4FMFES-PET Imaging of ER+ Advanced Breast Cancers

Evaluation of the Diagnostic, Prognostic and Follow-up Potential of 4,16α-[16α-18F]Difluoro-11β-methoxyestradiol (4FMFES) PET Imaging for Estrogen Receptor Positive Advanced Breast Cancers

Estrogen Receptor (ER) is a crucial prognostic factor and treatment target in breast cancer patients. Knowledge of its status greatly influences the choice of the optimal course of treatment. Pathological evaluations of primary tumor, axillary nodes, and metastases are the only confirmatory approach to ER status determination and are limited to known and accessible sites. However, it is known that many advanced breast cancer patients harbor diseases presenting inter-tumor or temporal ER heterogeneity, as ER expression can vary between tumor foci and can evolve during treatment and at time of recurrence, hence the need for whole-body, non-invasive assessment of ER status.

In the last decades, 16α-[18F]fluoroestradiol (FES) was developed and evaluated as an ER-targeting positron emission tomography (PET) tracer. FES correlated with ER expression, and recently was shown to be able to predict hormone therapy response. Our Center designed and evaluated 4-fluoro-11β-methoxy-16α-[18F]fluoroestradiol (4FMFES), a successor PET tracer for ER imaging. Paired comparison during a phase II clinical trial showed that 4FMFES produced images of better quality, with less overall non-specific signal than FES. It resulted in a significantly improved tumor contrast and tumor detectability using 4FMFES-PET leading to increased diagnosis confidence in early-stage breast cancer compared to FES-PET. Those results demonstrated that, as of now, 4FMFES-PET is the best imaging modality worldwide for whole-body ER status determination, but further validations are necessary to position this method as a standard and essential tool for breast cancer management. Like what was observed for FES-PET, preliminary data suggest that 4FMFES-PET combined with FDG-PET will yield very high sensibility for breast tumor detection, each method being complementary.

In continuity with previous work, we seek to expand our clinical knowledge of this high-potential diagnostic imaging through the following main objective:

Launch a phase II clinical trial to explore the full potential and benefit of 4FMFES-PET in combination with FDG-PET for advanced ER+ breast cancer patients to demonstrate it is an essential tool for cancer management.

This proposed project will focus on 3 specific aims:

1. Compare and complement 4FMFES-PET with FDG-PET and conventional imaging modalities, and evaluate how they improved prognosis and staging of ER+ advanced breast cancer patients;
2. Correlate 4FMFES/FDG uptake and staging with pathological data (histology, receptor status, grade), including distal biopsy metastases sampling;
3. Correlate 4FMFES/FDG uptake and staging with longitudinal outcomes (treatment response, progression-free survival, time-to-relapse) to determine which cohort of patient benefit most from 4FMFES.

Study Overview

• Status: Recruiting
• Conditions: ER+ Breast Cancer
• Intervention / Treatment: Diagnostic test: 4FMFES-PET

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michel Paquette, PhD; Phone Number: 11-982 819-346-1110; Email: michel.paquette@usherbrooke.ca
• Study Contact Backup: Name: Stephanie Dubreuil; Phone Number: 16617 819-346-1110; Email: Stephanie.dubreuil2@usherbrooke.ca

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H5N4
      • Recruiting
      • Université deSherbrooke
      • Contact: Eric E Turcotte, MD; Phone Number: 11887 346-1110; Email: eric.e.turcotte@usherbrooke.ca
      • Sub-Investigator: Brigitte Guérin, PhD
      • Sub-Investigator: Michel Pavic, MD
      • Sub-Investigator: Guy-Anne Turgeon, MD
      • Sub-Investigator: Étienne Rousseau, MD
      • Contact: Michel Paquette, PhD; Phone Number: 11982 819-346-1110; Email: michel.paquette@usherbrooke.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Advanced breast cancer patients, i.e. stage 3 or 4 diseases.
• Aged 18 or older at the time of breast cancer diagnosis.
• Histopathologic review confirming diagnosis of ER positive breast cancer.
• Male patients, although rare, can participate.
• Patient must have given informed consent.
• ECOG performance status 0-3.
• ER must be positive in at least 10% of tumor cells in either the core biopsy or a therapeutic surgical resection.
• Any HER2-neu status.
• Patient eligible for and willing to receive systemic treatment.

