Based on the data as described above, we hypothesize that the FES-PET heterogeneity score can predict progression free survival (PFS) in individual patients prior to start of 1st line endocrine treatment and CDK 4/6 inhibition in ER+ advanced breast…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The study parameters and endpoints are entirely the same as in the original
SONImage side study.
The primary study endpoint (1) is PFS (according to RECIST 1.1 criteria,
Appendix 1) after first line treatment (PFS1).
Secondary outcome
Secondary study endpoints are:
- Interaction between baseline FES-PET heterogeneity score, treatment
allocation, and PFS1 (according to RECIST 1.1 criteria) (2)
- Correlation between response measurements of individual lesions to baseline
FES-PET heterogeneity score and detailed FES and FDG imaging features (3)
- Development of a multivariable model to predict individual PFS benefit to
first-line aromatase inhibitor ± CDK 4/6 inhibition, based on detailed FES/FDG
image features and standard clinicopathological information (4)
- Validation of this prediction model (5)
- To determine circulating tumor DNA (ctDNA) in plasma, to investigate the
prognostic and possibly predictive values of these measures (6)
- Percentage change in FES-PET heterogeneity score after 1st line endocrine
treatment ± CDK 4/6 inhibition visualized with FES-PET and FDG-PET imaging at
PFS1 (7).
Study parameters: the following candidate predictors will be evaluated for
their potential association with the primary and secondary endpoints:
1. Baseline FES-PET heterogeneity score per patient measured in categories
(0%-, 1-99%- and 100% FES-positive disease) and as a continuous variable.
2. Detailed baseline FES- and FDG-PET features and other radiomics features of
within-patient and within-lesion heterogeneity patterns, including features of
disease indolence and aggressiveness.
3. Standard baseline clinicopathological predictors and treatment allocation.
This analysis will allow development of a multivariable prediction model to
predict individual PFS benefit to first-line aromatase inhibitor ± CDK 4/6
inhibition which will then be validated in other MBC patient cohorts with
similar procedures at baseline
4. FES-PET heterogeneity score per patient measured in the aforementioned
categories at progression
Background summary
Currently, the estrogen receptor (ER) is the only reliable predictive biomarker
for responsiveness to endocrine therapy in combination with cyclin-dependent
kinase (CDK) 4/6-inhibitors in patients with metastatic breast cancer (MBC).
The ER status of a single biopsy alone, however, might not be representative of
the ER status of all cancerous lesions in one patient. One of the factors at
play here is presumably disease heterogeneity. The 18F-fluoroestradiol
(FES)-PET scan visualizes ER expression in lesions throughout the body,
providing insight in whole body ER heterogeneity (1,2,3). Previously, we
performed baseline FES-PET and 18F-fluorodeoxyglucose (FDG)-PET scans in 30
patients with ER+ advanced breast cancer, prior to start of the aromatase
inhibitor and the CDK 4/6 inhibitor palbociclib. In this study, we used the
term FES-PET heterogeneity score, which refers to the percentage of ER+
metastases in the body (seen on FES-PET) compared to the total number of
metastases (seen on FDG-PET); therefore, homogenous ER+ disease yields highest
score. Using categories based on this FES-PET heterogeneity score, it was found
that median time to progression (TTP) was 73 weeks for patients who had FES
uptake (SUVmax >=2) in all FDG positive metastases (100% FES-positivity ), 27
weeks with a heterogeneous disease (1-99% FES-positivity), and only 15 weeks
without FES-positive disease (0% FES-positivity) (3).
Study objective
Based on the data as described above, we hypothesize that the FES-PET
heterogeneity score can predict progression free survival (PFS) in individual
patients prior to start of 1st line endocrine treatment and CDK 4/6 inhibition
in ER+ advanced breast cancer. In SONImage, we want to investigate this
hypothesis further. Ultimately the goal is to develop a molecular imaging based
multivariable model, to predict individual PFS benefit to 1st line aromatase
inhibition (aromatase inhibitor) ± CDK 4/6 inhibition. This would allow
patients and providers to weigh individual benefits and (long-term) burden for
optimized treatment decisions. In addition, we hypothesize that first line
endocrine treatment ± CDK 4/6 inhibitor treatment itself can induce (further)
heterogeneity of whole-body ER expression which can affect response to
subsequent second line (fulvestrant ± CDK 4/6 inhibition) treatment in ER+ MBC.
