BACKGROUND: Invasive lobular carcinoma (ILC) accounts for approximately 10-15% of all breast cancers and is characterized by hormone receptor positivity (HR+), lack of HER2 amplification, low Ki-67 score, and loss of cell adhesion receptors such as e-cadherin. While these tumors tend to be indolent initially, late recurrences and distant metastasis are common. Effective systemic treatments that can improve both surgical and long-term outcomes for these patients are needed. ILC has very low rates of pathologic complete response (pCR) to both neoadjuvant chemotherapy (3%) and neoadjuvant endocrine therapies (ET, 0%). HER2 mutations are enriched in about 5-10% of unselected ILC, with some reports showing the prevalence as high as 27% in pleomorphic and higher grade ILCs. HER2 mutations in ILC are associated with antiestrogen resistance and a worse prognosis. Neratinib, an FDA-approved adjuvant treatment for HER2-amplified (HER2+) early-stage breast cancer, has shown safety and efficacy in combination with ET in metastatic HER2-mutant HR+ breast cancer. Our hypothesis is that the combination of neratinib and ET will improve clinical and molecular activity in HER2-mutant HR+ ILC, representing a novel and rational neoadjuvant therapy option. TRIAL DESIGN: We propose an unblinded, multi-institutional Phase II clinical trial for 30 patients with Stage I- III ILCs with HER2 mutations. Patients will be initially randomized to either 4 weeks of neratinib + ET OR ET alone; a biopsy will be done at the end of the lead-in phase. All patients then will receive a combination of 20 weeks of ET and neratinib prior to proceeding to surgery. KEY ENDPOINTS: The primary objective of this study is to determine the pre-operative endocrine prognostic index (PEPI) score on the surgical sample in these patients. The secondary clinical objectives will be to evaluate the pCR rate, residual cancer burden (RCB) index, and rates of breast conserving surgery. In addition, we propose correlative studies that will promote understanding of how neratinib synergizes with antiestrogen therapies by evaluating tumor cell cycle arrest and apoptosis markers in the pre-treatment and on-treatment (4 week) biopsy in both the ET ± neratinib arms. Finally, we will study the longitudinal evolution of therapy tolerance and resistance in HER2-mutated breast cancer. We will develop patient-derived organoids and perform single- cell RNA and ATAC sequencing and DNA sequencing to elucidate transcriptional and epigenetic programs that permit breast cancer survival upon continuous HER2-directed therapy and somatic alterations that drive resistance. We hypothesize that the combination of neratinib and ET will improve clinical and molecular activity in HER2- mutant HR+ ILC, addressing an unmet need for this challenging to treat breast cancer subtype.