Abstract A72: A phase II randomized trial with nimesulide, simvastatin, and placebo in subjects at increased risk for breast cancer

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Abstract Background: Breast cancer (BC) prevention has been successful for estrogen receptor positive cancer, whereas no significant results have been reached so far to prevent hormone non-responsive tumors. Epidemiological and in vitro studies have suggested the possible preventive role of several compounds, in particular NSAIDs (nonsteroidal anti-inflammatory drugs) and more recently statins. Several data suggest the ability of NSAIDs to reduce the risk of many tumors including BC. Nimesulide is a NSAID largely used in several European countries. It is defined as a preferential COX-2 inhibitor, because it maintains a modest inhibitory activity on COX-1. The incomplete COX-2 selectivity of nimesulide gives a favorable profile, avoiding most side effects of the nonspecific COX inhibitors and the super-selective COX-2 inhibitors. Statins are widely used for the treatment of lipid disorders in cardiovascular disease prevention. They have shown a possible role in cancer prevention through the modulation of cell cycle arrest and apoptosis. 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 BC, focused particularly on hormone nonresponsive tumor risk. Study design: 150 women will be randomized to receive nimesulide versus simvastatin versus placebo for one year followed by a second year of follow-up. Eligible subjects are: patients with previous estrogen receptor negative ductal intraepithelial neoplasia (DIN) or lobular intraepithelial neoplasia (LIN) or atypical hyperplasia (AH), and unaffected subjects carrying a mutation of BRCA1/2 or with a probability of mutation >10% (according to BRCAPRO). At baseline, 6, 12 and 24 month clinical examination, blood tests and annual mammography are scheduled. Ductal lavage (DL) or fine needle aspirate (FNA) — if for any reason the DL is not possible or result inadequate — is performed annually to obtain a breast cell sample. For safety reasons the blood tests are performed also at 3 and 9 month time. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or FNA samples, after 12 months of treatment and 12 months after treatment suspension. Secondary endpoints are: treatment safety and the modulation of a large set of cell and circulating surrogate endpoint biomarkers (SEBs) of breast cancerogenesis. Recruitment and preliminary results: at August 2010 we have randomized 140 subjects of which 64 ER neg DIN, 48 LIN and AH and 28 subjects with mutation or mutation probability. So far 83 subjects completed the study. The treatment is very well tolerated and the safety blood tests did not show any significant liver toxicity, only few subjects had grade 1 liver enzyme alterations. CPK alteration was seen in 9 subjects (grade 1 toxicity). One case was included in the study with a baseline level of CPK grade 2, the patient was withdrawn from the study. Including this last case five subjects dropped out: two for gastrointestinal symptoms, one for muscle ache, and one refused to continue. To our knowledge this is the first randomazied placebo controlled trial to study SEBs and their modulation after intervention with DL. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A72.