Study design
This is an extension to the SONImage study, an imaging biomarker side study to
the Dutch SONIA trial. In the SONIA trial, patients with ER+ advanced breast
cancer were randomized to endocrine treatment combined with CDK 4/6 inhibition
either in first or second line. Due to the COVID-19 pandemic disproportionally
affecting inclusion in SONImage compared to SONIA, the inclusions goals of
SONImage could not be met before the closure of the SONIA trial. Instead of 100
patients, 53 patients have been entered in SONImage: 31 were randomized to
endocrine therapy plus a CDK 4/6 inhibitor (strategy A SONIA) and 22 patients
to standard first-line endocrine therapy (strategy B SONIA). To meet the
primary endpoint of SONImage after the completion of SONIA, SONImage will be
extended as an independent study to complete inclusion of 50 evaluable patients
in the CDK 4/6 inhibitor treatment arm. For the endocrine treatment alone arm,
the total number of 50 evaluable patients will be complemented by random
sampling from the completed IMPACT MBC trial (NCT01957332, Schröder PI), in
which similar patients received exactly the same imaging modalities prior to
start of 1st line endocrine treatment (without CDK 4/6 inhibition) for ER+
advanced breast cancer.
Study burden and risks
The FES-PET scan performed at baseline and at PFS1, plus low-dose CT scan, will
induce an extra radiation burden of about 6.1 mSv each (210 MBq injected per
scan for an average patient of 70 kilogram body weight). This additional
radiation burden is justifiable in this category of adult patients with
advanced cancer according to the International Commission on Radiological
Protection (ICRP) guidelines. One venous blood sample (6 mL) will be drawn
during the FES-PET procedure for sex hormone binding globulin (SHBG)
measurement and, in case the patient gives consent, three venous blood samples
(30mL) at baseline and PFS1 for ctDNA analysis. The time between FES-PET and
standard FDG-PET (in no specific order) should be at least 24 h to allow for
sufficient decay of the radiotracer. Patients and physicians will be blinded
for the FES-PET results but not for FDG-PET. The results generated from this
imaging side study will have no clinical implications for the individual study
participants.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Adult women (>= 18 years of age) with proven diagnosis of adenocarcinoma of
the breast with locoregional recurrent or metastatic disease not amenable to
resection or radiation therapy with curative intent and for whom chemotherapy
is not clinically indicated.
2. Previously untreated with any systemic anti-cancer therapy for metastatic
HR+ disease, with the exception of recently started (within 14 days of start
treatment) endocrine therapy.
Special considerations:
a. Previous systemic treatment for locoregional recurrent disease is not an
exclusion criterion, provided that the intent was curative at the time of
systemic therapy.
b. In case of previous systemic treatment for oligometastatic disease, patients
are not eligible for SONImage
3. Documentation of histologically confirmed diagnosis of ER expression >10%
breast cancer
based on local results (on the primary tumor or on a metastatic lesion).
4. Patients that are planned to start with an aromatase inhibitor + CDK 4/6
inhibitors within 28
days of signing informed consent.
5. Women who are not post-menopausal must receive ovarian ablation or
suppression with
administration of LHRH agonist. Postmenopausal status is defined as:
a. prior bilateral surgical oophorectomy, or
b. for patients >=60 years: spontaneous cessation of regular menses for at least
12 consecutive months without OAC;
c. for patients <60 years: spontaneous cessation of regular menses for at least
12 consecutive months without OAC ánd estradiol and FSH levels that meet
postmenopausal values according to local reference values at screening
6. Able to give written informed consent and to comply with the SONImage
protocol.
Exclusion criteria
1. Contra-indication for aromatase inhibitors.
2. Contra-indication for PET imaging.
3. Use of ER ligands (i.e., tamoxifen or fulvestrant) <= 5 weeks before FES-PET
imaging.
4. Use of CDK4/6 inhibitor before FES-PET or FDG-PET imaging.
5. Use of aromatase inhibitors > 2 weeks before FES-PET or FDG- PET imaging.
Prior to FDG/FES-PET CT imaging performed after PFS1 before start of second line
fulvestrant ± CDK 4/6 inhibition, the same in- and exclusion criteria apply. In
addition:
1. Patients must be included in SONImage at start of first line therapy.
2. Patients are excluded when there is a contra-indication for fulvestrant
3. Patients are excluded when fulvestrant is used > 2 weeks before FDG-PET
imaging
4. Patients are excluded when fulvestrant is used before FES-PET imaging
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04125277 |
| CCMO | NL82504.041.22 |