Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of invasive breast
cancer

- Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer (3+
staining by immunohistochemistry or HER2 gene amplification by fluorescent in situ
hybridization[FISH] or silver in situ hybridization [SISH] ≥ 2.2)

- Brain metastases that fulfill 1 of the following:

- Progressive parenchymal brain metastases following stereotactic radiosurgery for
1-3 brain metastases, with at least 1 new measurable lesion

- Progressive parenchymal brain metastases following surgical resection of 1-3
brain metastases, as long as at least 1 brain metastasis is measurable

- At least 1 measurable, unirradiated parenchymal brain lesion (≥ 10 mm on T1-weighted
gadolinium-enhanced MRI) within 21 days prior to study entry

- No leptomeningeal disease

- Karnofsky performance status ≥ 60%

- Able to swallow and retain oral medication (Note: for patients unable to swallow
tablets, an oral suspension preparation is acceptable)

- Absolute neutrophil count (ANC) ≥ 1,200 cells/mm³

- Platelets ≥ 70,000 cells/mm³

- Hemoglobin [Hgb] ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to
achieve Hgb ≥ 8.0 g/dL is acceptable)

- Creatinine < 1.5 times institutional upper limit of normal (ULN)

- Bilirubin < 1.5 times institutional ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 times
institutional ULN with or without liver metastasis

- Women of childbearing potential must have a negative serum pregnancy test within 21
days prior to study entry

- Sexually active women of childbearing potential and sexually active men must practice
adequate contraception during therapy and for 12 months after protocol treatment
completion

- Women should not breastfeed while on this study

- No 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

- No prior invasive malignancy (except non-melanomatous skin cancer) unless disease
free for a minimum of 3 years

- No severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of study entry

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of study entry

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
hepatic or biliary disease that is acute or currently active or that requires
antiviral therapy (with the exception of patients with Gilbert syndrome,
asymptomatic gallstones, liver metastases, or stable chronic liver disease per
investigator assessment)

- History of left ventricular ejection fraction (LVEF) below institutional normal
unless repeated and within institutional normal range within 90 days of study
entry

- No grade 2 or greater rash of any cause at time of study entry

- No grade 2 or greater diarrhea of any cause at time of study entry

- At least 14 days between FINAL dose of prior chemotherapy and study entry, with
recovery of toxicities to grade 0 or 1

- No prior whole-brain radiation therapy (WBRT)

- No prior lapatinib therapy

- No prior radiotherapy to the region of the study cancer that would result in overlap
of radiation therapy fields except patients who have progressed following
stereotactic radiosurgery for 1-3 brain metastases, with at least one new lesion

- No concurrent intensity-modulated radiation therapy