Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia
Status:
Active, not recruiting
Trial end date:
2023-12-01
Target enrollment:
Participant gender:
Summary
The long-lasting phase of precursors of invasive cancer, i.e. dysplasia or intraepithelial
neoplasia (IEN), is particularly relevant among risk determinants. At present, about 15-20%
of all breast cancers are diagnosed in a non-invasive phase. Despite their good prognosis,
women with breast IEN (lobular and ductal intraepithelial neoplasia, LIN and DIN) have a
10-15/1000 annual risk of invasive disease (8-10 times the same age general population), and
thus represent an important target for chemoprevention. In the National Surgical Adjuvant
Breast and Bowel Project (NSABP-P1 trial), tamoxifen use at 20 mg/day was associated with a
86% reduction of invasive breast cancer 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
Lobular Carcinoma in situ (LCIS) (RR=0.44, 95% IC, 0.16-1.06). However, tamoxifen use in this
setting is hampered by serious adverse events attributable to its partial estrogenic
activity, such as increased risk of endometrial cancer and of venous thromboembolism, which
have significantly limited its broad use in chemoprevention.
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 the dose can be reduced up to 1 mg/day with no
loss of tamoxifen antiproliferative activity on breast cancer. By contrast, a dose of 5
mg/day does not increase endometrial proliferation and is associated with a decrease of the
estrogenic activity of tamoxifen on insulin like growth factor (IGF-I), sex hormone-binding
globulin (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 promising clinical activity of 5 mg/day of tamoxifen is
supported by an ongoing 2x2 phase IIb trial of low-dose tamoxifen and fenretinide in
premenopausal women, where tamoxifen lowers breast cancer events compared with placebo. The
cytochromeP450 2D6 (CYP2D6) enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen,
the most active metabolite of tamoxifen. The single nucleotide polymorphism (SNP) CYP2D6*4
(1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype and poor metabolizers
showed a trend to a higher risk to develop a breast event compared to wildtype.
Phase:
Phase 3
Details
Lead Sponsor:
Andrea DeCensi
Collaborators:
Associazione Italiana per la Ricerca sul Cancro European Institute of Oncology