Abstract A56: Randomized, placebo-controlled, phase III trial of low-dose tamoxifen in women with intraepithelial neoplasia
Authors: Zanardi Silvia , Branchi Daniela , Ponti Antonio , Cruciani Giorgio , D'Amico Cosimo , Cortesi Laura , Falcini Fabio , Gulisano Marcella , Giardina Giovanni , Canavese Giuseppe , Calabrese Massimo , DeCensi Andrea , Puntoni Matteo , Campora Sara , Argusti Alessandra , Bonanni Bernardo , Guerrieri-Gonzaga Aliana , Johansson Harriet , Pacquola Maria Grazia , D'Aiuto Giuseppe 
Published: June 2012

Abstract
Rationale: The annual risk of invasive disease in women with breast intraepithelial neoplasia (IEN) is about 8–10 times higher than in the general population, thus IEN can be considered an important target for chemoprevention strategies. The NSABP-P1 trial showed that women with LCIS randomized to tamoxifen at 20 mg/day reduced their risk of invasive breast cancer by 56% (RR=0.44, 0.16–1.06) and women with previous ADH by 86% (RR=0.14, 95% IC, 0.03–0.47). The issue was the increased risk of endometrial cancer and of venous thromboembolism, which significantly limited tamoxifen broad use in a chemoprevention setting. To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on IGF-I, SHBG and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day 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 tamoxifen. The SNP CYP2D6*4 (1846G&gt;A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype which have been associated with a higher risk to develop a breast event compared to wild-type (Serrano D et al. Pharmacogenomics J. 2011;11:100–7).
Study design and enrollment report: We designed a chemoprevention multicenter randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of tamoxifen at daily dose of 5 mg or placebo for a total treatment duration time of 3 years, to reduce breast cancer incidence in women with previous IEN (LIN 2–3 and ER-positive or unknown DIN 1b-3). At present in Europe no standard treatment exists to treat these patients, since tamoxifen is not registered for women with prior DCIS (DIN 2–3). With an 80% power and a 1-sided 5% alpha level, we calculated a total sample size of 1400 women to detect a 50% reduction in incidence of breast cancer (Hazard Ratio = 0.5) in the tamoxifen arm. Secondary endpoints are: incidence of other non-invasive breast disorders (i.e., LIN, ductal atypical hyperplasia), endometrial cancer, clinical bone fractures, cardiovascular events, venous thromboembolic events and clinically manifest cataract. We planned also a pharmacogenetic sub-study to assess whether CYP2D6 genotype can explain modulation on surrogate biomarkers of tamoxifen efficacy and safety, such as circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes, but also clinical events.
As of August 1, 2011, 15 enrolment centers have been activated, n=421 women have been screened and n=166 have been randomized, 181 women refused to participate, 74 women were excluded for ineligibility. Main ineligibility reasons were: ER negative IEN (9 women), cataract (8), previous neoplasms (7), previous use of tamoxifen (6) and age limits (5). Only 1 serious adverse event (venous thrombosis) was registered. No suspected unexpected serious adverse reactions were registered.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A56.