Letrozole, Everolimus, and Anti-Endoglin Chimeric Monoclonal Antibody TRC105 in Treating Postmenopausal Patients with Hormone-Receptor Positive or HER2 Negative Breast Cancer That Can Be Removed by Surgery

Inclusion Criteria

• Newly diagnosed, histologically confirmed breast cancer
• Hormone receptor positive and HER2 negative breast cancer; patients with HER2/neu positive tumors irrespective of their hormone receptor status will be excluded; at least 10% of tumor cell nuclei should be immunoreactive for hormone receptors (ER and/or PR) to be deemed eligible for the study; Her2/neu negative is defined as: * Immunohistochemistry (IHC) score of 0 (no staining is observed or membrane staining that is incomplete and is faint/barely perceptible and within =< 10% of tumor cells) OR * IHC score of 1 (incomplete membrane staining that is faint/barely perceptible and within < 10% of tumor cells) OR * Fluorescence in situ hybridization (FISH) HER2/chromosome enumeration probe 17 (CEP17) ratio of < 1.8 or average HER2 gene copy number of < 4 signals/nucleus for test systems without an internal control probe * Equivocal results for HER2/neu (defined as: IHC 2+ or FISH HER2/CEP17 ratio of 1.8-2.2 or average HER2 gene copy number 4-6 HER2 signals/nucleus for test systems without an internal control probe) should prompt reflex test (same specimen using an alternative method) or order a new test (new specimen if available, using IHC or FISH)
• Histological grade I, II, or III according to the modified Bloom Richardson scale
• Stage at diagnosis T2 through T4a-c, N0 through N2, and M0; patients with inflammatory breast cancer or metastatic disease at diagnosis will be excluded; patients with multicentric, multifocal, and/or bilateral disease are allowed to participate so long as all tumors meet the histologic criteria of the study
• Postmenopausal status, as defined by the National Comprehensive Cancer Network * Age > 60 years old OR * Prior bilateral oophorectomy regardless of age * If patient < 60 years old and amenorrheic for > 12 months or in the absence of ovarian suppression, follicle-stimulating hormone (FSH) and estradiol have to be in the postmenopausal range
• No prior treatment with therapeutic intent for breast cancer
• No life threatening parenchymal disease or rapidly progressing disease warranting cytotoxic chemotherapy
• Patients must have disease that can be measured and followed by mammogram and/or breast ultrasound (in special cases a dedicated breast magnetic resonance imaging [MRI] may be clinically indicated); the target lesion must not have been previously irradiated
• Resectable/operable or potentially resectable/operable breast cancer as determined by the treating surgical oncologist
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 6 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Hemoglobin >= 10 gr/dL
• Platelets >= 100,000/mcL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN) (except for known Gilbert’s syndrome/familial non-hemolytic jaundice)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN
• Creatinine up to 1.5 ULN, or
• Creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• International normalized ratio (INR) =< 2
• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• Children are excluded from this study
• No bleeding from gastrointestinal ulcers or other sites of bleeding
• Ability to understand and willingness to sign a written informed consent document
• Signed informed consent obtained prior to any screening procedures

Exclusion Criteria

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of the investigational therapy (including chemotherapy, radiation therapy, antibody based therapy)
• HER2/neu positive or estrogen and progesterone receptor negative breast cancer; patients with triple negative breast cancer are also excluded
• Metastatic breast cancer
• Inflammatory (T4d) breast cancer
• Patients may not be receiving any other investigational agents; if patients are currently part of or have participated in any clinical investigation with an investigational drug, the last administration of the investigational study should be at least 1 month prior to dosing
• Inoperable breast cancer even after neoadjuvant treatment as assessed by the treating surgical oncologist
• Pre- or perimenopausal status or menopausal status that cannot be accurately assessed (e.g. equivocal measurements of estradiol and FSH)
• Disease that cannot be measured and/or accurately followed by mammogram and/or breast ultrasound and/or dedicated breast MRI
• Target lesion that has been previously irradiated
• History of allergic reactions, intolerance or hypersensitivity attributed to compounds of similar chemical or biologic composition to TRC105 and/or everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
• Leukocytes < 3,000/mcL
• Absolute neutrophil count < 1,500/mcL
• Hemoglobin < 10 gr/dL
• Platelets < 100,000/mcL
• Total bilirubin > 2 x institutional ULN (except for known Gilbert’s syndrome/familial non-hemolytic jaundice)
• AST(SGOT)/ALT(SGPT) > 2.5 x institutional upper limit of normal
• Creatinine > 1.5 ULN, or
• Creatinine clearance < 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• INR >= 2
• Uncontrolled diabetes mellitus as defined by glycated hemoglobin (HbA1c) > 8% despite adequate therapy; patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; examples of uncontrolled medical conditions include: * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease * Symptomatic congestive heart failure of New York Heart Association class III or IV * Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable Hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive Hepatitis B surface antibody [HbsAg], quantifiable Hepatitis C virus [HCV]-ribonucleic acid [RNA]) * Known severely impaired lung function (spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) 50% or less of normal and O2 saturation 88% or less at rest on room air) * Active, bleeding diathesis
• Chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
• Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study; patient should also avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette–Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
• ECOG performance status > 2 (Karnofsky < 60%)
• Pregnant women and women of childbearing potential are excluded from this study
• Known history of human immunodeficiency virus (HIV) seropositivity
• Need for concurrent treatment with medications that strongly interact with everolimus (cytochrome P450 family 3 subfamily A member 4 [CYP3A4] inducers or inhibitors)
• History of another malignancy within the last five years except non-melanoma skin cancer, carcinoma in–situ of uterine cervix, uteri, and breast from which the patient has been disease free for at least 3 years; second primary breast cancers are allowed regardless of the number of years since they were first diagnosed
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the course of the study; as an example, port placement or core biopsies are not considered major surgical procedures