A Phase II Study of Lapatinib in Combination With Trastuzumab in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

Inclusion Criteria:

- Patient must have histologically or cytologically confirmed metastatic breast cancer

- The breast cancer has been tested negative for HER2 (0 or 1+ by immunohistochemistry
[IHC] or non-amplified by fluorescence in-situ hybridization [FISH])

- Patient may have measurable or evaluable disease

- If given prior radiotherapy and/or prior chemotherapy, the patient must have
completed radiation therapy and be at least 1 week from the last chemotherapy
administration, with adequate recovery of bone marrow and organ functions, before
starting lapatinib or trastuzumab

* Note that the HER2 sequencing analysis can be performed while patient is receiving
other systemic therapies so the results could be used to determine whether the
patient is eligible to receive lapatinib and trastuzumab when disease progresses from
current therapy

- Patient must have had at least one lines of systemic therapy for metastatic breast
cancer

- Patient must have disease that progressed on his/her most recent treatment regimen

- Patient must be > 18 years of age.

- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =<
2

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) unless due to
Gilbert's syndrome

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 3.0 x IULN with/without liver metastases

- Creatinine =< 1.5 x IULN

- Patient must have a left ventricular ejection fraction (LVEF) >= institutional lower
limit of normal (ILLN) to be eligible for study treatment; to avoid the cost of
screening, patients with known recent LVEF < LLN or symptoms of congestive heart
failure are not eligible for registration

- Women of childbearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control, abstinence) prior to
study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she must
inform her treating physician immediately

- Patient (or legally authorized representative if applicable) must be able to
understand and willing to sign an institutional review board (IRB) approved written
informed consent document

- Patients with known treated brain metastasis are eligible, but must have received
radiation and be off steroids and stable for 3 months

- Patients meeting all inclusion criteria listed above and exclusion criteria will be
registered to undergo HER2 mutation analysis; only patients with mutations in HER2
either in the primary or metastatic tumor are eligible for study therapy with
lapatinib and trastuzumab; those without mutations in HER2 are not eligible for
study drug therapy; information and tissue collected from patients without HER2
mutations will be used for molecular epidemiology studies of HER2 negative breast
cancer

Exclusion Criteria:

- Patient must not be receiving any other investigational agents

- Patient must not have an 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

- Patient must not have acute or currently active/requiring antiviral therapy hepatic
or biliary disease (with the exception of patients with Gilbert's syndrome,
asymptomatic gallstones, liver metastases, or stable chronic liver disease per
investigator assessment)

- Patient must not be pregnant and/or breastfeeding

- Patient must not have a history of significant cardiac disease, cardiac risk factors,
or uncontrolled arrhythmias

- Patient must not have symptomatic intrinsic lung disease or extensive tumor
involvement of the lungs resulting in dyspnea at rest