Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify novel drivers, and prognostic biomarkers, using in-house (n=25), METABRIC (n=125) and TCGA (n=145) samples. Using in silico integrative analyses a 194-gene set was derived that is highly prognostic in ILC (P=1.20 × 10−5) we named this metagene LobSig. Network analysis identified few candidate pathways, though gene sets related to proliferation were identified, and a LobSig-high phenotype was associated with the TCGA proliferative group (c2 P<8.86×10−4). Within a 10-year follow-up period, LobSig outperformed the Nottingham Prognostic Index, PAM50 risk-of-recurrence (Prosigna), OncotypeDx, and MapQuantDx (Genomic Grade Index) in a stepwise, multivariate Cox proportional hazards model, particularly in grade 2 cases (χ2P=9.0×10−6) which present most frequently and are difficult to prognosticate clinically. Importantly, LobSig status predicted outcome with 96.6% accuracy amongst cases classified as moderate risk according to Nottingham Prognostic Index in the METABRIC cohort. LobSig is a clinically relevant prognostic signature which warrants future development.
17 Mar 2019 - 20 Mar 2019