after symptoms occur. However, it is not known whether a surveillance strategy is feasible or acceptable to patients.

All participants in this study will undergo a baseline contrast-enhanced brain MRI. Patients without evidence of CNS metastases on the baseline scan will be randomised (1:1) to either:

CNS surveillance with repeat brain MRI at 6 and 12 months, or No routine surveillance imaging (standard of care), with imaging only if clinically indicated.

The primary objective is to determine whether more than 30% of eligible patients approached agree to undergo screening and randomisation. The study will approach up to 193 patients and will be considered feasible if 69 patients consent to screening with intent to randomise.

Secondary objectives include:

Determining the proportion of patients with previously undetected (occult) CNS metastases at baseline; Determining the incidence of occult CNS metastases during surveillance; Recording symptomatic CNS presentations; Describing management of CNS metastases, including surgery or radiotherapy. Participants will be followed for 14 months from baseline.

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