This phase II trial studies the side effects and how well letrozole and imatinib mesylate work in treating postmenopausal participants with estrogen or progesterone positive breast cancer that has spread to other places in the body. Letrozole is an antihormonal drug used in the standard treatment of hormonal sensitive breast cancer. Imatinib mesylate is a drug that binds to certain proteins on the tumor cells and prevents them from further growth. Imatinib mesylate is thought to prevent the potential resistance to letrozole, which may make the letrozole more effective. Giving letrozole and imatinib mesylate may work better in treating participants with breast cancer.

PRIMARY OBJECTIVES:

I. To determine the efficacy of letrozole plus imatinib mesylate in patients with estrogen receptor (ER) and or progesterone receptor (PgR) positive metastatic breast cancer.

II. To determine the safety and tolerability of letrozole plus imatinib mesylate in patients with metastatic breast cancer.

III. To determine the time to disease progression and overall survival in patients with metastatic breast cancer who are treated with letrozole plus imatinib mesylate.

OUTLINE:

Participants receive imatinib mesylate orally (PO) twice daily (BID) and letrozole PO once daily (QD) for 8 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 1 and 4 weeks and at 2, 4, 6, 9, and 12 months.

Inclusion Criteria:

• Postmenopausal women able to comply with the protocol requirements with metastatic breast cancer, whose tumors are estrogen (ER) and/or progesterone (PgR) positive, defined by core biopsy immunohistochemistry with greater than 10% positive malignant epithelial cells
• Patients must have documented expression of either PDGFR or CD117 (c-kit) by immunohistochemistry
• Patients may have received tamoxifen in the adjuvant/neoadjuvant or setting. Patients may have previously received chemotherapy in the adjuvant/ neoadjuvant setting, though this is not required. Prior chemotherapy for metastatic breast cancer is allowed. Concomitant bisphosphonates are allowed for patients with bone metastases and who have another site of measurable disease
• Post menopausal status defined by one of the following: no spontaneous menses for at least 1 year, in women greater than or equal to 55 years spontaneous menses within the past 1 year in women greater than or equal to 55 years with postmenopausal gonadotrophin levels (luteinizing hormone [LH] and follicle stimulating hormone [FSH] levels greater than 40 IU/L ) or postmenopausal estradiol levels (less than 5 mg/dl) or according to the definition of "postmenopausal range" for the laboratory involved bilateral oophorectomy
• Performance status, Eastern Cooperative Oncology Group (ECOG) greater than or equal to 2
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 10 mm with conventional techniques. Bone disease only will not be accepted as measurable disease. Pleural or peritoneal effusions will not be accepted as measurable disease
• Absolute neutrophil count (ANC) = 1.5 x 10 to the 9th power/L
• Platelets greater than or equal to 100.0 x 10 to the 9th power/L
• Hemoglobin greater than 10.0 g/dL
• Creatinine less than 1.5 mg/dl
• Total (T.) bilirubin less than 1.5 x normal
• Aspartate aminotransferase (AST) less than 2.5 x normal
• A life expectancy of at least 6 months
• Localized radiotherapy, which does not influence the signal of evaluable lesion, is allowed prior to the initiation of imatinib mesylate. Patients must have recovered from the myelosuppressive effects of previous radiotherapy (at least 2-4 weeks)
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Prior treatment with Femara or Gleevec
• Uncontrolled endocrine disorders such as diabetes mellitus, confirmed hypo- or hyperthyroidism, Cushing's syndrome, Addison's disease (treated or untreated)
• Patients with unstable angina, or uncontrolled cardiac disease (e.g. class III or IV New York Heart Association's functional classification)
• Other concurrent malignant disease with the exception of cone-biopsied in situ carcinoma of the cervix uteri, or adequately treated basal or squamous cell carcinoma of the skin, or other curable cancers e.g. Hodgkin's disease or non-Hodgkin lymphoma (NHL), provided 5 years have elapsed from completion of therapy, and there has been no recurrence
• Concomitant treatment with steroids, e.g. glucocorticoids for indications other than cancer, except aerosol for obstructive airways diseases and steroid injection to the joints for treatment of inflammation
• Other investigational drugs within the past 3 weeks and the concomitant use of investigational drugs
• History of non-compliance to medical regimens and patients who are considered potentially unreliable
• Patients with known brain metastasis
• Patients with known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis)
• Patients with known diagnosis of human immunodeficiency virus (HIV) infection
• Patients who received chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to study entry, unless the disease is rapidly progressing
• Patients who previously received radiotherapy to greater than or equal to 25% of the bone marrow
• Patients who had a major surgery within 2 weeks prior to study entry