Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.
OBJECTIVE
Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer.


METHODS
In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers.


RESULTS
In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry.


CONCLUSIONS
Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.
Fabian
Carol J
CJ
University of Kansas Medical Center, Kansas City, Kansas 66160, USA. cfabian@kumc.edu
Kimler
Bruce F
BF
Anderson
Julie
J
Tawfik
Ossama W
OW
Mayo
Matthew S
MS
Burak
William E
WE
O'Shaughnessy
Joyce A
JA
Albain
Kathy S
KS
Hyams
David M
DM
Budd
G Thomas
GT
Ganz
Patricia A
PA
Sauter
Edward R
ER
Beenken
Samuel W
SW
Grizzle
William E
WE
Fruehauf
John P
JP
Arneson
Dora W
DW
Bacus
James W
JW
Lagios
Michael D
MD
Johnson
Karen A
KA
Browne
Doris
D
D016588:Anticarcinogenic Agents / Q000633:toxicity; D001706:Biopsy; D001943:Breast Neoplasms / Q000517:prevention & control* / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000097:blood; D005260:Female; D006728:Hormones / Q000097:blood; D006801:Humans; D008875:Middle Aged; D018579:Patient Selection; D010880:Piperidines / Q000633:toxicity*; D017698:Postmenopause; D012086:Reoperation; D020845:Selective Estrogen Receptor Modulators / Q000633:toxicity*; D013876:Thiophenes / Q000633:toxicity*
D016588:Anticarcinogenic Agents; D006728:Hormones; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; D004970:Estrone; D004958:Estradiol; C115121:LY 353381