Letrozole with and Without Simvastatin for the Treatment of Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Inclusion Criteria:

• Age >= 18 years

• Biopsy proven hormone receptor positive, HER2 negative stage I-III invasive breastcancer

• Estrogen receptor (ER) and/or progesterone receptor (PR) positivity are definedas >= 10% of cells expressing hormonal receptors via IHC analysis

• HER2 negativity is defined as either of the following by local laboratoryassessment

• IHC 0, 1+, or 2+ and in situ hybridization (ISH) non-amplified (ratio ofHER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4signals/cell)

• Minimum primary tumor size 5 mm on any breast imaging (mammogram, ultrasound,magnetic resonance imaging [MRI])

• Baseline Ki-67 IHC expression on tumor tissue >= 10%

• Post-menopausal women

• Prior bilateral oophorectomy

• Age >= 55 years

• Age < 55 and amenorrheic for 12 months or more in the absence of chemotherapy,endocrine therapy, or ovarian suppression and follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Prior treatment:

• No systemic therapy (chemotherapy, immunotherapy, endocrine therapy, and/orinvestigational therapy) within 3 months of trial enrollment

• No statins, fibrates, or ezetimibe within 3 months of trial enrollment

• No active liver disease

• Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention toachieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior toinitiation of study treatment)

• Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growthfactor support or transfusion) (within 14 days prior to initiation of studytreatment)

• Platelets >= 100,000/mcL (within 14 days prior to initiation of study treatment)

• Total bilirubin =< 2 institutional upper limit of normal (ULN) (within 14 days priorto initiation of study treatment)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 institutionalULN (within 14 days prior to initiation of study treatment)

• Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 mL/min) (within 14days prior to initiation of study treatment)

• Willingness and ability of the subject to comply with scheduled visits, drugadministration plan, protocol-specified laboratory tests, other study procedures,and study restrictions

• Be willing and able to provide written informed consent for the trial

Exclusion Criteria:

• Patients who are receiving any other investigational agents or an investigationaldevice within 3 months before administration of first dose of study drugs

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to simvastatin and/or letrozole

• Concomitant use of strong CYP3A4 inhibitors (i.e. clarithromycin, erythromycin,itraconazole, ketroconazole, nefazodone, Posaconazole, voriconazole, proteaseinhibitors [including boceprevir and telaprevir], telithromycin,cobicistat-containing products), cyclosporine, danazol, and gemfibrozil

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, substance abuse disorders, or psychiatric illness/social situations thatwould limit compliance with study requirements

• Significant cardiovascular disease (e.g., myocardial infarction, arterialthromboembolism, cerebrovascular thromboembolism) within 3 months prior to start ofstudy therapy; angina requiring therapy; symptomatic peripheral vascular disease;New York Heart Association class 3 or 4 congestive heart failure; or uncontrolledgrade >= 3 hypertension (diastolic blood pressure >= 100 mmHg or systolic bloodpressure >= 160 mmHg) despite antihypertensive therapy

• Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma ofthe skin that has undergone potentially curative therapy