Randomized Double-Blind 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in High-Risk Premenopausal Women

Abstract

A B S T R A C T PurposeTamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. Patients and MethodsA total of 235 premenopausal women with pT1mic/pT1a breast cancer (n ϭ 21), or intraepithelial neoplasia (IEN, n ϭ 160), or 5-year Gail risk Ն 1.3% (n ϭ 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. ResultsDuring the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n ϭ 48) was 3.5% Ϯ 1.0%, 2.1% Ϯ 0.8%, 4.7% Ϯ 1.3%, and 5.2% Ϯ 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen ϫ fenretinide adverse interaction P ϭ .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. ConclusionDespite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

IGF-1 and risk of additional breast cancer in the WHEL study

“…Furthermore, our results are not inconsistent with a retrospective study of 130 African Americans and Latino breast cancer patients where plasma IGF1 levels were not associated with increased risk of breast cancer recurrence among postmenopausal women (Vadgama et al 1999), although a significant association was found among premenopausal women. In a recent trial that investigated the influence of tamoxifen on IGF1 among 235 premenopausal breast cancer women (Decensi et al 2009), tamoxifen Table 3 The sample size, median (IQR), mean (S.E.M. ), and hazard ratio (stratified by matched pairs) for IGF1 as a predictor of additional breast cancer events (recurrence or new primary) in WHEL among the full and postmenopausal samples…”

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

“…Conversely, in UM or even EM, the tamoxifen dose may be personalized to a lower range, for example, 5-10 mg per day, because we showed that low-dose tamoxifen maintains antiproliferative activity on BC whereas toxicity may be reduced. [38][39][40] CYP2D6 genotyping could be evaluated together with serum endoxifen levels and biomarkers of tamoxifen activity and safety (for example, mammographic density, IGF-I, SHBG, lipids and endometrial thickness) after a short period of treatment. Such interaction may be a key point to personalized treatment and dose, in a manner that is similar to monitoring statin therapy with cholesterol levels and biphosphonates with bone density.…”

Breast composition: Measurement and clinical use

“…An important characteristic of breast density is that it is reducible, [64][65][66][67][68][69] and preliminary studies have shown that breast density may serve as a biomarker for the effect of preventive interventions on breast cancer risk. 17 The first International Breast Cancer Intervention Study (IBIS) trial of Tamoxifen TM versus placebo showed that women in the Tamoxifen group who had a 10% or greater reduction in breast density demonstrated a 63% reduction in breast cancer risk but those who experienced less than 10% breast density reduction showed no risk reduction.…”