Neratinib in Treating Older Patients With Stage IV HER2-Positive Breast Cancer

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance 0-2
* Life expectancy of greater than 12 weeks
* Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically)
* Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies
* HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
* If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act \[CLIA\] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775\_G776insYVMA aka Y772\_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778\_S779insCPG, P780\_781insGSP aka G778\_P780dup, L755\_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed)
* Both measurable as well as non-measurable disease will be allowed
* Hemoglobin \>= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration
* Total bilirubin within normal institutional limits within 4 weeks of pre-registration
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration
* Creatinine clearance \>= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration
* Baseline left ventricular ejection fraction LVEF \>= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
* All grade \>= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement
* Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib
* Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study
* Provide written, informed consent to participate in the study and follow the study procedures

Exclusion Criteria:

* Prior treatment with neratinib
* Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade \>= 2 must have resolved by the time of study commencement (except alopecia)
* Any major surgery =\< 28 days prior to the initiation of investigational products
* Received chemotherapy or biologic therapy =\< 3 weeks prior to the start of neratinib
* Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of \>= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia
* Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval \>= 450 milliseconds in men and \>= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes
* Inability to take oral medication
* Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas
* Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade \>= 2 National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] v.4.0 diarrhea of any etiology at baseline)
* Known clinically active infection with hepatitis B or hepatitis C virus
* Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s judgment, makes the patient inappropriate for this study