Purpose: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer, but distinct treatment strategies are limited. Better characterization of the genomic and transcriptomic landscape is critical to elucidate ILC tumor biology, improve histologic classification, and define precision medicine treatment approaches.

Materials and Methods: We retrospectively analyzed de-identified next-generation sequencing data of 4,613 metastatic patients from the Tempus database including 637 with ILC, 91 with mixed lobular/ductal histology, and 3,885 with invasive breast carcinoma of no special type (IBC-NST). Samples were profiled using the Tempus xT assays.

Results: Mutations in CDH1 occurred in 71% of ILC patients (453/637). The median tumor mutational burden was significantly higher in CDH1-mutant ILC samples compared to wild type (p=0.008). Mutations in PIK3CA (55% vs. 28%), ERBB2 (13% vs. 4.3%), and TBX3 (12% vs. 3.8%) were enriched in CDH1-mutant ILC versus CDH1-wild type ILC. CDH1 expression was similar between CDH1-mutant ILC and wild type ILC samples (p=0.11). Patients with CDH1-mutant mixed histology or IBC-NST had lower CDH1 expression than CDH1-wild type mixed histology or IBC-NST patients (p<0.001). ILC had a different distribution of PAM50 subtypes compared to IBC-NST and mixed (p<0.001).

Conclusions: Our real-world data illustrate the distinct molecular landscape of CDH1-mutant metastatic ILC, and therapies targeting ERBB2 and PIK3CA should be further investigated in CDH1-mutant ILC. ILC differs from mixed and IBC-NST at a transcriptional level, suggesting the possibility of using CDH1 RNA expression levels to improve classification of ILC.

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