Neoadjuvant targeted therapy in early resectable HER2-mutant lobular breast cancer.

TPS630 Background: Invasive lobular carcinoma (ILC) accounts for approximately 10-15% of all breast cancers and is characterized by hormone receptor positivity (HR+), 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, and ILC has very low rates of pathologic complete response (pCR) to both neoadjuvant chemotherapy and endocrine therapy (ET). HER2 ( ERBB2) mutations are enriched in about 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 ET resistance and a worse prognosis. Neratinib is a HER2 tyrosine kinase inhibitor (TKI) currently FDA-approved for adjuvant treatment of HER2-amplified (HER2+) early-stage breast cancer. It has shown safety and efficacy in combination with ET in metastatic HER2-mutant HR+ breast cancer. We hypothesize that neoadjuvant treatment with neratinib and ET will improve pathologic responses in newly diagnosed HER2-mutant HR+ ILC. Methods: This study (NCT05919108) is an open label multi-site Phase II clinical trial for 30 patients with Stage I-III ILCs and a HER2 activating mutation. Patients will be identified by next generation sequencing (NGS) of the diagnostic biopsy and randomized to 4 weeks of ET +/- neratinib; a biopsy will be done at the end of the lead-in phase. All patients will then receive ET and neratinib for 20 weeks prior to proceeding to surgery. To optimize tolerability, the first cycle of neratinib will include a dose escalation and antidiarrheal prophylaxis. The primary objective of this study will be the pre-operative endocrine prognostic index (PEPI) score, which will be compared to a historical PEPI-0 rate for patients with HR+ breast cancer treated with neoadjuvant ET. Secondary objectives will include pCR, residual cancer burden, and rates of breast conserving surgery. Correlative studies will include biomarkers of tumor cell cycle arrest, apoptosis, HER2 pathway activation, and gene expression on the pre- and on-treatment (4 week) biopsy from the lead-in phase to document molecular synergy between neratinib and ET. Patient-derived organoids from the 4-week biopsies will be established and subjected to single-cell RNA, ATAC seq, and DNA sequencing to study tumor evolution and elucidate epigenetic programs and somatic alterations that allow breast cancer survival despite continuous HER2-directed therapy. This is a first-in-kind, mechanism-based, molecularly targeted combination of a HER2 TKI and ET in HER2-mutant ILC. We posit results from this study may generate a clear signal of clinical activity leading to a randomized phase III trial aimed at incorporating HER2-directed therapies as a treatment for operable, early stage ILC. This signal may also suggest for the first time the added value of NGS in patients with newly diagnosed HR+ breast cancer. Clinical trial information: NCT05919108 .