Patient description: The patient is a 42 year-old postmenopausal woman who had a screening sonogram which revealed an abnormality in the right breast. She had no palpable masses on breast exam. Core biopsy was done and revealed a 1.8 cm infiltrating ductal breast carcinoma in the left upper outer quadrant. Lumpectomy was done and the surgical margins were clear. The tumor was HER2-positive and ER/PR negative. Axillary sampling revealed 1 positive lymph node out of 12 sampled. CXR was unremarkable. She is using “well women” multivitamins daily and no other medication. She smokes frequently and consumes alcohol occasionally. She is in a relation with only one partner and has a history of 3 pregnancies and live births. She breastfed all three children.

Clinical trial eligibility criteria: eligible ages (years): 18.0-999.0,  Breast Cancer Participants must have histologically or cytologically confirmed inoperable locally advanced or metastatic ER+ breast cancer. To fulfill the requirement for ER+ disease, a breast cancer must express, by immunohistochemistry (IHC), ER in ≥10% of cells, on the most recent biopsy. If ER quantification is not available, a determination of ER+ by IHC will suffice. Central confirmation of ER status is not required Participants must have documented HER2+ disease by overexpression and/or gene amplification on the most recent biopsy, per current ASCO-CAP (American Society of Clinical Oncology College of American Pathologists) guidelines. Central confirmation of HER2 status is not required Participants must have received prior therapy with the following agents in any combination, and in setting (i.e., neoadjuvant, adjuvant, metastatic, etc.). These therapies do not need to be the most recent line of therapy Trastuzumab Pertuzumab Ado-trastuzumab emtansine (T-DM1) Participants must agree to undergo a research biopsy of a reasonably accessible metastatic lesion (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast, bones, lung, and liver metastases). If a reasonably accessible metastatic lesion is not available, the patient may go on study provided that archived tissue is available. However, if a reasonably accessible site is available for biopsy, the patient must agree to biopsy. Any patients not undergoing biopsy must be approved for study enrollment by the Overall Principal Investigator at DFCI. Biopsies may be done with local anesthesia or intravenous conscious sedation, according to institutional guidelines. If a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is clinically indicated, and excess tissue may be collected for research purposes. Patients without sites available for biopsy must have available tissue [archived formalin-fixed paraffin embedded blocks (FFPB), blocks from which slides can be created, or fresh frozen tissue from original diagnosis or metastatic setting] for correlative studies. Tissue needs to be located and available at the time of registration See Section 9.3 for more details Women ≥ 18 years of age. Men are not eligible Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A)  Participants who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or fulvestrant Participants who have known hypersensitivity to any component of loperamide or colestipol Participants who have received previous therapy with neratinib Participants who have received anti-cancer therapy (including chemotherapy, biological therapy, investigational agents, hormonal therapy, or other anti-cancer therapy) or radiotherapy within ≤14 days prior to the planned initiation of investigational products, or those who have not recovered to grade ≤1from adverse events due to their most recent therapy (excepting alopecia) Participants who have had any major surgery ≤28 days prior to the planned initiation of study therapy, or those who have not recovered from adverse events due to agents/surgery administered more than 4 weeks earlier Participants who are receiving any other investigational agents Participants with known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with a history of treated central nervous system (CNS) metastases are eligible. Treated brain metastases are defined as those without ongoing requirement for corticosteroids, as ascertained by clinical examination and/or brain imaging (magnetic resonance imaging or CT scan) completed during screening. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥ 7 days prior to registration. Treatment for brain metastases may whole brain radiotherapy, radiosurgery, surgery or a combination as deemed appropriate by the treating physician. Radiation therapy must be completed at least 14 days prior to registration Participant has active, uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia Participant has a QTc interval >470 ms or known history of QTc prolongation or Torsade de Pointes Participant has an active infection or unexplained fever >38.5°C (101.3°F)