Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer.
Idoxifene is a novel selective estrogen receptor modulator. It has reduced agonist activity on breast and uterine cells compared with tamoxifen and antiproliferative effects in tamoxifen-resistant breast cancer cells. Previous studies have shown that a short course of treatment with other antiestrogens prior to surgery caused a significant reduction of the growth fraction when measured by immunohistological staining using the mouse monoclonal antibody Ki67. In this study, we assessed the effect of idoxifene on biological markers of cell proliferation (Ki67) and apoptosis (TdT-mediated dUTP-biotin nick end labeling), and estrogen and progesterone receptor (ER/PR) expression was also evaluated. Core-cut biopsies were obtained in 77 postmenopausal patients with primary breast cancer at diagnosis. Patients were randomized to 40 mg/day idoxifene or placebo for 14-21 days prior to obtaining a second biopsy sample at surgical resection. The percentage of Ki67-positive cells fell from a mean 19.7 +/- 2.7% (SE) to 13.4 +/- 3.4% in idoxifene-treated ER-positive tumors (n = 30; P = 0.0043), but there was no significant effect in placebo-treated ER-positive tumors (n = 27). No effect was seen on ER-negative tumors in either group. Idoxifene had no significant effect on apoptotic index but produced a statistically significant fall in idoxifene-treated ER immunohistochemical score and a small increase in PR that did not reach statistical significance (0.05 < P < 0.10). Idoxifene was well tolerated in all patients. Idoxifene has an antiproliferative effect in ER-positive but not ER-negative breast cancers, and no significant effect on apoptosis in the short-term.
Dowsett
M
M
Department of Academic Biochemistry, Royal Marsden Hospital, London, United Kingdom. mitch@icr.ac.uk
Dixon
J M
JM
Horgan
K
K
Salter
J
J
Hills
M
M
Harvey
E
E
D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004311:Double-Blind Method; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D010919:Placebos; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors
D015415:Biomarkers; D004965:Estrogen Antagonists; D019394:Ki-67 Antigen; D010919:Placebos; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C071362:idoxifene