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Comparison of the Short-Term Biological Effects of 7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17ß-diol (Faslodex) versus Tamoxifen in Postmenopausal Women with Primary Breast Cancer¹

Department of Surgery, Nottingham City Hospital, Nottingham, United Kingdom [J. F. R.]; Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff, Wales CF10 3XF [R. I. N., J. M. W. G.]; Department of Surgery, South Manchester University Hospital, Manchester M20 8LR, United Kingdom [N. J. B.]; Clinical Research Department, Christie Hospital National Health Service Trust, Manchester M20 4BX, United Kingdom [E. A.]; Department of Biochemistry, Royal Marsden Hospital, London SW3 6JJ, United Kingdom [M. Do.]; Bristol Royal Infirmary, Bristol DS2 8HW, United Kingdom [Z. R.]; Castle Hill Hospital Cottingham, East Yorkshire HU16 5JQ, United Kingdom [J. N. F.]; AstraZeneca, Macclesfield SK10 4TF, United Kingdom [A. W., A. E. W., C. M.]; and Department of Surgery, Western General Hospital, Edinburgh EH4 2XU, Scotland [M. Di.]

7-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17ß-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 tamoxifen-treated 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.

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