The Effect of Simvastatin on Breast Cancer Cell Growth in Women With Stage I-II Breast Cancer

The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women With Early Stage Breast Cancer

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03454529

Enrollment

Registered

2018-03-06

Start date

2018-03-09

Completion date

2021-10-06

Last updated

2023-08-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Invasive Breast Carcinoma, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage I Breast Cancer AJCC v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage II Breast Cancer AJCC v6 and v7

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.

Interventions

OTHERLaboratory Biomarker Analysis

Correlative studies

DRUGSimvastatin

Given PO

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

19 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Ki-67 Expression Assessed in Tumor Tissue by Immunohistochemistry	Baseline up to 4 weeks	Differences in % positive cells pre and post treatment along with 95% confidence interval

Other

Measure	Time frame	Description
Cleaved Caspase-3 (CC3) as a Marker of Apoptosis	Baseline up to 4 weeks	The difference in (percentage of cells cleaved caspase-3 (CC3)+) from pre-treatment to post-treatment
C-reactive Protein (CRP) as a Marker of Inflammation	Baseline up to 4 weeks	c-reactive protein (CRP) as a marker of inflammation.
Change in Percentage of Cells P27+ From Pre-treatment to Post-treatment	Baseline up to 4 weeks	The difference in percentage of cells P27+ from pre-treatment to post-treatment
Changes in p27 Cytoplasmic Intensity	Baseline up to 4 weeks	the difference in (p27 cytoplasmic intensity) from pre-treatment to post-treatment
Changes in Cyclin D1	Baseline up to 4 weeks	the difference in % cyclin D1+ stained out of total cells from pre-treatment to post-treatment;
Change in (% Intracellular p27 +) From Pre-treatment to Post-treatment	Baseline up to 4 weeks	the difference in (% intracellular p27 +) from pre-treatment to post-treatment

Countries

United States

Participant flow

Participants by arm

Arm	Count
Treatment (Simvastatin) Patients receive simvastatin PO daily for 2-4 weeks in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Simvastatin: Given PO	17
Total	17

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Did not receive treatment	6
Overall Study	Received < 80% doses	1

Baseline characteristics

Characteristic	Treatment (Simvastatin)
Age, Continuous	63 years
Estrogen Receptor Status Negative	2 Participants
Estrogen Receptor Status Positive	15 Participants
HER2 Status Negative	12 Participants
HER2 Status Positive	0 Participants
HER2 Status Unknown	5 Participants
Progesterone Receptor Status Negative	6 Participants
Progesterone Receptor Status Positive	11 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	6 Participants
Race (NIH/OMB) White	9 Participants
Region of Enrollment United States	17 participants
Sex: Female, Male Female	17 Participants
Sex: Female, Male Male	0 Participants
Tumor Stage Stage 0: limited to the inside of the milk duct; is non-invasive; does not invade nearby tissues.	6 Participants
Tumor Stage Stage I: Invasive; Primary Tumor < 20mm; No lymph nodes affected; No metastasis.	11 Participants
Tumor Stage Stage II: Primary Tumor 20-50 mm; 0-<4 lymph nodes in the same side of the breast; No metastasis	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 17
other Total, other adverse events	2 / 17
serious Total, serious adverse events	0 / 17