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