Metformin Hydrochloride in Treating Women With Stage I or Stage II Breast Cancer That Can Be Removed By Surgery

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I trial is studying how well metformin hydrochloride works in treating women with stage I or stage II breast cancer that can be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary To determine the in situ effects of metformin hydrochloride on proliferation (Ki67) and apoptosis (caspase-3) in women with operable stage I or II breast cancer. Secondary To determine the in situ biologic effect of metformin hydrochloride on the AMP kinase, MTOR/PI3K, and IGF pathways in breast cancer (tissue S6K and phospho S6K, p53, p63, and p73 levels as well as p53 [(Ser-15), if wild-type p53 is present], p63 [Ser-66/68, Ser-301, and Ser-361], and p73 [Y-99] phosphorylation, PTEN [clone 6H2.1], phospho-Akt [S473], insulin receptor substrate 1 and 2 [IRS-1 and IRS-2], and LKB1). To determine if molecular classification (basal-type vs luminal A vs luminal B) and the established p63 and p73 RNA microarray gene signatures correlate with the metformin hydrochloride-induced effects on proliferation (Ki67), apoptosis (caspase-3) and the selected biomarkers (listed above) in breast cancer. To collect and analyze pre- and post-treatment peripheral blood specimens for serum glucose and insulin levels, as well as circulating IGF-1 and IGF binding protein 3 (IGFBP3). OUTLINE: Patients receive oral metformin hydrochloride twice daily for 7-21 days. Approximately 24-36 hours after the last dose of metformin hydrochloride, patients undergo surgical resection (total mastectomy or segmental resection with lymph node evaluation) of tumor. Patients undergo blood and tissue sample collection periodically for biomarker analysis.

Official Title
-----------------
Pre-Surgical Trial of Metformin in Patients With Operable Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: metformin hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: Patients must provide informed written consent Eastern Cooperative Oncology Group performance status 0-1. Clinical stage I, II or IIIA invasive mammary carcinoma, any estrogen receptors(ER), progesterone receptors (PR), or Human Epidermal Growth Factor Receptor (HER2/NEU) status Patients who have measurable residual tumor at the primary site Measurable disease: a mass that can be reproducibly measured by physical examination and/or ultrasound and is at least 1 cm in size by physical examination or ultra-sound measurement Patients who will undergo surgical treatment with either segmental resection or total mastectomy with lymph node evaluation Consultations: All patients should be evaluated by a surgeon prior to study entry. Available core biopsies from the time of diagnosis. These may include sections paraffin-embedded material. Female subjects ≥18 years of age No prior chemotherapy for this primary breast cancer. Patients with a prior history of contralateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer. Women may have been taking tamoxifen or raloxifene as a preventive agent prior to study entry but must have discontinued the drug for at least 21 days prior to study enrollment. Patients must have adequate hepatic and renal function. All tests must be obtained less than 4 weeks from study entry. This includes: Creatinine </= to 1.5X upper limits of normal Bilirubin, SGOT, SGPT < or = to 1.5X upper limits of normal Able to swallow and retain oral medication Exclusion: Patients with locally advanced disease who are candidates and wish to undergo preoperative chemotherapy at the time of initial evaluation. Patients with operable locally advanced disease (stage IIIA) are eligible for participation. Locally recurrent breast cancer Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.) History of diabetes mellitus Pregnant or lactating women Metformin treatment within 30 days of study entry Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded. History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinomas are eligible Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. History of a medical condition leading to chronic hypoxemia and/or ischemia (congestive heart failure, emphysema or chronic lung disease requiring supplemental oxygen) Chronic metabolic acidosis (serum HCO3- < or = to 20 or requiring sodium bicarbonate supplementation) Concurrent anti-cancer therapy (chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or any other biologic therapy) Concurrent treatment with an investigational agent Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years


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<br>Metformin: 850 mg orally (PO) twice daily (BID) for 7-21 days, discontinued 24-36 hrs prior to surgery | Drug: metformin hydrochloride<br>* Metformin: 850 mg orally (PO) twice daily (BID) for 7-21 days, discontinued 24-36 hrs prior to surgery<br>Other: laboratory biomarker analysis<br>* Blood and tissue collection to determine the in situ biologic effect of metformin<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ki67 Levels Before and After Treatment | Change in Ki67 levels in pre-treatment, pre-surgery and post-treatment, surgically excised breast tissue. Measured by percentage of positive-staining nuclei with a minimum of 0% to a maximum of 100%. A mean score is determined. | baseline and between 8-23 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Circulating Insulin-like Growth Factor 1 (IGF-1) and IGF Binding Protein 3 (IGFBP-3) | Effect of study drug on circulating IGF-1 and IGFBP-3 as measured in ng/mL in peripheral blood samples taken pre-treatment and post-treatment with metformin | baseline and 23 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage I breast cancer, stage II breast cancer