• To determine the maximal tolerated dose and feasibility of lapatinib when combined with cranial radiation in patients with CNS metastases from HER2-positive breast cancer. [ Time Frame: Years ] [ Designated as safety issue: Yes ]
  

• To describe the time to progression, site of first progression, objective response in CNS and non-CNS sites, neurologic outcomes, quality of life, overall survival, and cause of death. [ Time Frame: years ] [ Designated as safety issue: No ]
  

Drug: Lapatinib
Orally twice daily
Procedure: Whole Brain Radiation
15 treatments over a period of 3 weeks

• Participant's will be given a study medication-dosing calendar for each treatment cycle. Each treatment cycle lasts four weeks. On the first day of the treatment cycle, participants will take 1 lapatinib orally twice per day, 12 hours apart. After the first day, lapatinib will be taken once a day in the morning.
• Whole brain radiation treatments will begin approximately 1-8 days after the first dose of lapatinib. The radiation treatments will follow standard guidelines and will be supervised by a radiation oncologist. Radiation will be given in 15 treatments over a period of three weeks.
• Some participants will also undergo stereotactic radiosurgery (SRS). SRS is a highly focused and intense form of radiation treatment generally done as an outpatient procedure in a single treatment.
• After whole brain radiation treatments are completed, lapatinib will be continued at the same dose for one more week. After that, the lapatinib dose may change. In addition at the same time, Herceptin will be started. Participants will continue with both lapatinib and herceptin together as long as there is evidence that they are benefitting from it.
• During all treatment cycles participants will have a physical exam and be asked general questions about their health. Photographs will be taken of the tumor, if visible, to assess the response of the tumor to the treatment. An assessment of the tumor by CT scan of the body, and MRI imaging of the brain will be performed every two months. An assessment of heart function by MUGA scan or echocardiogram will be performed every 8 weeks. The participant will also be asked to complete a brief questionnaire measuring quality of life and asking about symptoms related to the cancer at baseline, 6 months, and one year. Blood tests will be performed every 4 weeks.

Inclusion Criteria:

• Histologically or cytologically-confirmed invasive breast cancer
• HER2 overexpressing breast cancer defined as 3+ staining by immunohistochemistry, or HER2 gene amplification by FISH
• At least one parenchymal brain metastasis
• Disease progression in the CNS as assessed by at least one of the following; new neurological signs or symptoms; new lesion(s) in the CNS on an imaging study; progressive lesions on an imaging study
• At least two weeks since prior radiotherapy, last chemotherapy, immunotherapy, biologic therapy, or major surgery for cancer
• 18 years of age or older
• Life expectancy of greater than 12 weeks
• ECOG performance status 0-2
• Normal organ and marrow function as described in the protocol
• Left ventricular ejection fraction > 50%
• Able to swallow and retain oral medications

Exclusion Criteria:

• Prior WBRT
• Receiving any other investigational agents
• Concurrent chemotherapy, immunotherapy, biologic therapy or hormonal therapy for treatment of their cancer
• History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition to herceptin or lapatinib
• Leptomeningeal carcinomatosis as the only site of CNS involvement
• Concurrent treatment with medications that are either inducers of inhibitors of CYP3A4
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis
• History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents
• Other known contraindication to MRI
• Uncontrolled intercurrent illness
• History of other active malignancy except curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix
• Pregnant or breastfeeding women