An Integrated Molecular Analysis Of Invasive Lobular Carcinoma

Background: Invasive lobular carcinoma (ILC) is the most commonly diagnosed special histological type of breast cancer, accounting for up to 15% of all cases. Accumulating data suggests the biology and clinical features of ILC differ to those of the more commonly diagnosed Invasive Carcinoma of No Special Type (IC-NST), including evidence of there being an overall worse long term outcome associated with ILC. Several large-scale molecular profiling studies have recently been published regarding ILC, highlighting molecular heterogeneity and important drivers of tumour behaviour. We hypothesize that an integrative analysis of gene expression and DNA copy number data will identify novel drivers, and prognostic and predictive biomarkers of lobular phenotype. Methods: Gene expression and copy number data from ILC tumours profiled in-house (n=25), METABRIC (n=125) and TCGA (n=145) were assembled and analysed. Integration of genome and transcriptome data was performed using two methods. Firstly, by Spearman correlation with a meta-analysis by combining gene level correlation coefficients from each study using a random effects model, weighting each study with inverse variance. Secondly using ANOVA, followed by combining gene level p-values across studies using Stouffers Z-score. Disease specific survival was examined at an individual gene level and using all genes simultaneously (via a Cox Boost analysis) to identify gene expression changes that are associated with poor outcome. Results: DNA copy number profiling identified recurrent gains (1q, 8q, 16p), losses (11q, 16q) and amplifications (1q32, 8p12-p11.2, 11q13). 11q13 amplifications were prevalent at a higher frequency in patients with poor outcome compared to patients with better outcome. The integrative analysis identified 1928 candidate genes whose expression was associated with gene copy number; as expected being enriched from genome regions highlighted above. One hundred and sixty of these genes were of prognostic significance in the METABRIC ILC cohort, several are known cancer drivers ( e.g. PBX1 , CCND1 ) and five new candidates are being investigated as novel prognostic biomarkers by immunohistochemistry. Conclusions: An integrated molecular analysis of ILC has identified a large number of gene expression changes that are dictated by gene copy number in ILC. Some of these are expected to influence tumour behavior and to highlight aggressive cancers with poor prognosis. Citation Format: Lal S, McCart Reed A, Nones K, Wockner L, Song S, Lakhani S, Simpson P. An integrated molecular analysis of invasive lobular carcinoma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-16.