An Open Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With HER2+ Breast Cancer Treated With Neratinib With or Without Trastuzumab

Study start date: October 9, 2018

INCLUSION CRITERIA: * Age \>= 18 years * Histologically confirmed clinical or pathological stage 2 through stage 3c primary adenocarcinoma of the breast * Documented human epidermal growth factor receptor 2 (HER2) overexpression or gene-amplified tumor by a validated approved method * Patients can have hormone receptor (HR)+ or HR-negative disease * Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed * Patients can be premenopausal or postmenopausal * Completion of neoadjuvant or adjuvant chemotherapy * Completion of adjuvant locoregional radiation, if indicated, is required prior to starting study treatment * Histologically confirmed clinical or pathological stage 2 through stage 3c primary adenocarcinoma of the breast * Documented HER2 overexpression or gene-amplified tumor by a validated approved method * Patients can have hormone receptor (HR)+ or HR-negative disease * Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed * Patients can be premenopausal or postmenopausal * Completion of neoadjuvant or adjuvant chemotherapy * Completion of adjuvant locoregional radiation, if indicated, is required prior to starting study treatment * At the time of study enrollment, patients can still be receiving adjuvant trastuzumab monotherapy or be within 2 years of completing adjuvant trastuzumab +/- pertuzumab maintenance, or adjuvant T-DM1. * Patients who are within 2 years of completing trastuzumab +/- pertuzumab or T-DM1 will receive neratinib monotherapy (and not neratinib + trastuzumab) * Adjuvant T-DM1 is the standard of care for patients who have residual disease after neoadjuvant chemotherapy. Patients with residual disease after neoadjuvant chemotherapy should receive T-DM1 before enrolling on the study. If not, the option of T-DM1 should be discussed with the patient * Clinically no evidence of metastatic disease at the time of study entry. Patients with fully resected locoregional recurrence with no evidence of disease are eligible * Left ventricular ejection fraction (LVEF) \>= 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO) * Eastern Cooperative Oncology Group (ECOG) status of 0 to 1 * Negative beta-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause; (women are considered postmenopausal if they are \>= 12 months without menses, in the absence of endocrine or anti-endocrine therapies) * Trastuzumab can cause embryo-fetal harm when administered during pregnancy and the effects of neratinib on the developing human fetus are unknown. Women of child-bearing potential must agree and commit to use of a highly effective double-barrier method of contraception (e.g., a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of informed consent until 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab). Men without confirmed vasectomy must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of investigational products, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 3 months after the last dose of study medication) * Recovery (i.e., to grade 1 or baseline) from all clinically significant adverse event (AE)s related to prior therapies (excluding alopecia, neuropathy, and nail changes) * Provide written, informed consent to participate in the study and follow the study procedures EXCLUSION CRITERIA: * Clinical or radiologic evidence of metastatic disease prior to or at the time of study entry. Locoregional recurrent disease that is resected is allowed * Currently receiving chemotherapy, radiation therapy, investigational immunotherapy, or investigational biotherapy for breast cancer * Major surgery (including breast surgery) within \< 30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy \< 14 days prior to the initiation of investigational products (except adjuvant endocrine therapy) * Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of \>= 2; including individuals who currently use digitalis, beta-blockers, or calcium channel blockers specifically for congestive heart failure), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia * Corrected QT (QTc) interval \> 0.450 seconds (males) or \> 0.470 seconds (females), or known history of QTc prolongation or Torsade de Pointes (TdP) * Absolute neutrophil count (ANC) =\< 1,000/microliter (uL) * Platelets =\< 100,000/uL * Hemoglobin =\< 9 g/dL * Serum creatinine \>= 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance =\< 30 mL/min for patients with creatinine levels \> 1.5 x institutional ULN \* Creatinine clearance should be calculated per institutional standard * Serum total bilirubin \>= 1.5 x ULN OR direct bilirubin \>= ULN for patients with total bilirubin levels \> 1.5 x ULN * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (\[SGOT)) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) \>= 2.5 x ULN * Second malignancy for which the patient will be receiving active treatment during the time of study participation. * Currently pregnant or breast-feeding * 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 Version 4.0 (CTCAE v.4.0) diarrhea of any etiology at baseline) * Clinically active infection with hepatitis B or hepatitis C virus * Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the investigator's judgment, make the patient inappropriate for this study * Known hypersensitivity to any component of the investigational products * Unable or unwilling to swallow tablets