Oestrogen receptor expression in human breast cancer during long-term fulvestrant treatment

Abstract

536 Background: Fulvestrant (Faslodex) is an estrogen receptor (ER) antagonist with no agonist activity that reaches steady-state levels after 3–5 monthly intramuscular (IM) injections. Fulvestrant for 14–21 days prior to surgery for primary breast cancer (BC) caused a dose-dependant reduction in ER (Cancer Res 2001;61:6739–46). Here, we examine the long-term changes in ER levels in patients receiving fulvestrant as first-line endocrine therapy for locally advanced/metastatic BC. Methods: 30 patients with lesions suitable for biopsy were recruited. Fulvestrant was given as a monthly 250 mg IM injection. Biopsies were taken pre-treatment, after 4 weeks and 6 months of treatment, and at disease progression (PD). Changes in ER levels were analyzed using SPSS analysis. Tumors were assessed every 3 months using UICC criteria. Results: 23 patients had evaluable disease at 6 months: 5 had PD and 18 had clinical benefit (CB; complete response, n=1; partial response, n=5; stable disease ≥24 weeks, n=12). Overall, ER downregulation was seen at 4 weeks (p=0.016) and at 6 months (p=0.011) compared with pre-treatment samples. There was a trend for continued downregulation from 4 weeks (mean Hscore 170.8 [range 50–280]) to 6 months (mean Hscore 132.33 [range 0–260]). In patients who progressed de novo (n=5), there was no significant reduction in ER (p=0.461). In patients achieving CB, ER downregulation was statistically significant (p=0.029, 4 weeks; p=0.011, 6 months). In both groups (CB and PD) ER was present at the time of PD/resistance. Conclusion: This is the first dataset to show continued downregulation of the ER beyond the presurgical period and confirms that fulvestrant can maintain ER suppression for an extended time. At the current clinical dose (250 mg), fulvestrant showed good clinical activity. The presence of ER at PD supports the use of further endocrine therapies and also provides insights into possible mechanisms of resistance through growth factor receptor cross-talk. Ongoing studies are investigating whether loading dose/high-dose regimens lead to earlier/increased ER downregulation and further improvement of clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Astrazeneca AstraZeneca AstraZeneca