Title
A Pilot Study of FES Imaging to Optimize Tamoxifen Dose for Metastatic Breast Cancer Patients with ESR1 Mutations

Description
Despite broad advancements in endocrine therapy for ERα+ breast cancer, resistance ultimately develops. A common driver of resistance are known ESR1 mutations that lead to constitutively active receptor signaling and transcriptional regulation that is always "turned on" despite the absence of estrogen. Patients with ESR1 mutations are expected to have decreased binding affinity for tamoxifen and thus may be underdosed on standard therapy. [18F]-fluoroestradiol Positron Emission Tomography/Computed tomography (FES-PET/CT) imaging is a novel functional imaging technique that can non-invasively measure ERα expression and inhibition in metastatic ERα+ breast cancer. The proposed a pilot study uses FES-PET/CT imaging to measure ERα blockade to determine the optimal dose of tamoxifen in patients with ESR1 mutations.

Objective
Primary Outcome Measures:

Rate of FES Blockade at each dose level to determine the Optimal Tamoxifen Dose [ Time Frame: up to 6 weeks to compare baseline and treatment images ]


Reduction in FES uptake will be described and analyzed by Fisher's exact test. Rates or proportion of responses at each dose level will be provided in data listings. If the SUVmax for all 5 target lesions have decreased by > 75% or all 5 lesions have SUVmax<1.5 on the second scan, then these participants will be prospectively defined as having complete FES blockade. If the SUVmax for any of the 5 lesions has not decreased by > 75% or if any new lesions arise with SUVmax greater than or equal to 1.5, then these subjects will be defined as having incomplete FES blockade.

FES uptake at each dose level: SUVmax [ Time Frame: up to 6 weeks to compare baseline and treatment images ]


FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.


FES uptake at each dose level: SUVmean [ Time Frame: up to 6 weeks to compare baseline and treatment images ]


FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.


FES uptake at each dose level: Tumor-to-Normal tissue ratio [ Time Frame: up to 6 weeks to compare baseline and treatment images ]


FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.


FES uptake at each dose level: Tumor-to-Blood Pool ratio [ Time Frame: up to 6 weeks to compare baseline and treatment images ]


FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.


Objective Response Rate at each dose level [ Time Frame: up to 6 months ]


The objective response rate is the proportion of all participants with confirmed Partial Response or Complete Response according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).


Safety: Number of Participants Experiencing Grade 3 or higher Adverse Events [ Time Frame: Up to 21 days on treatment (up to 6 weeks on study) ]


All grade 3-4 adverse events occurring between cycle 1, day 1 to cycle 2 day 1 and at least possibly related to therapy will be reviewed by the principal investigator prior to starting enrollment in the next dose cohort. If 2 or more of the 3 participants in any cohort experience grade 3-4 adverse events, then dose escalation will be halted.

Treatment Experimental: Tamoxifen Dose Levels
Three participants will be enrolled to each dose level of oral tamoxifen (n = 12)
Dose Level 1 = 20 mg daily Dose Level 2 = 80 mg daily Dose Level 3 = 160 mg daily Dose Level 4 = 200 mg daily
Tamoxifen should be started within 14 days of the FES-PET/CT scan, at least 24 hours after FES injection. Participants will continue tamoxifen therapy until there is radiologic or clinical evidence of progressive disease or drug intolerance.

Key Eligibility Inclusion Criteria:

Participants must have histologically confirmed breast cancer that is metastatic or unresectable with the following:


Estrogen receptor expression by immunohistochemistry greater than or equal to 10%

ESR1 mutation identified using a Clinical Laboratory Improvement Amendments (CLIA) certified assay via tumor biopsy tissue or circulating free DNA (cfDNA)

human epidermal growth factor receptor 2 (HER2) negative


Participants must have measurable disease as defined by RECIST 1.1 or evaluable bone-only disease with at least one lesion measuring 10 mm or greater in size. Participants with liver-only disease are not eligible due to the inherent hepatic uptake related to the radiopharmaceutical's hepatobiliary route of elimination.

Participants must have received at least 1 prior line of non-tamoxifen containing endocrine therapy in the metastatic setting or have had progression within 12 months of adjuvant non-tamoxifen endocrine therapy.

Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (See Appendix A)

Life expectancy of greater than 12 weeks.

Ability to take oral medications.

Informed consent: participant must be informed of the investigational nature of the study and must be able to sign a written informed consent.

Participants with central nervous system (CNS) metastases must be stable after therapy for CNS metastases (such as surgery, radiation, or stereotactic radiosurgery) for at least 1 month.

Participants must have adequate normal organ and bone marrow function as defined below:


Absolute neutrophil count >/= 1,000/mcL

Hemoglobin >/= 9.0 g/dL

Platelets >/= 100,000/mcL

Total bilirubin
AST (SGOT)/ ALT (SGPT)
Creatinine /= 50 mL/min

Applicable Disease Sites
Breast

Participating Institutions
UW Cancer Center at ProHealth; UW Health 1 S. Park Medical Center; UW Health Eastpark Medical Center; UW Health University Hospital