THE SYNTHETIC RETINOID FENRETINIDE LOWERS PLASMA INSULIN-LIKE GROWTH FACTOR-I LEVELS IN BREAST-CANCER PATIENTS

We studied the effect of fenretinide [N-(4-hydroxyphenyl)retinamide (4 -HPR)], a synthetic analogue of retinoic acid, on plasma insulin-like growth factor I (IGF-I) levels in a consecutive cohort of stage I brea st cancer patients belonging to a randomized phase III trial of breast cancer chemoprevention. Thirty-two women receiving 4-HPR 200 mg/daily and 28 untreated controls entered the study. IGF-I levels were determ ined, after acid-ethanol extraction, on plasma obtained at randomizati on and after a mean time of 10.8 +/- 0.3 months. At baseline, there wa s no difference in IGF-I levels between the two groups [152.9 +/- 9.4 versus 159.2 +/- 7.0 ng/ml in treated and control group (P = 0.59), re spectively]. After follow-up time, while plasma IGF-I levels were unch anged in control patients (163.3 +/- 7.4 ng/ml; P = 0.5), they were si gnificantly reduced to 134.6 +/- 8.1 ng/ml in the patients treated wit h 4-HPR (P = 0.003 and P = 0.011 versus baseline and control values, r espectively). Multiple regression analysis showed that treatment was t he only determinant of IGF-I decline. Moreover, the interaction betwee n treatment and age was significant, in that the decrease of IGF-I lev els induced by 4-HPR administration was much more pronounced in younge r patients, while an age-related decline was observed in controls. We conclude that the synthetic retinoid 4-HPR lowers circulating IGF-I le vels in early breast cancer patients. Although the importance of this observation for the clinical prevention of breast cancer remains to be established, it further substantiates the rationale of the combinatio n of 4-HPR with tamoxifen, which is known to decrease IGF-I as well an d to act synergistically with the retinoid in preclinical models.