Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients.
OBJECTIVE
Raloxifene is a selective estrogen receptor (ER) modulator approved for prevention and treatment of postmenopausal osteoporosis. This is an exploratory study of raloxifene in primary breast cancer patients.


METHODS
Postmenopausal women (50-80 years of age), with histological or cytological diagnosis of stage I or II primary breast cancer, were randomly assigned to 14 days of placebo, 60 mg/day raloxifene, or 300 mg twice daily (600 mg/day) of raloxifene. A core biopsy of the primary tumor was obtained before therapy, and a representative sample of the excised tumor was obtained from the operative specimen after treatment. Paired baseline and endpoint biopsies from each patient were analyzed for Ki67, apoptosis, and estrogen and progesterone receptors. Treatment group differences in efficacy measurements were primarily evaluated for baseline-to-endpoint change and percentage change using a one-way ANOVA with treatment as the fixed effect.


RESULTS
Of 167 enrolled patients, 143 had evaluable efficacy data. Most breast cancer cases were invasive (98.6%), stage I (76.6%), and ER-positive (83.2%). In patients with ER-positive tumors, Ki67 increased 7% from baseline on placebo and decreased by 21% on 60 mg/day raloxifene (P = 0.015 versus placebo) and by 14% on 600 mg/day raloxifene (P = 0.064 versus placebo). Raloxifene did not affect apoptosis. ER decreased significantly with 60 mg/day or 600 mg/day raloxifene compared with placebo (P < 0.01 for each comparison). Raloxifene had no statistically significant effects on Ki67 among patients with ER-negative tumors. There were no treatment differences in adverse events.


CONCLUSIONS
In this exploratory trial, 60 mg/day raloxifene showed a significant antiproliferative effect in ER-positive breast cancer, demonstrated by the decrease in Ki67, with no effect in ER-negative cancer. This provides support for raloxifene having a breast cancer preventive effect in postmenopausal women.
Dowsett
M
M
Royal Marsden NHS Trust, London, England SM2 5PT.
Bundred
N J
NJ
Decensi
A
A
Sainsbury
R C
RC
Lu
Y
Y
Hills
M J
MJ
Cohen
F J
FJ
Veronesi
P
P
O'Brien
M E
ME
Scott
T
T
Muchmore
D B
DB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D019394:Ki-67 Antigen / Q000187:drug effects*; D008875:Middle Aged; D017698:Postmenopause; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride