Safety and efficacy of HRT and low-dose tamoxifen in a phase II trial (HOT): Analysis of mammographic density and endometrial thickness.

Abstract

1527 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer (BC) incidence by approximately 40%, but serious adverse events are a barrier to its broad use. The Italian trial in hysterectomized women showed a positive risk/benefit ratio in the subgroup of hormone replacement therapy (HRT) users in the T arm, with fewer BC and no cardiovascular diseases (CVD) excess. In a dose-ranging study, T 5 mg/day and HRT showed a safe gynecological profile and did not increase menopausal symptoms. Moreover, in a preoperative trial 5 mg/day of T maintained the same antiproliferative effects as the standard dose. We are conducting a multicentric, phase III trial of T 5 mg/day in HRT users: the HOT study. Methods: Current or de novo HRT users were randomized to T 5 mg/day or placebo for 5 years. Here we present the planned analysis on two study subgroups on mammographic density (MxD) modifications and TVUS endometrial changes. MxD was measured at baseline and year 1 using a computer assisted method and was centrally measured by a single trained radiologist. TVUS was performed at baseline and repeated with an endometrial biopsy after 3 years of treatment. Results: MxD was evaluated in 120 subjects. At 12 months T induced a non-significant reduction of MxD, with a significant trend in women aged <55 (relative difference between HRT+placebo and HRT+T = +5.5 vs−2.8; p=0.001). TVUS was performed in 176 subjects. Endometrial thickness increased in the T arm compared to placebo: we observed a reduction of−0.6 mm in the placebo arm and an increase of 1.5 mm in the T arm (p<.0001). There were only 4 endometrial polyps in the T arm, and no cases of endometrial hyperplasia or cancer on 142 biopsies performed. Conclusions: These findings support the safety of the association of HRT and low dose T in early postmenopausal women. Furthermore 5 mg a day of T showed a significant trend to a MxD reduction, further supporting a significant biological activity at this dosage. The clinical results of the main clinical trial are expected within a year.