Evaluation of 18F-Fluoroestradiol PET/CT Impact on Management of ER+ HER2- Metastatic Breast Cancer Relapsing Post-Hormone Therapy

The primary objective of this study is to assess the impact of **FES PET/CT** on the management of patients with metastatic breast cancer, characterized by overexpression of estrogen receptors (ER) and absence of HER2 overexpression, who are in relapse following first-line treatment with hormone therapy. This evaluation is clinically relevant as it aims to optimize therapeutic strategies and improve patient outcomes by utilizing advanced imaging techniques to guide treatment decisions.

Secondary objectives include:

• Evaluating the impact of substantial therapeutic measures on progression-free survival of the second midline, with the establishment of a historical group.
• Determining the relevance at three months of the therapeutic measures implemented following the baseline FES PET/CT.
• Identifying parameters of FES PET/CT associated with substantial therapeutic measures.
• Conducting exploratory analyses to evaluate the primary endpoint in sub-groups based on breast cancer type (ductal or lobular), presence of oligometastatic disease, and stage of metastatic disease (initially metastatic or recurrent after curative treatment). Additionally, comparing the quality of life of patients receiving substantial therapeutic measures versus others.

The clinical trial involves **female** participants aged 18 years and older, diagnosed with **metastatic breast cancer** characterized by overexpression of estrogen receptors and absence of HER2 overexpression. The study population is specifically selected from individuals who have relapsed after a first-line treatment combining hormone therapy and a CDK4/6 inhibitor. Participants are required to have a life expectancy of at least 12 months and an ECOG performance status of 0, 1, or 2. The trial does not include male subjects, and the sponsor has not provided the total number of participants. The selection criteria ensure that participants have undergone a PET/CT with FDG during the follow-up of the first metastatic line or at baseline during the extension assessment of the second line. The trial population is considered vulnerable, and the study does not provide specific information on lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the impact of **18F-fluoroestradiol (FES)** Positron Emission Tomography (PET) on the management of patients with metastatic breast cancer characterized by overexpression of estrogen receptors (ER) and absence of HER2 overexpression, who are in relapse following first-line treatment with hormone therapy. This is a Phase IV, randomized, double-blind, controlled trial. The trial is expected to run from November 2021 to June 2025, with participant involvement lasting approximately 12 months. The study will include several key visits: an initial screening visit to confirm eligibility, multiple follow-up visits to monitor treatment response and safety, and a final end-of-study visit to assess overall outcomes.

Participants will be required to meet specific inclusion criteria, such as being female, aged 18 years or older, with a primary breast cancer expressing hormonal estrogen receptors and HER2 negative status. They must be at a metastatic stage with identifiable lesions and have relapsed after a first-line treatment combining a CDK4/6 inhibitor and hormone therapy. The primary endpoint will assess the therapeutic impact by evaluating the percentage of patients for whom a substantial therapeutic measure is implemented following the PET-FES examination. Secondary endpoints include progression-free survival and the relevance of therapeutic measures at three months post-baseline PET/CT FES.

Study visits will be structured as follows: the inclusion visit will involve comprehensive screening to ensure all eligibility criteria are met. Follow-up visits will occur at regular intervals to monitor the patient's response to treatment and any changes in therapeutic strategy. The end-of-study visit will involve a final assessment of the patient's condition and the collection of data for analysis. Participants may be withdrawn from the study if they experience adverse events, fail to comply with study procedures, or withdraw consent. The trial aims to provide valuable insights into the role of FES PET in optimizing treatment strategies for this patient population.

The clinical trial involves the use of **FLUOROESTRADIOL F-18**, a radiopharmaceutical agent, as the experimental medication. **FLUOROESTRADIOL F-18** is administered in the form of a **solution for injection**. The active substance, **fluoroestradiol F-18**, is a chemically synthesized compound. The administration route is via **injection**, with a dosage of up to 4 MBq/kg (megabecquerel(s)/kilogram) per day, not exceeding a total dose of 10 ml (millilitre(s)). The maximum treatment period is limited to one day. The product is identified by the sponsor product code **EstroTep**, with an ATC code of **V09IX11**. This agent is not formulated for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial focuses solely on the impact of **FLUOROESTRADIOL F-18** in the management of patients with metastatic breast cancer characterized by overexpression of estrogen receptors (ER) and absence of HER2 overexpression, particularly in cases of relapse following first-line hormone therapy. Participant compliance with the dosing schedule will be monitored to ensure adherence to the specified administration protocol.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the therapeutic impact of **18F-fluoroestradiol (FES) Positron Emission Tomography (PET)** on patients with ER+ and HER2- metastatic breast cancer in relapse after first-line therapy. The primary endpoint involves determining the percentage of patients for whom a substantial therapeutic measure has been implemented following the analysis of the PET-FES examination. This will be evaluated using a standardized questionnaire completed by the prescribing clinician at the time of requesting the PET/CT at FES and again within a maximum of 15 days after the PET/CT FES to specify the final therapeutic measure. Changes in therapeutic modalities, such as modifications in hormone therapy, chemotherapy, systemic treatments, radiotherapy, and surgical plans, will be documented.

Secondary endpoints include the assessment of 2nd line progression-free survival (PFS), defined as the time between the date of the final therapeutic measure and relapse. This will be compared using the Kaplan Meier test with a 12-month censorship. Additionally, the relevance of the therapeutic measures implemented following the baseline PET/CT FES will be evaluated at 3 months by an independent jury of expert clinicians, including oncologists, nuclear physicians, radiotherapists, and radiologists, based on all data in the patient's medical file, including treatment response evaluation.