Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer

Abstract

Summary We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-' and during the sixth month was 12.6 ng ml-l. The AUCs were 140.5 and 206.8 ng day ml-' on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Sideeffects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed 'no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

C‐myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells

“…15,16 The pure antiestrogen ICI 182,780 (ICI), however, has been reported to be effective even in patients with hormone-independent breast cancer. 17 Several mechanisms for antiestrogen action have been proposed, including the inhibition of c-myc gene expression, 12,13 downregulation of the estrogen receptor (ER), impairment of ER dimerization and ER shuttling. 15,16 In addition, ICI attenuated the cells' response to growth factors, however, it is unclear if these effects are dependent upon ER function.…”

A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers

“…Moreover, magnetic resonance imaging of the uterus in ovarectomised monkeys also suggests that fulvestrant is an effective antioestrogen (Dukes et al, 1992(Dukes et al, , 1993. The data surrounding the clinical potential of fulvestrant in postmenopausal patients with breast cancer have been encouraging (Defriend et al, 1994;Howell et al, 1996Howell et al, , 2002Osborne et al, 2002). In this group of patients, fulvestrant inhibits tumour cell proliferation associated with a profound decrease in immunocytochemically detectable ER protein (Defriend et al, 1994;Robertson et al, 2001).…”

“…In this group of patients, fulvestrant inhibits tumour cell proliferation associated with a profound decrease in immunocytochemically detectable ER protein (Defriend et al, 1994;Robertson et al, 2001). One small phase II trial, involving 19 postmenopausal patients with tamoxifen refractory disease, suggested that fulvestrant might have fewer side effects in terms of menopausal symptoms than tamoxifen, with no negative effects being observed on the liver, brain or genital tract (Howell et al, 1996). The pharmacokinetic data associated with these studies in breast cancer patients showed that monthly intramuscular (i.m.)…”

“…The pharmacokinetic data associated with these studies in breast cancer patients showed that monthly intramuscular (i.m.) injections of fulvestrant 250 mg maintained detectable plasma levels of drug over a period of 28 days and resulted in a marked reduction in levels of ER protein (Howell et al, 1996;Robertson et al, , 2001. Fulvestrant was shown to be at least as effective as the aromatase inhibitor anastrozole in terms of time to progression, and secondary endpoints including objective response and clinical benefit, in two randomised phase III trials in postmenopausal women with locally advanced or metastatic breast cancer who had progressed following prior endocrine therapy for either advanced or early breast cancer (Howell et al, 2002;Osborne et al, 2002).…”

“…There has been no suggestion to date that fulvestrant produces ovarian or endometrial stimulation in postmenopausal women (Defriend et al, 1994;Howell et al, 1996) and the lack of agonist activity associated with fulvestrant suggests an improved efficacy and tolerability profile relative to tamoxifen. The present trial was conducted in healthy postmenopausal volunteers to specifically assess the pharmacological effects of fulvestrant on the postmenopausal endometrium.…”