Pre-Surgical Trial of the Combination of Metformin and Atorvastatin in Newly Diagnosed Operable Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the effects of combining metformin and atorvastatin treatment in patients with newly diagnosed breast cancer during the interval between breast biopsy and surgery. This study is designed to assess whether tumor proliferation, as measured by the natural log expression of Ki-67 staining of breast tumor cells, is reduced following approximately 2 weeks of treatment with the combination of metformin plus atorvastatin in patients with newly diagnosed breast cancer.

Detailed Description
-----------------
Breast cancer cells require energy homeostasis shifts with enhanced anabolism to enable rapid growth and continued proliferation. The main energy regulatory system in eukaryotes and breast cancer cells is the AMP-activated kinase (AMPK) pathway. AMPK is triggered by changes in the AMP/Adenosine triphosphate (ATP) ratio thus impacting energy reserves and requirements. AMPK pathway closely interacts with the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, affecting the downstream function of the master regulator mammalian target of rapamycin (mTOR). Activation of AMPK has been shown in vitro to result in inhibition of proliferation of various cancer cell lines. Utilizing a pre-surgical model, the investigator plans to conduct a pilot study of 40 women with newly diagnosed invasive breast cancer or ductal carcinoma in-situ (DCIS) who will receive oral metformin and atorvastatin daily in the interval between diagnostic breast biopsy and definitive breast surgery. The goal is to determine if dual combination treatment with metformin plus atorvastatin significantly impacts tumor-based markers, such as proliferation, and blood-based biomarkers.

Official Title
-----------------
Pre-Surgical Window of Opportunity Trial of the Combination of Metformin and Atorvastatin in Newly Diagnosed Operable Breast Cancer

Conditions
-----------------
Breast Cancer, Breast Tumors, Cancer of Breast

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Atorvastatin
* Procedure: Breast surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female subjects with histologically-confirmed operable invasive breast cancer or DCIS, who undergo core needle biopsy followed by surgical excision at least 2 weeks after enrollment ≥ 5 mm by imaging/pathology of core to ensure enough pre- and post-treatment tissue for analysis Age ≥ 21 years. Breast cancer is uncommon in patients less than this age. No prior chemotherapy, radiation therapy, or breast resection within 6 months of study entry Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Signed informed consent Exclusion Criteria: Currently on medication for diabetes or hypercholesterolemia Treatment with other investigational drugs within 6 months of study entry Strong Cytochrome P450 3A4 (abbreviated CYP3A4) (e.g., clarithromycin, HIV protease inhibitors, and itraconazole), given potential interactions with atorvastatin Renal impairment with a creatinine > 1.4 mg/dl Hepatic impairment: Aspartate transaminase (AST)/(SGOT), Alanine Transaminase(ALT)/(SGPT) ≥ 2.5 x upper limit of normal range (ULN), OR Total bilirubin ≥ 1.5 x ULN (subjects with Gilbert's syndrome can have bilirubin of up to 1.5 x ULN), OR Alkaline phosphatase > 2.5 x ULN

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin-Atorvastatin combination<br>Patients will receive metformin and atorvastatin for approximately 2 weeks prior to breast surgery. | Drug: Metformin<br>* Metformin is an oral diabetes medicine that helps control blood sugar levels. Dosage/Frequency: 1500 mg per day: divided 500 mg in the morning and 1000 mg in the evening Metformin is for people with type 2 diabetes. Metformin is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes.<br>* Other names: Glucophage;Drug: Atorvastatin<br>* Atorvastatin is in a group of drugs called statins. Atorvastatin reduces levels of bad cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood while increasing levels of good cholesterol (high-density lipoprotein, or HDL). Dosage/Frequency: 80 mg once a day at bedtime Atorvastatin is used to treat high cholesterol, and to lower the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.<br>* Other names: Lipitor;Procedure: Breast surgery<br>* (Non-experimental) Female subjects with histologically-confirmed operable invasive breast cancer or DCIS will undergo core needle biopsy with a plan of surgical excision.<br>* Other names: No other name;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tissue levels of the proliferation marker Ki-67 | Tumor proliferation, as measured by the natural log expression of Ki-67 staining of breast tumor cells. | Baseline, 2 weeks after start of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, Metformin, Atorvastatin, Ki-67