Preliminary results of a randomized phase iib double-blind 2x2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention

Background and Purpose: Low-dose tamoxifen and fenretinide, a vitamin A derivative, have both shown to modulate biomarkers of breast cancerogenesis in premenopausal women. In the present study we are investigating whether the combination of the two drugs have a synergistic effect on putative surrogate biomarkers of breast cancerogenesis in premenopausal women at increased risk for breast cancer. Additionally, we are interested in studying the safety and the endometrial effects of the drug combination. Patients and Methods: Between October 1998 and April 2002, 235 women were randomly assigned in a double-blind 4-arm trial to tamoxifen 5 mg/day, fenretinide 200 mg/day, both agents, or placebo for 2 years. All subjects are being followed for three additional years. The primary endpoints were the changes in circulating insulin-like growth factor-I (IGF-I) and computerized mammographic percent density. Results: Subjects were included because of a previously excised DCIS (57%), LCIS (13%), micro-invasive breast cancer (7%), or a 5-year Gail risk ≥1.3% (23%). There was a 15% reduction on IGF-I levels on tamoxifen, as early as after 6 months of treatment, while the reduction on fenretinide was about 2%. Recruitment was stopped earlier, based on the lack of a synergistic interaction of the two drugs on plasma IGF-I levels. After a median follow-up of 40 months, 35 subjects dropped the study for refusal (n=19) or adverse events (n=16). So far, 24 primary or recurrent breast cancers have been observed, with no difference among arms. Of the three serious adverse events, one stage-I endometrial cancer occurred in the fenretinide arm, one optic nerve ischemia and one deep venous thrombosis occurred in the tamoxifen arm. There was no increased endometrial thickness and no difference in endometrial polyps among the four arms. Conclusions: The combination of low-dose tamoxifen and fenretinide is safe and well tolerated, but is not synergistic in lowering circulating IGF-I levels. Low-dose tamoxifen does significantly reduces IGF-I levels and does not affect endometrial proliferation. Mammographic percent density is currently under evaluation and updated results will be presented at the conference.