A Prevention Trial in Subjects at High Risk for Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      The primary objective of the proposed trial is to assess. The efficacy and the safety of a
      daily administration of nimesulide or simvastatin to change the expression of a large set of
      tissue and circulating surrogate endpoint biomarkers (SEBs) of breast carcinogenesis in women
      at higher risk of developing a hormone non-responsive (ER neg) breast cancer. The primary
      endpoint is the change in prevalence of atypical cells and cellular proliferation (Ki-67),
      after 12 months of treatment.
    

Detailed description: 
      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.
    

Intervention name(s): nimesulide; Simvastatin; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): Nimesulide 100 mg (capsules). 100mg/die every day for 1 year. Oral administration; Simvastatin 20 mg (capsules). 20mg/die every day for 1 year. Oral administration; Placebo (capsules). 1 cps/die every day for 1 year. Oral administration
Other intervention name(s): Aulin; Sivastin
Intervention MeSH terms: Nimesulide; Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Prevention; Breast Cancer; Proliferation; Breast Cancer Prevention