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A Randomized Phase II Prevention Trial in Subjects at High Risk for Hormone Non-responsive Breast Cancer

Phase 2
18 Years
65 Years
Open (Enrolling)
Breast Cancer

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Trial Information

A Randomized Phase II Prevention Trial in Subjects at High Risk for Hormone Non-responsive 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

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

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.

Inclusion Criteria:

- Female, 18-65 years old inclusive

- Histologic confirmation of hormone non-responsive DCIS (ER<5%, PgR<5%), or AH or LIN,
radically excised in the previous 12 months;

- Positivity for BRCA1 mutation;

- >10% probability of being a BRCA1/2 mutation carrier, according to Berry Parmigiani
and/or Couch model;

- Performance Status (SWOG) = 0;

- Unwillingness to be pregnant during the study and three months after drug suspension.
Women will be informed that the use of contraceptive pill is contraindicated because
it may interfere with the study drugs and may be harmful to a woman who has been
diagnosed with breast cancer;

- Willingness to sign the informed consent form

Exclusion Criteria:

- Evidence of residual disease as documented by mammograms, histologic confirmation of
margin involvement or distant disease;

- Previous or concurrent malignancy (with the exception of basal cell carcinoma
and CIN);

- Severe gastrointestinal disorders;

- Current use of NSAIDs;

- Current use of statins

- Current use of fibrates

- Current use of potent CYP3A4 inhibitors (ciclosporin, mibefradil, itraconazole,
ketoconazole, erythromycin, clarithromycin)

- Proven hypersensitivity to nimesulide and/or simvastatin;

- Mild or higher alterations of hematologic, liver and renal function (i.e., WBC
<3,500/mm3, Plt <120,000/mm3, HgB <10 g/dL, AST >45 U/L, ALT >45 U/L, creatinin
>1.5 mg/dL, bilirubin >1.15 mg/dL, CPK 250 mg/dL);

- CNS diseases and major psychiatric diseases or inability to comply to the
protocol procedures;

- Active infections;

- Cardiac failure, class I-IV ;

- Current anticoagulant or antiplatelet aggregation therapy;

- Mitral and/or tricuspid valvulopathy or valvular prosthesis; Angina; Severe
arterial hypertension; Chronic and/or paroxysmal atrial fibrillation; Previous
myocardial infarction;

- Current childbearing and inability to prevent it during the intervention period
and for at least 3 months after cessation of treatment;

- Current lactation.

- Any other factor that in the investigator's discretion contraindicates the use
of one or both drugs.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Ki 67 variation

Outcome Description:

changes of cellular proliferation marker Ki-67 in blood, ductal lavage fluid at the end of treatment withe respect to baseline. A further assessment will be done at the end of a furter 12 months follow-up.

Outcome Time Frame:

baseline and 12 months

Safety Issue:



Italy: The Italian Medicines Agency

Study ID:

IEO S222/604



Start Date:

April 2005

Completion Date:

December 2013

Related Keywords:

  • Breast Cancer
  • Prevention
  • Breast Cancer
  • Proliferation
  • Breast Cancer Prevention
  • Breast Neoplasms