Inclusion Criteria:
Each patient will be entered into this study only if all of these criteria are met:
* Subjects aged 18 years or older at signing of informed consent.
* New diagnosis of clinical stage I-III HR+ histologically-proven (i.e. absent or decreased e-cadherin expression) invasive lobular carcinoma
* Synchronous breast tumors are permitted as long as the synchronous tumor is ER+ and HER2-negative.
* ER+ disease defined as ≥1% estrogen receptor (ER) positive consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines)
* At the time of screening, histologically confirmed cancers in patients with previously documented activating HER2 mutation (see Appendix A) confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory.
* Archival tissue availability (if not available a fresh tumor biopsy will be required) and subject must agree to submission of sample for central testing
* Minimum tumor size of ≥1.5 cm by US, mammogram, MRI imaging, or clinical breast exam
* ECOG performance status 0 or 1
* Patients must have adequate hematologic, hepatic, and renal function. All laboratory tests must be obtained within 1 month of study entry. This includes:
* Estimated glomerular filtration rate of ≥50 mL/min
* Albumin ≥ 2.5 g/dL
* ANC ≥1500/mm\^3
* Platelet count ≥100,000/mm\^3
* HgB ≥ 9 g/dL
* Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
* AST and ALT ≤ 3 x ULN
* Pre-, peri-, or post-menopausal, confirmed by history or laboratory testing as needed
* Diagnostic biopsy tissue availability with sufficient tumor to permit NGS (if not available, a fresh biopsy will be required)
* No prior treatment for current diagnosis of breast cancer
* For patients who are not postmenopausal (women) or surgically sterile (absence of ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal ligation), during the treatment period and for at least 30 days after the last dose of study treatment. Hormone based oral contraceptives are not allowed on study. Postmenopausal is defined as:
* Age ≥ 55 years
* Age ≤ 55 years and amenorrheic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone and estradiol in the postmenopausal range. Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception that has a low user dependency consistently and correctly.
Note: The effects of neratinib on the developing fetus are unknown and endocrine therapy is contraindicated in pregnancy. For this reason and because teratogenic effects have been observed in nonclinical studies and neratinib, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of the study participation, and for 1 month after the last dose of study medication. Should a woman become pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation and 3.5 months after completion of study treatment.
Exclusion Criteria:
* Evidence of distant metastatic disease
* Synchronous breast cancer that is estrogen receptor negative OR HER2-amplified OR requires treatment with neoadjuvant chemotherapy per the judgement of the treating physician
* Patients harboring ineligible somatic HER2 mutations, such as those that are subclonal in nature or those resulting in the expression of truncated proteins including alterations that result in premature stop codon or a change in reading frame (ie, frame shift mutations).
* Prior endocrine therapy for breast cancer within the last 2 years
* Women who are pregnant, are planning to become pregnant, or are breast-feeding
* Any investigational treatment for the current diagnosis of breast cancer
* HER2 amplification by FISH (HER2:CEP17 ratio \>2.0) or IHC (HER2 (3+)
* Hepatic function impairment as defined by AST or ALT \> 3x ULN OR total serum bilirubin \> 1.5 (in patients with known Gilbert syndrome, a total bilirubin of \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN)
* Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events Version 4.0 \[CTCAE version 4.0\] diarrhea of any etiology at baseline.
* 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 product, required combination therapy, or loperamide.
* Unable or unwilling to swallow tablets.
* Unable or unwilling to complete study procedures such as research biopsies or imaging
* Any medical condition that in the judgement of the co-investigator would impair the patient's ability to complete the planned study therapy
