A randomized 2x2 biomarker trial of low-dose tamoxifen and fenretinide in premenopausal women at-high risk for breast cancer

Tamoxifen and fenretinide have been shown to reduce breast cancer incidence in pre-menopausal women at increased risk. Their combination is synergistic in reducing mammary tumor formation in animal models. We conducted a double-blind placebo controlled trial in women at high risk to determine whether there is an interaction between the two agents on putative breast cancer surrogate endpoint biomarkers. The primary outcome measures were the change in insulin-like growth factor-I (IGF-I) and in mammographic percent density after 2 years of intervention. Additional endpoints include changes in endometrial thickness and proliferation, presence of ovarian cysts and atypia in random fine needle aspirates. Between October 1998 and April 2002, 235 women were randomized either to tamoxifen 5 mg/d, or fenretinide 100 mg bid, or both agents, or placebo for 2 years. Subjects were included because of a previously excised DCIS (57%), LCIS (13%), micro-invasive breast cancer (7%), or because of a 5-year Gail risk ≥1.3% (23%). The mean±SD age is 46.2±4.7 years and the mean±SD BMI is 23.5±3.5 kg/m2. Recruitment was prematurely stopped by the DSMB based on the lack of an interaction between agents on the primary endpoint biomarkers. After a median follow-up of 38 months, 40 subjects are still on treatment, 35 have dropped the study either for refusal (19) or adverse events (16). Two serious adverse events occurred: one stage I endometrial cancer in the fenretinide arm and one optic nerve ischemia in the tamoxifen arm. A preliminary safety analysis on endometrial effects showed no increase in endometrial thickness and no difference in endometrial polyps among the four arms. Twenty-seven primary or recurrent breast cancers have been observed. Treatment compliance as assessed by pill count and self-reporting show a greater than 80% adherence in >90% of the subjects. These data show that both agents are safe. Biomarker measurements are ongoing and preliminary results in terms of efficacy and safety will be presented at the conference.