RO4929097 and Letrozole in Treating Post-Menopausal Women With Hormone Receptor-Positive Stage II or Stage III Breast Cancer

Inclusion criteria

* Pathologically confirmed invasive breast cancer * Stage II or III disease (T2-T3, N0-2) * No N3, T4 disease * Estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) * H score ≥ 10 or positivity ≥ 10% * HER2 negative as determined by IHC (1 or 2+) or FISH (\< 2.0+) * Bilateral disease allowed as long as all tumors are ER+ and ≥ 1 is T2-T3 * Patient must have disease that is palpable on physical exam and able to be imaged via breast ultrasound * Defined as ≥ 1 T2 tumor \> 2 cm * Multifocal disease allowed provided that ≥ 1 of the tumors is \> 2 cm * No metastatic disease by CT scans of the chest, abdomen, and pelvis, a PET/CT bone scan, or nuclear medicine bone scan * No inflammatory breast cancer or presence of breast tumor cells in the dermal lymphatics of the breast * Post-menopausal meeting 1 of the following criteria: * Bilateral oophorectomy * Age ≥ 50 years and amenorrheic for \> 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression (spontaneous amenorrhea) * ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%) * Life expectancy \> 3 months * ANC ≥ 1,000/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9 g/dL * Total bilirubin normal * AST and ALT ≤ 2.5 times upper limit of normal * Creatinine normal OR creatinine clearance ≥ 60 mL/min * Baseline QTcF ≤ 470 msec * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma secretase inhibitor RO4929097 or other agents used in the study * No malabsorption syndrome or other condition that would interfere with intestinal absorption * Able to swallow tablets * Not serologically positive for hepatitis A, B, or C, or have a history of liver disease, other forms of hepatitis, or cirrhosis * No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation * No uncontrolled intercurrent illness including, but not limited to, any of the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * History of torsades de pointes or other significant cardiac arrhythmia other than chronic, stable atrial fibrillation * Psychiatric illness and/or social situations that would limit compliance with study requirements * Recovered to \< grade 2 CTCAE toxicities related to prior therapy * No prior chemotherapy, hormonal therapy, radiotherapy, or biological therapy for breast cancer * Prior treatment for non-melanoma skin cancer or carcinoma in situ of the cervix allowed * No prior hormone therapy for ductal carcinoma in situ (DCIS) * No other concurrent investigational agents * No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) * No concurrent medications that are strong inducers and/or inhibitors or substrates of CYP3A4 * Switching to alternative medications allowed * No concurrent combination antiretroviral therapy for HIV-positive patients * No concurrent antiarrhythmics or other medications known to prolong QTc * No other concurrent anticancer agents or therapies * No concurrent grapefruit juice