Personalised Disease Monitoring in Metastatic Breast Cancer

Study Overview
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Brief Summary
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Patients with metastatic breast cancer may respond well to treatment and metastases can remain stable for several years. Despite personalised medicine being increasingly used for diagnosis and treatment, follow-up still include radiological response evaluation every 3-4 months, which renders a significant number of 'unnecessary' exams for patients with long-term stable disease. Increasing evidence indicates that tumour markers such as circulating tumour DNA (ctDNA), thymidine kinase 1 (TK1) and cancer antigen 15-3 (CA15-3) may be useful for disease monitoring in the metastatic setting. However, algorithms that accurately define the time-points at which imaging can be foregone or reinstituted when progression is forecast, have not been developed. This study will measure ctDNA, TK1 and CA15-3 at all imaging time-points. The primary aim is to develop an algorithm based on these biomarkers, alone or in combination, that with sufficient specificity and sensitivity can advise whether a scan can be safely admitted at a specific time-point, for patients with MBC receiving first line therapy with AI plus cyclin dependent kinase 4/6 inhibitor (CDK4/6i). Additional samples will be stored such that novel biomarkers can also be tested in future. The cost-effectiveness of using the devised biomarker protocol will be evaluated.

Detailed Description
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One hundred patients with estrogen receptor positive (ER+)/ Human epidermal growth factor receptor negative (HER2-) metastatic or locally advanced breast cancer, eligible for 1st line endocrine therapy with AI + CDK4/6i will be included. Patients will receive standard therapy (AI + CDK4/6i) and follow-up will proceed according to local guidelines, namely cross sectional imaging with CT thorax/abdomen/pelvis +/- MRI as required and analysis of CA 15-3, every 3 cycles for the first year and every 3-4 cycles thereafter. Participation in the study will include serial blood sampling for the bespoke study biomarkers. Decisions on progression will be made according to the routine imaging tests and the biomarkers will be subsequently analysed. The investigators hypothesise that the biomarkers ctDNA, TK1 and CA15-3, alone or in combination, will accurately correlate with disease status in patients receiving AI + CDK4/6i for metastatic breast cancer such that routine imaging can be delayed until predefined levels of biomarker progression. Primary aim: To develop a biomarker-based prediction model to be used in patients with metastatic breast cancer, receiving first line therapy with AI and CDK4/6i, that provides the physician with a recommendation whether or not a radiological examination is required, based on the likelihood that the scan will actually show progressive disease. Secondary aims To define the lead time between rising biomarker and subsequent progression on imaging To define the clinical utility of the bespoke biomarkers for disease monitoring The relative value of analysing TK1 on CDK4/6i treatment versus off CDK4/6i treatment for disease monitoring To define the economic impact of implementation of the chosen prediction model

Official Title
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Personalised Disease Monitoring During Treatment With an Aromatase Inhibitor + Cyclin Dependent Kinase (CDK) 4/6 Inhibitor as 1st Line Endocrine Therapy in Patients With ER-positive/HER2-negative Metastatic Breast Cancer

Conditions
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Breast Cancer Metastatic, Estrogen Receptor-positive Breast Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced breast cancer ER-positive/HER2-negative For patients who have had a prior non-breast malignancy within the last 5 years (excluding in situ carcinoma of the cervix and basal cell carcinoma of the skin) biopsy of a metastatic site is required to confirm the diagnosis of metastatic ER+/HER2- breast cancer. Eligible for 1st line endocrine therapy with an aromatase inhibitor and a CDK4/6 inhibitor Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2 Age ≥ 18 years Life expectancy > 3 months Radiologically assessable disease Exclusion Criteria: Known central nervous system (CNS) metastases, carcinomatous meningitis or leptomeningeal disease unless treated with radiotherapy and symptomatically stable at least 2 weeks after discontinuation of steroids Concurrent disease(s) or familial, sociological or geographical condition that would, in the investigator's opinion, preclude compliance with study procedures Any serious medical disorder that would compromise the patient's safety Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood levels of ctDNA, CA15-3 and TK-1 assays from baseline to disease progression | ctDNA, CA15-3 and TK-1 assays will be performed at baseline, 2 weeks and at every imaging timepoint to develop a statistical algorithm to predict disease progression taht can be tested prospectively in future studies. | 3-5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best time for TK1 analysis during CDK4/6i treatment (on treatment vs off treatment) | The relative value of analysing TK1 on CDK4/6i treatment versus off CDK4/6i treatment for disease monitoring | 3-5 years | 
| The economic impact of implementation of the chosen prediction model | Cost effectiveness analysis of the using the prediction model | 3-5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Neoplasms, Neoplasm Metastasis, Precision Medicine, disease monitoring, Biomarkers, Tumor, Circulating Tumor DNA, Thymidine Kinase