Neu Direction: Testing the Efficacy of Adding HER Inhibition to Standard of Care in Metastatic MLH1-low Endocrine-resistant ER+/HER2- Breast Cancer

The goal of this clinical trial is to learn if neratinib, an FDA-approved oral pan-HER2/3/4 inhibitor, improves disease control for participants with metastatic endocrine-resistant ER+/HER2-negative breast cancer. Neratinib is already approved for the treatment of HER2-postive breast cancers. The study will also learn about the safety of adding this drug to standard of care treatments. The main questions it aims to answer are: 1. Does adding neratinib to standard of care systemic therapy improve disease control for patients with metastatic hormone-driven breast cancer that is resistant to endocrine therapy? 2. What side effects do participants have when adding neratinib to standard of care therapy? Researchers will compare standard of care endocrine therapy regimens with and without neratinib to see if neratinib improves control of treatment-resistant metastatic breast cancer that has continued to progress while eon first line endocrine therapy. Participants will: 1. Take standard of care endocrine therapy for metastatic endocrine-resistant breast cancer as determined by their medical oncologist or standard of care therapy with neratinib daily 2. Visit the clinic every 3 months for checkups, tests and imaging studies

Inclusion Criteria: 1. Female over the age of 18 at the time of study enrollment 2. Not pregnant, planning to become pregnant or breast feeding 3. Metastatic ER+/HER2- breast cancer that has progressed on 1st line therapy including endocrine therapy +/- CDK4/6 inhibitors 4. At least one metastatic lesion visible on imaging (including FDG-PET) 5. At least one metastatic lesion must be biopsied and confirmed ER+ and HER2- by immunohistochemistry within 6 months of study screening (HER2 equivocal disease will be confirmed HER2- by FISH) 6. Tumors must be MLH1-low defined by \ 3 9. Life expectancy \> 1 year 10. Ability to get serial imaging studies Exclusion Criteria: 1. History of concurrent use of other HER2-targeted therapy 2. Concurrent use of other targeted systemic therapy 3. History of other cancers other than non-melanoma skin cancer 4. Actionable mutations on tumor genomic sequencing will be ineligible, and those participants encouraged to proceed with the relevant targeted therapy 5. Participants where there is not at least one imaging apparent lesion that has not been treated with prior targeted therapy (for example palliative radiation or cryoablation) 6. Contraindications to Neratinib use including allergy or hypersensitivity 7. Baseline grade 3+ diarrhea