Background: Invasive lobular carcinoma (ILC) comprises 10-15% of breast tumors and is the second most common histological type after invasive ductal carcinoma (IDC). Patients with ILC are often diagnosed at an older age and more advanced stage than those with IDC. Late recurrences and worse long-term survival suggest the need for improved approaches to treatment optimization and exploration of molecular pathways unique to ILC. Although previous reports have described comprehensive transcriptomic profiling of ILC, these were limited by small sample sizes. Furthermore, differential gene expression between ILC and IDC within genomic risk groups and molecular subtypes has yet to be explored. Here we characterize differential gene expression between ILC and IDC in a large, age-matched patient subset categorized by 70-gene signature/MammaPrint (MP) risk and 80-gene signature/BluePrint (BP) subtype.

Methods: The prospective FLEX Registry (NCT03053193) includes stage I-III primary invasive breast cancer patients who receive MP/BP testing and consent to full transcriptome and clinical data collection. This sub-analysis included 450 ILC patients enrolled from 2017 to present. Compared with a random selection of IDC patients (n=450, mean age, 60 years), ILC patients were older (mean, 63 years, p<0.001). Thus, we selected an age-matched subset for differential gene expression analysis. There were few non-Luminal ILCs; thus, gene expression analyses were limited to BP Luminal tumors. A subset of 413 age-matched pairs (n=826) of ILC and IDC were used for analysis. Gene expression data were quantile normalized using R limma package, and differentially expressed genes (DEGs) were compared between groups. DEGs with an adjusted p<0.05 and log2 fold change > ± 1.0 were considered significant.

Results: ILC represented 13% of FLEX cases (n=450/3562), and were 81% lymph node-negative, 99% ER+, 94% HER2-negative, and 68% MP Low Risk (LR). By BP, ILC were 99% Luminal, 1% HER2, and <1% Basal type. BP Luminal ILC were predominantly grade 2 (63%), T1 (61%), node-negative (84%), and MP LR (69%). Menopausal status, nodal status, ethnicity, BMI distribution, and frequency of type 2 diabetes mellitus were similar between ILC and IDC. However, IDC were more likely to be MP HR (46% IDC vs. 31% ILC, p<0.001) and grade 3 (15% IDC vs. 4% ILC, p<0.001). ILC were more likely to be T3 (10% ILC vs. 1% IDC, p<0.001). We found 4 DEGs common to all comparisons: all Luminal ILC vs. IDC, MP LR ILC vs. IDC, and MP HR ILC vs. IDC. ILC had lower expression of CDH1 (E-cadherin) than IDC, regardless of MP risk. Including CDH1, 6 unique genes were differentially expressed in LR ILC compared with IDC, and 21 genes were differentially expressed in HR ILC compared with IDC. Genes with increased expression in HR ILC were related to immune cell migration/chemotaxis, hormone signaling, and growth factor signaling. HR ILCs were also enriched for TGFβ signaling and angiogenesis pathway genes.

Conclusions: Here we report differential clinical and molecular characteristics between ILC and IDC in a large, age-matched patient subset. Regardless of MP risk, expression of CDH1 was lower in ILC compared with IDC. Approximately one-third of ILCs were MP HR, and we report a greater number and diversity of DEGs between HR ILC and HR IDC compared with LR tumors, in particular genes related to TGFβ signaling. TGFβ pathway genes play a variety of roles in the tumor microenvironment, including induction of angiogenesis, fibroblast growth factor stimulation, and inhibition and/or exclusion of an immune response. These results suggest that therapeutic strategies targeting the TGFβ pathway may be future avenues of exploration in ILC, although further studies are warranted to characterize underlying molecular mechanisms.

Citation Format: Beth-Ann Lesnikoski, Jennifer A. Crozier, Gordan Srkalovic, Patricia Robinson, Clodia Osipo, Kaylan Banda, Heather M. Kling, Josien Haan, William Audeh, FLEX Investigators Group. Differential gene expression in luminal-type invasive lobular carcinoma and invasive ductal carcinoma by MammaPrint risk stratification [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-03.