Exclusion Criteria:

• Patients who are pregnant or nursing.
• Patients unable to tolerate PET/CT for 30 minutes.
• Patients taking anti-ER hormone therapy that can pharmacologically blockade estrogen receptors (ex: Tamoxifen, Fulvestrant). Patients can undergo 4FMFES-PET if anti-ER therapy was interrupted at least 8 weeks prior imaging. Aromatase inhibitors and LHRH analogs are not expected to interfere with 4FMFES uptake and are thus permitted to be taken prior and during this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4FMFES-PET imaging at 0, 6 and 18 months; Patients burdened with ER+ advanced breast cancers and recruited in the trial will undergo an experimental 4FMFES-PET imaging within a 4-week interval of a medically-prescribed FDG-PET. The 4FMFES-PET procedure will be repeated at 6 and 18 months following the initial scan.	Diagnostic test: 4FMFES-PET; Intravenous 4FMFES injection, followed with PET imaging; Other Names: 4,16α-[16α-18F]difluoro-11β-methoxyestradiol PET

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of 4FMFES-PET uptake with histopathological markers, notably ER immunohistochemistry (IHC) score	4FMFES-PET targets Estrogen Receptors (ER) in ER+ cancers with high affinity, at least in vitro. 4FMFES-PET was already compared to the similar PET tracer FES, whose uptake is known to correlate with ER status and IHC score, and shown to have superior diagnostic properties. 4FMFES-PET will now be correlated with the ER IHC score, along with other histopathological markers.	18 months
Evaluation of progression-free survival versus 4FMFES-PET uptake threshold	This outcome aims to evaluate the prognostic potential of 4FMFES-PET. Kaplan-Meyer curves of progression-free-survival (PFS) will be drawn, with the studied population separated with A) a 4FMFES-PET SUVMax cut-off value of 1.5; and B) FDG-PET/4FMFES-PET tumor ratio cutoff value of 2.0, each for the lowest uptake tumor within the same patient at the initial assessment. It is expected that higher 4FMFES uptake and lower FDG/4FMFES ratio will be associated with better outcome for patients.Significant differences will be evaluated using the Log-Rank test.	18 months
Evaluation of time-to-recurrence versus 4FMFES-PET uptake threshold	This outcome aims to evaluate the prognostic potential of 4FMFES-PET. Kaplan-Meyer curves of time-to-recurrence (TTR) will be drawn, with the studied population separated with A) a 4FMFES-PET SUVMax cut-off value of 1.5; and B) FDG-PET/4FMFES-PET tumor ratio cutoff value of 2.0, each for the lowest uptake tumor within the same patient at the initial assessment. It is expected that higher 4FMFES uptake and lower FDG/4FMFES ratio will be associated with better outcome for patients.Significant differences will be evaluated using the Log-Rank test.	18 months
Correlation of treatment response with reduction of 4FMFES-PET uptake and number of assessable lesions at 6 and 18 months after the initial assessment	All patients on the study will be followed longitudinally with clinical questionnaire and examination as of their treating oncologist. Clinical information on treatment details, first progression and site of progression will be recorded on a follow-up form at each visit for at least 3 years. All stage 3 breast cancer patients with a breast in place will undergo annual mammograms with or without breast ultrasound as of current standard practice. Patients receiving chemo-, radio and/or hormone therapy will be longitudinally followed-up using 4FMFES-PET and FDG-PET at 6 months and 18 months following the initial scan. Imaging at shorter intervals could also be done if deemed necessary. Tracer uptake, number and size of lesions will be documented at each imaging. If it occurs, case of death will be sought from hospital or community medical records.	18 months
Complementarity analysis of FDG-PET with 4FMFES-PET	4FMFES-PET will be scheduled within two weeks of a clinically prescribed FDG-PET to allow 4FMFES to FDG comparison. Uptake (SUV: Standardized Uptake Value) and contrast (tumor SUVMax / background SUVMean ratio) will be measured and compiled for each lesion. Detection of each lesion will be determined by the contrast value: 1) higher or equal to 3 = positive; 2) between 1.5 and 3 = ubiquitous; 3) under 1.5 = negative. A study will be considered as 4FMFES-negative if 4FMFES-PET does not display any focal uptake other than normal physiological biodistribution, and the same will be done for FDG-PET. Unsuspected lesion visible on 4FMFES-PET or FDG-PET will be investigated by biopsy when possible to prove the lesion's histopathology. Follow-up images will be compared with the initial FDG and 4FMFES-PET scans for each patient, and both the total number of visible tumors and their uptake will be compared between each time point.	36 months

Collaborators and Investigators

• Sponsor: Centre de recherche du Centre hospitalier universitaire de Sherbrooke
• Collaborators: Université de Sherbrooke; Canadian Cancer Society (CCS)
• Investigators: Principal Investigator: Éric E Turcotte, MD, Université de Sherbrooke, Centre de Recherche du CHUS

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 24, 2021
• First Submitted That Met QC Criteria: March 26, 2021
• First Posted (Actual): April 1, 2021

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: CIMS-4FMFES-2021-3966

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No