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

18 Years
Not Enrolling
Breast Cancer

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Trial Information

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



- 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.


- 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

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

Patients undergo blood and tissue sample collection periodically for biomarker analysis.

Inclusion Criteria


- 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)

- 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

- Patients must have adequate hepatic and renal function. All tests must be obtained
less than 4 weeks from study entry. This includes:

- Creatinine
- Bilirubin, SGOT, SGPT < or = to 1.5X upper limits of normal

- Able to swallow and retain oral medication


- 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

- 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

- Chronic metabolic acidosis (serum HCO3- < or = to 20 or requiring sodium bicarbonate

- 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.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in Ki67 Levels Before and After Treatment

Outcome Description:

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.

Outcome Time Frame:

baseline and between 8-23 days

Safety Issue:


Principal Investigator

Ingrid Mayer, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

September 2009

Completion Date:

July 2011

Related Keywords:

  • Breast Cancer
  • stage I breast cancer
  • stage II breast cancer
  • Breast Neoplasms



Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
Emory University Hospital Atlanta, Georgia  30322
Vanderbilt-Ingram Cancer Center - Cool Springs Nashville, Tennessee  37064