Randomized, placebo controlled, phase III trial of low-dose tamoxifen in women with intraepithelial neoplasia

TPS1610 Background: Breast IntraEpithelial Neoplasia (IEN) is associated with a 8-10 fold increased risk of invasive disease, thus representing an important target for chemoprevention. The NSABP-P1 trial showed that tamoxifen (TAM) at 20 mg/day is associated with a 86% reduction of invasive breast cancer (BC) in women with previous atypical ductal hyperplasia (ADH) (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR=0.44, 0.16-1.06). However, TAM broad use in chemoprevention has been significantly hampered by the increased risk of endometrial cancer and of venous thromboembolism (VTE). We recently showed that a dose of 5 mg/day does not increase endometrial proliferation, is associated with a decrease of the estrogenic activity of TAM on IGF-I, SHBG and antithrombin-III, and attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of TAM. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of poor metabolizer phenotype which have been associated with a higher risk of a breast event compared to wildtype (Pharmacogenomics J. 2011;11:100-7). Methods: A randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of 5 mg/day TAM vs. placebo for 3 years in women with previous IEN (LIN 2-3 and ER+ or unknown DIN 1b-3). In Europe TAM is not registered in women with prior DCIS. 1400 women are needed to detect 50% reduction in the incidence of BC in the TAM arm (80% power, 1-sided 5% α error). Secondary endpoints are: incidence of other non-invasive breast disorders, endometrial cancer, clinical bone fractures, cardiovascular events, VTE events, and clinically manifest cataract. Pharmacogenetic endpoints includes the association between CYP2D6 genotype and modulation of biomarkers of TAM efficacy and safety (circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes) and clinical events. As of February 5, 2013, 18 enrolment centers have been activated and n=338 women have been randomized. No suspected unexpected serious adverse reactions were registered. Clinical trial information: NCT01357772.