Title: BRain dIffusion TEnsor imaging to predict immunotherapy response in METastatic melanoma (BRITEMET)
Funder: Cancer Research UK

Abstract: Background: Brain metastases (BM) are an increasingly common problem in cancer patients affecting up to 40% of those with tumours such as lung, breast and malignant melanoma. Despite an increasing incidence they are under-investigated and the prognosis remains poor. Immunotherapy is a potentially transformative treatment but in melanoma, only half of patients with BM respond whilst the treatment is expensive, time consuming and potentially harmful. Diffusion tensor imaging (DTI-MR) is a well established form of MRI which can be performed in a clinical setting and the Fractional Anisotropy (FA) is used to assess white matter tract disruption in the brain. Laboratory research has identified a strong relationship between the T-cell infiltration around BM and drop in FA. Aims: 1. Establish the range of values for FA in a population with melanoma BM. 2. Confirm that the peritumoural FA readings can be reliably obtained and measured in a clinical setting by different observers. 3. Investigate whether the baseline FA is associated with subsequent response to immunotherapy in a clinical cohort with melanoma BM. 4. Investigate whether the FA changes with treatment in those who are responders. 5. Refine the clinical pathway and standard operating procedure for obtaining and measuring values of FA for future studies. Methods: Patients being treated for melanoma BM at a single regional cancer centre will be enrolled and baseline clinical data gathered. A DTI-MR scan is taken at 0,6 weeks and the patient receives immunotherapy over 12 weeks as per routine clinical care. At 12 weeks the clinical and radiological response is determined using established parameters. How the results of this research will be used: This study will generate pilot data in a clinical cohort and refine the standard protocols and operating procedure for obtaining this biomarker in practice. This will serve as a basis for a larger multicentre study, either standalone or as part of a clinical trial in immunotherapy which is being planned by the NCRI brain metastases and meningioma subgroup. Such a study would record the pretreatment DTI-MR biomarker using the protocols refined here in a larger number of patients, to generate a ROC curve and determine the optimal cutoff for defining treatment responders.

Lay abstract: Background: Brain metastases (BM) are an increasingly common problem in cancer patients affecting up to 40% of those with tumours such as lung, breast and malignant melanoma. Despite an increasing incidence they are under-investigated and the prognosis remains poor. Immunotherapy is a potentially transformative treatment but in melanoma, only half of patients with BM respond whilst the treatment is expensive, time consuming and potentially harmful. Diffusion tensor imaging (DTI-MR) is a well established form of MRI which can be performed in a clinical setting and the Fractional Anisotropy (FA) is used to assess white matter tract disruption in the brain. Laboratory research has identified a strong relationship between the T-cell infiltration around BM and drop in FA. Aims: 1. Establish the range of values for FA in a population with melanoma BM. 2. Confirm that the peritumoural FA readings can be reliably obtained and measured in a clinical setting by different observers. 3. Investigate whether the baseline FA is associated with subsequent response to immunotherapy in a clinical cohort with melanoma BM. 4. Investigate whether the FA changes with treatment in those who are responders. 5. Refine the clinical pathway and standard operating procedure for obtaining and measuring values of FA for future studies. Methods: Patients being treated for melanoma BM at a single regional cancer centre will be enrolled and baseline clinical data gathered. A DTI-MR scan is taken at 0,6 weeks and the patient receives immunotherapy over 12 weeks as per routine clinical care. At 12 weeks the clinical and radiological response is determined using established parameters. How the results of this research will be used: This study will generate pilot data in a clinical cohort and refine the standard protocols and operating procedure for obtaining this biomarker in practice. This will serve as a basis for a larger multicentre study, either standalone or as part of a clinical trial in immunotherapy which is being planned by the NCRI brain metastases and meningioma subgroup. Such a study would record the pretreatment DTI-MR biomarker using the protocols refined here in a larger number of patients, to generate a ROC curve and determine the optimal cutoff for defining treatment responders.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS