Inclusion Criteria:

- Histologically or cytologically confirmed invasive breast cancer, with stage IV
disease

- HER2-positive breast cancer, defined as 3+ staining by IHC or gene amplification by
FISH

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension

- Willingness to undergo a research biopsy of recurrent or metastatic disease

- Prior chemotherapy treatment must be discontinued for at least 2 weeks prior to study
entry.

- Completed radiation therapy at least 7 days prior to beginning protocol treatment

- Cohort 1: No prior chemotherapy for advanced breast cancer; no prior trastuzumab in
the advanced breast cancer setting; nor prior treatment with lapatinib or other
HER2-directed therapy other than trastuzumab

- Cohort 2: Up to two prior chemotherapy regimens for the treatment of advanced breast
cancer; no prior treatment with lapatinib or other HER2-directed therapy except for
trastuzumab

- 18 years of age or older

- Life expectancy of greater than 12 weeks

- ECOG Performance Status 0-2

- Normal organ and marrow function as outlined in protocol

- Cardiac ejection fraction, as assessed by either MUGA scan or echocardiogram greater
than or equal to 50%

- Able to take oral medications

Exclusion Criteria:

- Patients may not be receiving any other investigational agents or concurrent
chemotherapy or hormonal therapy for treatment of metastatic disease

- Active brain metastases

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to lapatinib or other agents used in this study

- Clinically significant malabsorption syndrome

- Uncontrolled intercurrent illness

- Pregnant or breastfeeding women

- Concurrent use of the medications listed in the protocol because of possible
interaction with lapatinib