Comparison of the Short-Term Biological Effects of 7 -[9-(4,4,5,5,5- pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17 -diol (Faslodex) versus Tamoxifen in Postmenopausal Women with Primary Breast Cancer

7 -[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene3,17 -diol (ICI 182,780; Faslodex) is a novel steroidal antiestrogen. This partially blind, randomized, multicenter study compared the effects of single doses of long-acting ICI 182,780 with tamoxifen or placebo on estrogen receptor (ER ) and progesterone receptor (PgR) content, Ki67 proliferation-associated antigen labeling index (Ki67LI), and the apoptotic index in the primary breast tumors of postmenopausal women. Previously untreated patients (stages T1–T3; ER-positive or -unknown) were randomized and received a single i.m. dose of ICI 182,780 50 mg (n 39), ICI 182,780 125 mg (n 38), or ICI 182,780 250 mg (n 44) or oral tamoxifen 20 mg daily (n 36) or matching tamoxifen placebo (n 43) for 14–21 days before tumor resection surgery with curative intent. The ER and PgR H-scores, together with the Ki67LI were determined immunohistochemically in the matched pretreatment biopsy and the posttreatment surgical specimens. The apoptotic index was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling on the same samples. The effects of treatment on each of these parameters were compared using analysis of covariance. ICI 182,780 produced dose-dependent reductions in ER and PgR H-scores and in the Ki67LI. The reductions in ER expression were statistically significant at all doses of ICI 182,780 compared with placebo (ICI 182,780 50 mg, P 0.026; 125 mg, P 0.006; 250 mg, P 0.0001), and for ICI 182,780 250 mg compared with tamoxifen (P 0.024). For PgR H-score, there were statistically significant reductions after treatment with ICI 182,780 125 mg (P 0.003) and 250 mg (P 0.0002) compared with placebo. In contrast, tamoxifen produced a significant increase in the PgR H-score relative to placebo, and consequently, all doses of ICI 182,780 produced PgR values that were significantly lower than those in the tamoxifentreated group. All doses of ICI 182,780 significantly reduced Ki67LI values compared with placebo (ICI 182,780 50 mg, P 0.046; 125 mg, P 0.001; 250 mg, P 0.0002), but there were no significant differences between any doses of ICI 182,780 and tamoxifen. ICI 182,780 did not alter the apoptotic index when compared with either placebo or tamoxifen. Short-term exposure to ICI 182,780 reduces the ER in breast tumor cells in a dose-dependent manner by down-regulating ER protein concentration. The reductions in tumor PgR content by ICI 182,780 demonstrate that ICI 182,780, unlike tamoxifen, is devoid of estrogen-agonist activity. Reductions in tumor cell proliferative activity (as indicated by Ki67LI) show that ICI 182,780 is likely to have antitumor activity in the clinical setting. INTRODUCTION Estrogens act as endocrine growth factors for at least one-third of breast cancers (1), and their effects are mediated via the ER pathway. Several approaches have been adopted to treat hormone-sensitive breast cancer. In premenopausal women these include reducing circulating estrogen by ovarian ablation or by inhibiting ovarian estrogen production. In postmenopausal women, the mainstays of therapy are the prevention of estrogen binding to its receptor using an antiestrogen or lowering estrogen levels with aromatase inhibitors. The antiestrogen tamoxifen is the most widely used hormonal treatment for all stages of breast cancer (2). However, tamoxifen possesses partial agonist activity which has positive effects on bone (3, 4) and blood lipids (5), but which also has unwanted side effects, including increased endometrial proliferation (6), a small increase in the risk of endometrial cancer (7–9), tumor flare at the start of treatment (10), and tamoxifen-mediated tumor stimulation upon progression (11). Currently, there are two other clinically available nonsteroidal, mixed agonist/antagonist antiestrogens, toremifene, which is used in the treatment of breast cancer (12), and raloxifene, which is being used in the management of osteoporosis (13). These two agents, together with tamoxifen, comprise a group of compounds that are described as SERMs (14). No new SERM has yet provided significant advantages over tamoxifen in the treatment of breast cancer in terms of either efficacy or tolerability, and all SERMs discovered to date show some degree of partial agonist activity. Furthermore, crossresistance between the new SERMs and tamoxifen may limit their application in advanced disease after adjuvant tamoxifen treatment (15). Despite the potential advantages of the partial agonist properties of the SERMs, a drug that acts as a nonagonist (pure) antiestrogen may be an important step toward improving breast cancer treatment (16). Fulvestrant (Faslodex), formerly known as ICI 182,780, is a novel estrogen antagonist that, unlike tamoxifen, has no estrogen-agonist activity (Fig. 1). Preclinical and early clinical studies (17–40) suggest that ICI 182,780 has biological effects indicative of improved clinical efficacy in the treatment of breast cancer. The main features are ER down-regulation, antiproliferative activity, induction of apoptosis, lack of cross-resistance with tamoxifen, and the absence of ERagonist activity. ICI 182,780 has a binding affinity for the ER that is 100 times Received 11/9/00; accepted 7/25/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This trial was sponsored and funded by AstraZeneca Pharmaceuticals (Macclesfield, United Kingdom). 2 To whom requests for reprints should be addressed, at Department of Surgery, Nottingham City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom. 3 The abbreviations used are: ER, estrogen receptor(s); SERM, selective estrogen receptor modulator; ICI 182,780, 7 -[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra1,3,5, (10)-triene-3,17 -diol; PgR, progesterone receptor(s); Ki67LI, Ki67 proliferationassociated antigen labeling index; AI, apoptotic index; DAB, diaminobenzidine tetrahydrochloride; ANCOVA, analysis of covariance; ICA, immunocytochemical assay; NRS, normal rabbit serum.