Identification and molecular characterization of invasive lobular breast cancer models in a panel of 180 breast XPDX models

Background: Invasive lobular and ductal breast tumors have distinct histologies and clinical presentation. Invasive lobular cancer (ILC) characteristics include somatic alterations in the CDH1 gene leading to loss of E-cadherin expression, low HER2 expression, frequent loss of PTEN, increased AKT expression and mutations in PIK3CA, TBX3 and FOXA1 genes. Invasive ductal cancers (IDC) express E-cadherin and more often include HER2+ cancers and ESR1 mutations. The XenoSTART Patient-Derived Xenograft (XPDX) breast cancer platform includes over 180 models spanning all subtypes characterized with immunohistochemistry (IHC) including ERα, PR and HER2 protein levels, genomic and transcriptomic sequencing and in in vivo drug sensitivity. To further annotate our platform, we classified each breast XPDX model as ILC or IDC based on clinical history, E-cadherin staining, presence of variants in target genes and HER2 expression or amplification. Methods: XPDX models were established and validated as previously described and further characterized using IHC to determine E-cadherin protein levels (Abcam a-Rabbit ab15148). Analysis was performed on WES to identify variants in CDH1, PIK3CA, TBX3, FOXA1 and PTEN. RNAseq data was used to determine expression levels of AKT and HER2. Clinical histology data was also used for ILC versus IDC classification. Resulting models classified as ILC by our analysis were histologically confirmed by a clinical pathologist. Results: 180 breast models were examined by IHC and 25/180 (14%) lacked E-cadherin staining. Six of these 25 models (24%) reported CDH1 variants including deletions, frameshifts and point mutations. PIK3CA mutations, most notably H1047R, were reported in 5/25 models and FOXA1 (Q209E) was co-mutated in 2 of these models (ST2167 and ST2167/TDR). High AKT1 expression was reported in 5/25 models. While most E-cadherin-negative models were from clinically HER2 negative patients, 4/25 were from clinically HER2+ patients and corresponding models retained HER2 staining and amplification. 3/25 models were clinically classified as metaplastic and did not contain any target gene variant. Conclusion: We screened 180 models in our XPDX breast cancer platform and identified at least twenty-two ILC models based on E-cadherin staining, genomics and clinical histology, and confirmed heterogeneity of this subtype of breast cancer. Additonal analysis is underway to compare sensitivity of chemotherapy and targeted agents in ILC and IDC-classified breast models. No conflict of interest.