Inclusion Criteria:

- Patients (men or women) must have histologically or cytologically confirmed invasive
breast cancer, with metastatic disease. Patients without pathologic or cytologic
confirmation of metastatic disease should have unequivocal evidence of metastasis by
physical exam or radiologic study.

- Invasive primary tumor or metastatic tissue confirmation of HER2-positive status

- Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive
tumor cells) AND/OR HER2 gene amplification (> 6 HER2 gene copies per nucleus or a
FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.0)

- Note: Patients with a negative or equivocal overall result (FISH ratio of < 2.0 or ≤
6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not
eligible for enrollment

- No increase in corticosteroid dose in the week prior to baseline brain MRI

- Prior trastuzumab and lapatinib therapy are allowed.

- There is no limit to the number of previous lines of therapy (including chemotherapy,
trastuzumab, and endocrine therapies)

- No prior therapy with neratinib is allowed

- At least 2 weeks washout period post chemotherapy, any prior protocol therapy,
lapatinib, other targeted or biologic therapy, or radiation therapy is required prior
to study entry

- No washout is required for hormonal therapy but concurrent hormonal therapy is not
allowed for patients on study

Patients with progressive disease (Cohort 1):

- For cohort 1, patients must have new or progressive CNS lesions, as assessed by the
patient's treating physician.

- In cohort 1, patients must have measurable CNS disease, defined as at least one
parenchymal brain lesion that can be accurately measured in at least one dimension
with longest dimension ≥10 mm by local radiology review. Note: measurable non-CNS
disease is NOT required for study participation

- It is anticipated that some patients may have multiple progressive CNS lesions, one
or several of which are treated with SRS or surgery with residual untreated lesions
remaining. Such patients are eligible for enrollment on this study providing that at
least one residual (i.e. non-SRS-treated or non-resected) lesion is measurable (≥10
mm).

- Patients who have had prior cranial surgery are eligible, provided that there is
evidence of measurable residual or progressive lesions, and at least 2 weeks have
passed since surgery. If a patient has surgical resection followed by WBRT, then
there must be evidence of progressive CNS disease after the completion of WBRT.

- Patients who have had prior WBRT and/or SRS and then whose prior treated lesions have
progressed thereafter are also eligible. In this case, lesions which have been
treated with SRS may be considered as target lesions if there is unequivocal
evidence, in the opinion of the treating physician, of progression.

Patients with with operable disease (Cohort 2):

- In cohort 2, eligible patients will include those who have CNS disease that is
amenable for surgery (typically < 3 brain metastases and with planned resection by
neurosurgery). These patients may include those who have received or not received
previous treatment(s) for their CNS.

- It is anticipated that that patients who have intracranial disease amenable to
surgery will have measurable CNS disease prior to study entry and to resection.
However, this is not an eligibility requirement. Measurable disease is also not
required to continue on protocol subsequent to surgical resection.

- For patients who undergo surgery, postoperative whole brain radiation therapy will
not be allowed while patients are on study (concurrent neratinib and radiation
therapy has not been studied and toxicity of this is unknown). Patients will require
discontinuation of neratinib if radiation therapy will be administered.

Exclusion Criteria:

- Not pregnant or breastfeeding

- Participants who have had chemotherapy or radiotherapy (including investigational
agents) within 2 weeks prior to entering the study or those who have not recovered
adequately from adverse events due to agents administered more than 4 weeks earlier
(excluding alopecia). Washout from trastuzumab is not required.

- Participants who are currently receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to neratinib

- Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin,
carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or
primidone

- Patients who are receiving any cancer-directed concurrent therapy, such as concurrent
chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment
with bisphosphonates is allowed but should be started before the first dose of
neratinib.

- 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

- More than two seizures over the last 4 weeks prior to study entry

- Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or
ocular foreign body

- Those with leptomeningeal metastases as the only site of CNS disease

- Significant malabsorption syndrome or inability to tolerate oral medications

- Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea