Comparison of the short-term biological effects of 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17 beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer

7 alpha-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-tr iene3,17 beta -diol (ICI 182,780; Faslodex) is a novel steroidal antiestrog en. This partially blind, randomized, multicenter study compared the effect s of single doses of long-acting ICI 182,780 with tamoxifen or placebo on e strogen receptor (ER alpha) and progesterone receptor (PgR) content, Ki67 p roliferation-associated antigen labeling index (Ki67L1), and the apoptotic index in the primary breast tumors of postmenopausal women. Previously untr eated patients (stages T-1-T-3; ER-positive or -unknown) were randomized an d received a single i.m. dose of ICI 182,780 50 mg (n = 39), ICI 182,780 12 5 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 w ith the MOLT were determined immunohistochemically in the matched pretreatm ent biopsy and the posttreatment surgical specimens. The apoptotic index wa s determined by terminal deoxynucleotidyltransterase-mediated dUTP-biotin n ick end labeling on the same samples. The effects of treatment on each of t hese parameters were compared using analysis of covariance. ICI 182,780 pro duced dose-dependent reductions in ER and PgR H-scores and in the K167L1. T he 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 t amoxifen (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 signi ficant increase in the PgR H-score relative to placebo, and consequently, a ll doses of ICI 182,780 produced PgR values that were significantly lower t han those in the tamoxifen-treated group. All doses of ICI 182,780 signific antly reduced Ki67L1 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 di d not alter the apoptotic index when compared with either placebo or tamoxi fen. Short-term exposure to ICI 182,780 reduces the ER alpha in breast tumo r cells in a dose-dependent manner by down-regulating ER protein concentrat ion. The reductions in tumor PgR content by ICI 182,780 demonstrate that IC I 182,780, unlike tamoxifen, is devoid of estrogen-agonist activity. Reduct ions in tumor cell proliferative activity (as indicated by MOM) show that I CI 182,780 is likely to have antitumor activity in the clinical setting.