Clinical trial NCT04597580: Personalised Disease Monitoring in Metastatic Breast Cancer
Official title: 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
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Breast Cancer Metastatic
Estrogen Receptor-positive Breast Cancer
Keywords: Breast Neoplasms
Neoplasm Metastasis
Precision Medicine
disease monitoring
Biomarkers, Tumor
Circulating Tumor DNA
Thymidine Kinase
Lead sponsor: The Christie NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Sahlgrenska University Hospital
First posted: 2020-10-22
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with ER+/HER2- metastatic or locally advanced breast cancer, not amendable for curative surgery, eligible for 1st line endocrine therapy with aromatase inhibitor (AI) + CDK4/6-inhibitor (CDK4/6i).

Brief summary: 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: Change in blood levels of ctDNA, CA15-3 and TK-1 assays from baseline to disease progression
timeFrame: 3-5 years
Secondary outcomes:
measure: Best time for TK1 analysis during CDK4/6i treatment ("on treatment" vs "off treatment")
timeFrame: 3-5 years
measure: The economic impact of implementation of the chosen prediction model
timeFrame: 3-5 years
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Department of Oncology, Sahlgrenska University Hospital
city: Jönköping
country: Sweden
facility: Department of Oncology, Ryhov Hospital
city: Kalmar
country: Sweden
facility: Department of Oncology, Kalmar Hospital
city: Linköping
country: Sweden
facility: Department of Oncology, Linköping University Hospital
city: Stockholm
country: Sweden
facility: Department of Oncology, Södersjukhuset
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Wigan
country: United Kingdom
facility: Wigan Infirmary, Wrightington, Wigan and Leigh NHS Foundation Trust
Study officials:
affiliation: University of Manchester and The Christie NHS Foundation Trust
name: Dr Sacha Howell, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Gothenburg and Region Jönköping
name: Maria Ekholm, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: