Patient will be treated with neratinib, an aromatase inhibitor and trastuzumab for 24 weeks prior to surgery, following an initial 3 weeks of neratinib alone, aromatase inhibitor alone or the combination of neratinib and an aromatase inhibitor. A breast biopsy will be performed prior to Day 1 of week 4 of treatment. Following surgery, patients will receive standard of care HER2-directed and endocrine therapy at the treating physician's discretion.

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

• Age ≥ 18 years at the time of consent.

• Postmenopausal females. NOTE: Postmenopausal status defined as: prior bilateral oophorectomy, Age ≥ 60 years, or Age < 60 years and amenorrhea for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) or an estradiol level in postmenopausal ranges per local reference range.

• ECOG Performance Status of 0-2 within 28 days prior to registration.

• Anatomic, clinical stage I-III, invasive breast cancer, greater than 10mm

• HER2-positive (by the most recent ASCO-CAP criteria)

• ER positive (≥ 10%). NOTE: There is no requirement for PR status; PR positive or negative allowed.

• Resectable breast cancer in which pre-operative therapy is appropriate (T > 10mm and/or node-positive).

• Archival tissue from the diagnostic pre-treatment biopsy is required. This sample should be identified at screening and shipped by Week 4. If archival tissue is not available, the subject is not eligible for the study.

• Agreeable to repeat breast biopsy at 3 weeks after initiation of treatment.

• Candidate for either letrozole or anastrozole, as determined by the treating physician

• Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) documented within 4 weeks prior to the study treatment.

• Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.

  • Hematological

    • Platelet count ≥100,000/uL
    • Absolute Neutrophil Count (ANC) ≥1500/uL
    • Hemoglobin (Hgb) ≥10 g/dL

  • Renal

    ---Calculated creatinine clearance: CrCl ≥30 mL/min using the Cockcroft-Gault formula

  • Hepatic

    • Bilirubin ≤1.5 x upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) ≤ 2.5 × ULN
    • Alanine aminotransferase (ALT) ≤ 2.5 × ULN

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.

• For patients with known serologic evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial.

• Ability of the subject to understand and comply with study procedures for the entire length of the study, as determined by the enrolling physician or protocol designee.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• Locally advanced or inflammatory breast cancer. NOTE: Locally advanced is defined as Stage IIIC or greater.

• Evidence of metastatic disease. Systemic imaging is not required.

• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial: exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.

• Active infection requiring systemic therapy.

• Requirement for use of a moderate or strong CYP3A4 inhibitor or inducer during the study (see protocol).

• Treatment with any investigational drug within 14 days prior to registration or within 5 half-lives of the investigational product, whichever is longer.

• Subject has had major surgery within 14 days prior to registration or has not recovered from major side effects of the surgery (tumor biopsy is not considered as major surgery).

• Any impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) or significantly impair the ability to swallow capsules/tablets.

• Known history of myelodysplastic syndrome or acute myeloid leukemia.

• Subjects with any of the following conditions:

  • History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 28 days prior to registration.
  • Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to registration.
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to registration.
  • Symptomatic congestive heart failure (New York Heart Association III-IV) or documented current cardiomyopathy with left ventricular ejection fraction (LVEF) <50%.
  • Clinically significant cardiac ventricular arrhythmias (e.g. sustained ventricular tachycardia/ventricular fibrillation) or high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block) unless a pacemaker is in place.
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.

• Any concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate subject participation in the clinical study or compromise compliance with the protocol.