A Prevention Trial in Subjects at High Risk for Breast Cancer

Breast cancer (BC) is one of the four "big killers". The reduction of its incidence and mortality are a top priority. Early diagnosis and screening have modified the average prognosis, nonetheless a significant proportion of BCs ultimately eludes our control. Recently BC prevention has been greatly improved and the chemopreventive efficacy of various compounds, particularly SERMs and more recently AIs (aromatase inhibitors), 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. 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. Women with BRCA-1 mutations or ERnegative DCIS have a high risk of developing a ER negative tumor. Very importantly, in many of these subjects the onset of BC occurs often early in their lifetime and this one represents not only a clinical, but also a major social issue. Thus, they are suitable candidates for phase II chemoprevention trials with novel agents targeting important molecular pathways. An important potential molecular target for ER negative BC prevention is Cyclo-Oxygenase-2 gene (COX-2) overexpression, which has been strongly correlated with breast carcinogenesis. Other important targets include the inhibition of proteasome and the cholesterol pathway. Agents positively interfering with these pathways, like COX-2 inhibitors and statins, may offer new chances to prevent a form of serious breast disease affecting a large number of subjects worldwide. Importantly, both drugs proposed in this trial add an extensive background of safety to their promising BC prevention effects.

This research is relevant to the following issues in clinical/epidemiological cancer research:

1. the acceptability and the feasibility of cancer chemoprevention in a population at increased risk for breast cancer;
2. the efficacy of the administration of two target-oriented drugs to reduce BC development in a relatively early phase of carcinogenesis;
3. the safety of a low dose of both drugs, with special emphasis to the development of gastrointestinal side effects for nimesulide, and hepatologic side effects for simvastatin;
4. the study of the relationships between tissue biomarkers of carcinogenesis, the presence of intraepithelial neoplasia (including cancer precursors and pre-malignant lesions), and the onset of breast cancer in the placebo arm;
5. the study of the associations between computer-assisted cytometric, morphometric and markovian parameters (nuclear area, DNA index and configurable run length) and the development of breast cancer and their surrogate effect during intervention with nimesulide and simvastatin;
6. the study of the BC associations between insulin-like growth factor-I (IGF-I), IGF binding proteins, hormones and other circulating biomarkers, and the development of breast cancer and their surrogate effect during study intervention.

The proposed study can lead in a 3-year time period to a better understanding of all the above issues. Moreover, we may benefit here of the well-known advantages of the phase II studies on intermediate biomarkers upon larger phase III trials: the combination of lower costs, relatively short times to show results, the possibility to avoid taking "false steps", the concomitant validation of established and novel surrogate biomarkers.