Characterizing and Targeting ERBB2 Mutations in Invasive Lobular Carcinoma

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PROJECT SUMMARY Although invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer, there remains much to be learned about the unique nature of this disease. Compared to invasive ductal carcinoma (IDC), ILC is understudied, with distinct histological, genomic, and clinical characteristics. Despite key differences, women with estrogen receptor-positive (ER+) ILC will most likely receive the same treatment as women with ER+ IDC though often show inferior long-term outcomes. Recently, the Lee-Oesterreich Lab and others have identified enrichment of ERBB2 mutations in ILC compared to IDC. As ILC is characterized by loss of CDH1 (E-cadherin), our findings may suggest a potential interaction between loss of CDH1 and mutations in ERBB2 in driving ILC tumor progression. As ERBB2 mutations usually occur in the absence of ERBB2 amplification, there are currently no FDA-approved therapies targeting ERBB2 mutant ILC. Several clinical trials have reported promising efficacy of anti-HER2 tyrosine kinase inhibitors, including neratinib, in patients with ERBB2 mutant ILC. However, resistance to these therapies is inevitable. In order to identify the most effective combination therapies, the functional role of these recurrent ERBB2 mutations in ILC requires further investigation. Using a combination of clinical specimens, innovative in vitro models and CRISPR-based genome editing, our proposal will determine the prevalence of ERBB2 mutations in ctDNA collected from plasma samples of patients with metastatic breast cancer and investigate how these mutations influence HER2 activation and downstream signaling pathways and sensitivity/resistance to available anti-HER2 agents (Aim 1). We will also evaluate the effects of CDH1 knockout and re-expression on HER2 signaling and degradation in order to understand the cooperation between loss of CDH1 and mutations in ERBB2 in ILC and explore potential mechanisms of HER2 regulation by E-cadherin (Aim 2). Results of this and future research will help inform clinicians and researchers of the mechanisms, clinical relevance, and targetability of recurrent ERBB2 mutations and complement findings from ongoing clinical trials to identify the most effective therapy combinations for patients with ERBB2 mutant ILC.