Breast ductal lavage for biomarker assessment in high risk women: rationale, design and methodology of a randomized phase II clinical trial with nimesulide, simvastatin and placebo.

BACKGROUND: Despite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation. METHODS-DESIGN: From 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up. DISCUSSION: This is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial. TRIAL REGISTRATION: (ClinicalTrials.gov Identifier: NCT01500577).

Quality of life assessment in a chemoprevention trial: fenretinide and oral or transdermal HRT.

BACKGROUND: Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) relief menopause symptoms, but may increase breast cancer risk, while the effects of transdermal estradiol (E2) and MPA are less known. In previous studies, fenretinide decreased second breast malignancies in premenopausal but not in postmenopausal women, suggesting a hormone-sensitizing effect. We have evaluated the quality of life through a self-administered questionnaire during a randomized study of oral CEE or transdermal E2 and fenretinide or placebo. METHODS: A total of 226 postmenopausal women were randomly assigned to either CEE 0.625mg/day and placebo (n=55), or CEE and fenretinide 100mg/bid (n=56), or E2, 50microg/day and placebo (n=59), or E2 and fenretinide (n=56) for 12 months. Sequential MPA 10mg/day was added in all groups. Treatment effects were investigated using a validated questionnaire, the Menopause Quality of Life questionnaire (MENQOL). RESULTS: Oral CEE and transdermal E2 have a comparable activity in reducing menopausal symptoms (p=ns). Both routes ameliorate significantly the symptoms after 1 year of treatment (p<0.0001). Fenretinide does not modify the effects of hormonal replacement therapy. CONCLUSIONS: Oral CEE and transdermal E2 have similar effect on menopausal symptoms relief. The choice of the best estrogen replacement therapy (ERT) route should be decided based on a careful analysis of all the clinical aspects of every subject, considering that transdermal therapy may have a safer effect on the cardiovascular system.