Long-term effects of fenretinide, a retinoic acid derivative, on the insulin-like growth factor system in women with early breast cancer.
High insulin-like growth factor-I (IGF-I) levels are associated with an increased risk of breast cancer in premenopausal women. Because the synthetic retinoid fenretinide showed a beneficial effect on second breast cancers in premenopausal women in a Phase III trial, we studied its long-term effects on IGF-I levels. We measured, at yearly intervals for up to 5 years, the circulating levels of IGF-I, IGF binding protein (BP)-3, and their molar ratio in 60 subjects < or = 50 years of age and 60 subjects > 50 years of age allocated either to fenretinide or no treatment. In women < or = 50 years of age, measurements of IGF-II, IGFBP-1, and IGFBP-2 were also performed. The associations between biomarkers and drug or metabolite plasma concentrations were also investigated. All biomarkers were relatively stable over 5 years in the control group. Compared with controls and after adjustment for baseline, treatment with fenretinide for 1 year induced the following changes: IGF-I, -13% [95% confidence interval (CI), -25 to 1%] in women < or = 50 years of age and -3% (95% CI, -16 to 13%) in women > 50 years of age; IGFBP-3, -4% (95% CI, -12 to 6%) in both age groups; IGF-I:IGFBP-3 molar ratio, -11% (95% CI, -22 to 1%) in women < or = 50 years of age and 1% (95% CI, -11 to 16%) in women > 50 years of age. These effects were apparently maintained for up to 5 years, although fewer samples were available as time progressed. No change in other IGF components was observed. Drug and metabolite concentrations were negatively correlated with IGF-I and IGF-I:IGFBP-3 molar ratio in women < or = 50 years of age. Fenretinide induces a moderate decline of IGF-I levels in women < or = 50 years of age. The association between IGF-I change and the reduction of second breast cancers in premenopausal women warrants further study.
Decensi
A
A
Division of Chemoprevention, European Institute of Oncology, 20141 Milan, Italy. andrea.decensi@ieo.it
Johansson
H
H
Miceli
R
R
Mariani
L
L
Camerini
T
T
Cavadini
E
E
Di Mauro
M G
MG
Barreca
A
A
Gonzaga
A G
AG
Diani
S
S
Sandri
M T
MT
De Palo
G
G
Formelli
F
F
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D004334:Drug Administration Schedule; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage*; D005500:Follow-Up Studies; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000187:drug effects*; D008134:Long-Term Care; D008875:Middle Aged; D009367:Neoplasm Staging; D012016:Reference Values; D016896:Treatment Outcome; D014212:Tretinoin / Q000037:antagonists & inhibitors*
D014408:Biomarkers, Tumor; D017313:Fenretinide; D014212:Tretinoin; D007334:Insulin-Like Growth Factor I