A randomized double-blind 2x2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women. Updated results.

A142

Purpose: Premenopausal women (n=235) with DCIS or at increased risk by the Gail model were randomly assigned in a double-blind 4-arm trial to tamoxifen (T) 5 mg/day, fenretinide (F) 200 mg/day, T+F, or placebo for 2 years. In a preliminary report, we showed that T+F is safe but not synergistic in lowering IGF-I levels. Patients and Methods: The present analysis updates data, after a median of 54 months, on plasma IGF-I, IGF-I/IGFBP-3 ratio and mammographic %density (primary endpoints), gynecological and other adverse events, and breast cancer events. Results: Women with DCIS/micro T1 (n=181) had higher baseline mean IGF-I and IGF-I/BP-3 (10% higher) than those in the Gail strata (n=54, p=0.07). T induced a 20% reduction of IGF-I and IGF-I/BP-3 up to 24 months in the DCIS strata, and a 8-9% reduction in the Gail strata, whereas F only slightly lowered IGF levels, with no synergism over T. T lowered mammographic %density by 21% (16-26%) at 24 months, compared with 11% (3-20%) on placebo (p=0.026), whereas F did not change it. There were no additional SAE. T increased endometrial thickness and uterine volume only in women who became postmenopausal during the trial, whereas F induced a significant reduction of endometrial thickness and uterine volume. There was no difference among arms in endometrial polyps or hyperplasia, ovarian cyst number, and myoma. Women with higher baseline IGF-I had a greater risk of breast cancer than women in the lowest quartile (p-trend=0.08). Of a total of 42 breast cancers, the annual rate of events (%±SD) was 3.8±1.3 on T, 2.8±1.1 on F, 5.4±1.5 on T+F, and 5.5±1.5 on placebo. Conclusions: The combination of T+F is safe but, contrary to animal models, does not seem to be synergistic on breast cancer events. Low-dose T lowers IGF-I more profoundly in women with prior DCIS than in well women, and decreases mammographic density to the same extent than the standard dose. F exhibited antiestrogenic effects at uterine level which might explain its preventive activity. Plasma IGF-I is a risk biomarker of breast cancer in a clinical trial. Follow-up is ongoing to better elucidate these findings.