Identification and credentialing of patient-derived xenograft models of invasive lobular carcinoma.

Abstract

Invasive lobular cancer (ILC) is the most common special breast cancer subtype, accounting for 10-15% of all cases. The pathognomonic feature of ILC is loss of E-cadherin (encoded by CDH1), leading to discohesive single-file growth. Although ILCs show better prognostic factors than 'no special type' (NST) breast cancer, patients with ILC have worse long-term outcomes. We identified and validated patient-derived xenograft (PDX) models of ILC from 122 breast cancer PDX models based on truncating CDH1 mutations and/or low CDH1 mRNA expression. Eight PDX models were selected for validation using immunohistochemistry for E-cadherin, p120, estrogen receptor, progesterone receptor and HER2. Seven models were confirmed as ILC, and one showed mixed NST-ILC features. Confirmed ILC PDX models showed enrichment of truncating CDH1 mutations, significantly lower CDH1 mRNA expression and predominantly luminal subtypes compared to NST models, consistent with human ILC characteristics. Commonly altered genes included PIK3CA (57%), CDH1 (57%) and TP53 (57%). These validated ILC PDX models provide valuable tools to advance understanding of ILC biology and support development of targeted therapies.