Clinical trial NCT03454529: The Effect of Simvastatin on Breast Cancer Cell Growth in Women With Stage I-II Breast Cancer
Official title: The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women With Early Stage Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Invasive Breast Carcinoma
Stage I Breast Cancer AJCC v7
Stage IA Breast Cancer AJCC v7
Stage IB Breast Cancer AJCC v7
Stage II Breast Cancer AJCC v6 and v7
Stage IIA Breast Cancer AJCC v6 and v7
Stage IIB Breast Cancer AJCC v6 and v7
Lead sponsor: Barbara Ann Karmanos Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2018-03-06
Enrollment: 24
Sex: FEMALE
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this pilot phase II trial is to identify the molecular and genetic mechanisms by which statins influence breast cancer cell proliferation. Simvastatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and reduce the aggressiveness of breast cancer cells.

Detailed description: PRIMARY OBJECTIVES:

I. Evaluate the relationship between short-term use of oral simvastatin on change in expression of Ki-67 as a candidate biomarker of breast tumor proliferation among women with clinical stage 1 or 2- primary invasive breast cancer.

II. Evaluate the relationship between short-term use of oral simvastatin on changes in other candidate predictive markers of breast tumor proliferation (cyclin D1 and P27), changes in a marker of apoptosis (cleaved caspase-3 \[CC3\]), changes in a marker of inflammation (c-reactive protein \[CRP\]) and as novel additional biomarkers changes in the composition of the plasma membrane (lipid rafts) and changes in activation of signaling markers (phosphorylation \[p\]Akt, pMAPK, pEGFR, PHER2).

III. To conduct exploratory analyses comparing the effect of statins on breast tumor proliferation and apoptosis in groups defined by tumor expression of hydroxymethylglutaryl co-enzyme A (CoA) reductase (HMG-CoA), estrogen receptor (ER)/progesterone receptor (PR) status, HER2neu, and tumor grade.

OUTLINE:

Patients receive simvastatin orally (PO) daily for 2-4 weeks in the absence of disease progression or unacceptable toxicity.

Eligibility criteria: Inclusion Criteria:

* Provision of informed consent prior to any study specific procedures
* Histologic confirmation of invasive breast cancer with any measures of ER, PR and HER2neu
* Clinical stage I or II breast cancer for which there will be at least a 2 week period of time between diagnosis and definitive surgery
* Performance status (Eastern Cooperative Oncology Group \[ECOG\] 0-1)
* Not currently pregnant during the study; participants will be informed that the use of contraceptive pills is contraindicated because it may interfere with the study drug and it may be harmful to the woman who has been diagnosed with breast cancer

Exclusion Criteria:

* Plans for administration of neoadjuvant chemotherapy or hormonal therapy
* Insufficient tissue on diagnostic core breast biopsy for analysis
* Previous or concurrent malignancy (with the exception of non-melanomatous skin cancer)
* Severe gastrointestinal disorder
* Current use of statins or fibrates for any time during the 3 months prior to the study
* Proven hypersensitivity to statins
* White blood cell (WBC) \< 3,500/mm\^3
* Platelet (Plt) \< 120,000/mm\^3
* Hemoglobin (HgB) \< 10 g/dL
* Aspartate aminotransferase (AST) \> 45 U/L
* Alanine aminotransferase (ALT) \> 45 U/L
* Creatinine \> 1.5 mg/dL
* Bilirubin \> 1.15 mg/dL
* Creatine kinase measurement (CPK) \> or = 250 mg/dL
* Central nervous system (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 valvopathy or valvular prosthesis; angina; severe arterial hypertension; chronic and/or paroxysmal atrial fibrillation; previous myocardial infarction
* Current lactation

Primary outcomes:
measure: Change in Ki-67 Expression Assessed in Tumor Tissue by Immunohistochemistry
timeFrame: Baseline up to 4 weeks
Secondary outcomes:
Other outcomes:
measure: Change in Percentage of Cells P27+ From Pre-treatment to Post-treatment
timeFrame: Baseline up to 4 weeks
measure: Cleaved Caspase-3 (CC3) as a Marker of Apoptosis
timeFrame: Baseline up to 4 weeks
measure: C-reactive Protein (CRP) as a Marker of Inflammation
timeFrame: Baseline up to 4 weeks
measure: Change in (% Intracellular p27 +) From Pre-treatment to Post-treatment
timeFrame: Baseline up to 4 weeks
measure: Changes in p27 Cytoplasmic Intensity
timeFrame: Baseline up to 4 weeks
measure: Changes in Cyclin D1
timeFrame: Baseline up to 4 weeks
Locations:
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
Study officials:
affiliation: Barbara Ann Karmanos Cancer Institute
name: Michael Simon
role: PRINCIPAL_INVESTIGATOR
References:
citation: Asari K, Sun WT, Kok ZH, Lam YH, Ng BL, Saunders V, White DL, Chuah C, Xiang W. Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation. Anticancer Drugs. 2021 Jun 1;32(5):526-536. doi: 10.1097/CAD.0000000000001028.