Personalised Disease Monitoring in Metastatic Breast Cancer

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

Inclusion criteria

• Confirmed metastatic breast cancer (stage 4) or locally advanced disease not amendable to curative resection. Patients who have locoregional disease only an in whom a response to therapy would lead to potentially curative resection are not eligible.
• ER+/HER2- breast cancer (assessed locally). NOTE: If immunohistochemical analysis is not available from metastatic tissue, the ER and HER2 status from the primary tumour should be used.
• 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 treatment with AI + CDK4/6-inhibitor according to local guidelines.

NOTE: ≥ 12 month since termination of adjuvant AI if used NOTE: Patients may have received one prior line of chemotherapy for metastatic breast cancer but should have disease progression at study entry.

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 (Oken 1982).
• Life expectancy >3 months.
• Age ≥ 18 years
• Metastatic disease must be radiologically assessable, by means of at least one of the following techniques: computerised tomography (CT) and/or magnetic resonance imaging (MRI), i.e. lesions can be measurable or non-measurable according to RECIST 1.1, but must be clearly evaluable according to the radiologist and/or treating physician. Patients with bone predominant disease who lack evaluable disease on CT according to RECIST 1.1.

must have serial MRI including the representative area in addition to CT TAP. NOTE: Previously irradiated lesions are deemed measurable only if progression is documented at the site after completion of radiation.

• Willing and able to provide informed consent to undergo all trial procedures.

Exclusion criteria

• Known CNS metastases, carcinomatous meningitis or leptomeningeal disease unless treated with radiotherapy and symptomatically stable at least 2 weeks after discontinuation of steroids. For such patients, ongoing monitoring of CNS disease is required as standard of care. No screening is needed for asymptomatic patients.
• 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.