Molecular Imaging of Fulvestrant Effects on Availability of ER Binding Sites

• Visualize and quantify changes in FES uptake in tumor lesions during fulvestrant 500mg therapy [ Time Frame: baseline; 1 month; 3 months ] [ Designated as safety issue: No ]

  FES-uptake will be calculated for all tumor lesions at baseline, 1 month and 3 months.

  Changes between FES-uptake during fulvestrant therapy will be calculated for:

  • 3 months minus baseline
  • 3 months minus 1 month
  • 1 month minus baseline
  
  
• To evaluate the proportion of patients with an incomplete down-regulation/occupancy of ERs as determined by FES-PET [ Time Frame: baseline, 1 month and 3 months ] [ Designated as safety issue: No ]

  FES-uptake will be calculated for all tumor lesions at baseline, after 1 month and after 3 months.

  Incomplete down-regulation/ occupancy of ERs is defined as 1) an absolute SUV> 1.5, and 2) a relative decrease in SUV of <75% during fulvestrant therapy.

  The proportion of patients that match these criteria will be given for:

  • 1 month minus baseline
  • 3 months minus baseline
  
  

• The feasibility to quantify changes in FES-uptake in liver metastases [ Time Frame: baseline, 1 month and 3 months ] [ Designated as safety issue: No ]
  Liver metastases detected on PET/CT will be serially quantified at the 3 different time points to evaluate the feasibility to quantify liver lesions on FES-PET/CT
  
  
• to correlate FES-PET results to patient and tumor response on fulvestrant therapy [ Time Frame: baseline, 1 month, 3 months ] [ Designated as safety issue: No ]

  Patients will be categorized as responders and non-responders by standard follow-up (monthly visits, 3-monthly CT, other techniques when indicated).

  The predictive value of FES-PET for response to fulvestrant will be calculated for:

  • baseline FES-uptake
  • changes in FES-uptake from baseline to 1 month
  • changes in FES-uptake from baseline to 3 months

  Lesion-based evaluation will be performed for measurable lesions as defined by RECIST criteria, and changes in diameter will be correlated to changes in FES-uptake at:

  • 1 month minus baseline
  • 3 months minus baseline
  
  
• Explorative analysis to correlate several factors (among which tumor burden, ER-expression, fulvestrant levels, estradiol levels, patient weight) to FES uptake will be performed. [ Time Frame: baseline, 1 month and 3 months ] [ Designated as safety issue: No ]
  Explorative analysis to correlate several factors at different timepoints (baseline, 1 month, 3 months) to FES uptake.
  
  

The estrogen receptor (ER) is expressed in approximately 70% of the breast carcinomas. In these patients signaling via the ER induces proliferation and cell survival of malignant cells. Fulvestrant can inhibit this signaling route by blocking the receptor and decreasing ER-expression by increasing its turn-over rate.

The historical standard dose of fulvestrant was 250mg every 28 days i.m.; however studies performing serial biopsies showed that ER-downregulation was suboptimal. Recently the standard dose has been set to 500mg i.m. on day 1; 14; 28 and every 28 days thereafter. Although slightly more effective than the 250mg dose, still questions remain with respect to the required dose to establish maximal downregulation of ER-signaling.

Immunohistochemistry only provides static information, i.e. the level of ER-expression. However, dynamic information evaluating the effects of fulvestrant on occupancy of ERs, may also be valuable.

Whole-body imaging of the availability of ER binding sites using FES-PET may prove valuable to evaluate the effects of fulvestrant on the ER non-invasively in individual patients. This potentially allows adjustment of dosing in individual patients to aid therapy efficacy.

In this pilot-study we will evaluate 15 metastatic breast cancer patients. All patients will undergo FES-PET/CT at baseline, FES-PET after 1 month, and FES-PET/CT after three months. Hormone- and fulvestrant levels will be measured in all patients. Whenever possible, tumor biopsies will be performed to correlate to FES-PET results.