Breast cancer (BC) is now the most common cancer diagnosed in women worldwide and is the leading cause of deaths from cancer among women . Recently BC prevention has been greatly improved and the chemopreventive efficacy of various compounds, particularly Selective Estrogen Receptor Modulators (SERMs) and more recently aromatase inhibitors (AIs), has been repeatedly documented. However these drugs have shown to be effective almost exclusively in hormone-responsive (ER positive) BCs. At least one-third of BCs will not be influenced by hormonal interventions because of the absence of ER expression since the beginning and another number of cancers will subsequently “escape” the hormonal control and become resistant to tamoxifen and AIs. Unfortunately, ER negativity is frequently combined with other characteristics of biological aggressiveness (high grade and proliferation, overexpression of HER2/neu), resulting in a worse prognosis [2, 3]. Furthermore, women with a family history of breast and ovarian cancer have a higher risk of developing ER negative BC compared with the general population. In particular BRCA-1 mutation carriers have approximately 90% ER negative tumours, and display a characteristic gene expression profile . For all these reasons, methods to better select subjects at higher risk for ER negative BC and strategies to prevent it are actively being sought.
Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer [5–8].
The ductal lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis to provide individualized risk assessment with a sensitivity up to 3.2 times greater than that of Nipple Aspirate Fluid (NAF) in detecting abnormal intraductal cells .
Over-expression of cyclooxygenase-2 (COX-2) has been detected in a variety of human tumors in breast, prostate, lung, skin, and colon . Nimesulide, a preferential COX-2 inhibitor, has been used clinically as an anti-inflammatory agent in Europe, Asia and Africa. COX-2 inhibition by nimesulide has been shown to inhibit cancer cell proliferation and induce cancer cell apoptosis in vitro [11, 12], and prevent tumor growth and metastasis in vivo [13–15]. However, COX-2/PGE2-independent mechanisms have also been reported to mediate the anti-tumor activity of nimesulide [16, 17].
Statins (HMG-CoA reductase inhibitors), the most widely used medications in the western world to manage hypercholesterolemia and associated morbidities , may affect the occurrence or outcomes of other diseases—including cancer—either by downstream consequences of cholesterol reduction or by mechanisms outside of the cholesterol synthesis pathway [19, 20]. A recent metanalisis showed that Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I–III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed .
All these data, together with the long post-marketing surveillance of both compounds, make these two drugs most interesting to investigate in a chemoprevention trial in subjects at higher risk for ER negative breast cancer.
We are conducting a phase II, randomized, double blind, placebo controlled trial in 150 women at increased risk for hormone non-responsive breast cancer, randomly assigned to receive nimesulide 100 mg or simvastatin 20 mg once daily or matching placebo for 12 months, and then followed for another year. This paper describes the rationale and design of the study, thus focusing on the methodology and operational aspects of the clinical trial.