Capecitabine and Lapatinib Ditosylate With or Without Cixutumumab in Treating Patients With Previously Treated HER2-Positive Stage IIIB-IV Breast Cancer

Inclusion Criteria

• Histologically confirmed, locally advanced: (a T4 primary tumor and stage IIIB or IIIC disease) or metastatic breast cancer that has progressed after treatment with regimens that included trastuzumab and either an anthracycline or a taxane or both
• NOTE: Agents need not have been given concurrently, nor in the same regimen
• NOTE: Prior treatment with trastuzumab is required unless there is a contraindication for trastuzumab treatment
• Pre-treatment requirements:
• Prior treatment with trastuzumab in the neo-adjuvant, adjuvant or metastatic setting is required
• NOTE: Prior treatment with trastuzumab is required unless there is a contraindication for trastuzumab treatment
• NOTE: Concomitant use of trastuzumab is not allowed in this study
• Prior chemotherapy allowed in the neo-adjuvant, adjuvant, or metastatic setting; unlimited prior chemotherapy is allowed
• Prior hormonal therapy allowed in the neo-adjuvant, adjuvant, or metastatic setting; unlimited prior hormonal therapy is allowed
• HER2 positive, defined as:
• Validated immunohistochemistry (IHC) assay score of 3+ (defined as uniform, intense staining of > 30% of invasive tumor cells)
• -OR- Average HER2 gene copy number of > 6
• -OR- Gene amplified (HER2: D17Z1 ratio > 2.20)
• Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria
• Negative pregnancy test done = 9.0 g/dL (obtained = = 3,000/mL (obtained = = 1500/mL (obtained = = 75,000/mL (obtained = = 30 mL/min (calculated according to Cockcroft and Gault) (obtained = = 50% as determined by multi gated acquisition scan (MUGA) or echocardiogram
• Life expectancy > 3 months
• Has written informed consent been obtained?
• Willingness to return to a North Central Cancer Treatment Group (NCCTG) or other participating cooperative group institution for treatment and follow-up
• Patient willing to provide tissue and blood samples for research purposes
• Availability of diagnostic material (i.e., diagnostic slides confirming locally advanced/metastatic disease and HER2 stained slides) and operative and pathology reports from diagnosis of locally advanced or metastatic breast cancer
• NOTE: Biopsy of recurrent disease and submission of these materials is not required if materials available from initial diagnosis of locally advanced/metastatic disease
• Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception (as determined by the treating physician)
• Stage III or IV invasive cancer, other than breast cancer, in =< 5 years prior to registration
• Actively being treated for other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of the cervix; if there is a history of prior malignancy, patient must not be receiving other specific treatment for their cancer
• New York Heart Association class III or IV cardiovascular disease
• Current, active hepatic or biliary disease except Gilbert's syndrome or asymptomatic gallstones
• Evidence of active brain metastasis including leptomeningeal involvement; central nervous system (CNS) metastasis controlled by prior surgery and/or radiotherapy is allowed
• NOTE: To be considered controlled, there must be at least 2 months of no symptoms or evidence of progression prior to study entry and corticosteroid therapy must have been discontinued
• Major surgery, chemotherapy, or immunologic therapy =< 4 weeks prior to registration
• Radiotherapy =< 4 weeks prior to registration, except if to a non-target lesion only; prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed; if patient receives si