Characterization and clinical relevance of the genomic alterations defining lobular breast cancer

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer, is mostly estrogen receptor-positive (ER+) and has distinct clinico-pathological features when compared to ER+ invasive ductal carcinoma (IDC). In this study, we aimed to characterize the genomic alterations defining ILC in a large cohort of ILC patients with long-term follow up (FU). Material & methods: In 499 centrally histologically confirmed ILC patients (median FU= 9.8 years) we analyzed mutational data gathered from targeted sequencing of 360 cancer genes at an average coverage of 106X (alignment done with BWA, substitutions and indels –further referred to as mutations- called with Caveman and Pindel). Matched normal DNA was available for 242 patients. Genome-wide copy number (CN) data were available for 178 patients. E-cadherin (CDH1) and beta-catenin (CTNNB1) stains were carried out using the DakoTM antibodies. Invasive disease free survival (IDFS) was considered as primary survival endpoint. Results: A median of 6 [range:0-38] non-silent mutations was identified across the primary tumors of all patients. The most frequently mutated genes (>3%) are listed in Table 1. Of those, CDH1, PIK3CA, TBX3, FOXA1 and the chromatin-related genes MLL2, MLL3, ARID1A and ARID1B were more frequently mutated in our ER+/HER2- ILC (n= 451) compared to the ER+/HER2- IDC (n=266) from The Cancer Genome Atlas, whereas GATA3, TP53 and MAP3K1 were less frequently mutated. Samples with a CDH1 mutation were associated with changes at the protein level: 97.5% displayed a complete loss of the protein, associated with cytoplasmic staining for CTNNB1, compared to only 63% of the CDH1 non-mutated tumors. CDH1 mutated tumors were further characterized by increased mutational frequencies of the ERBB-genes: 15.4% for the CDH1 mutated tumors versus 3% in the CDH1 non-mutated tumors, most of those mutations being described in the literature as activating the pathway. Almost all tumors (97%) with CN data had a heterozygous loss of CDH1. The special alveolar, solid and trabecular lobular histotypes were associated with specific CN alterations and mutations. Tumors with mutated ARID1A or ATM were associated with worse IDFS at the univariate level and ARID1A remained significant in a multivariate analysis including standard parameters (HR =2.07, p=0.003). At the CN level, ATM and ARID1A losses, as well as HER2 and VEGFA gains/amplifications were associated with decreased IDFS, all but ARID1A holding significance at the multivariate level (HR_HER2=2.41, HR_VEGFA= 1.99, HR_ATM= 1.79, all p Conclusion: This is the first and largest study to our knowledge to report genomic alterations present in ILC and their association with survival. This work therefore opens new avenues for a better understanding of the disease and its clinical management. Citation Format: Christine Desmedt, Gunes Gundem, Gabriele Zoppoli, Giancarlo Pruneri, Elia Biganzoli, Marco Fornili, Debora Fumagalli, Francoise Rothe, David Brown, Peter Van Loo, Sylvain Brohee, Delphine Vincent, Naima Keddoumi, Samira Majjaj, Ghizlane Rouas, Thomas Van Brussel, Diether Lambrechts, Otto Metzger, Christine Galant, Francois Bertucci, Martine Piccart, Denis Larsimont, Giuseppe Viale, Peter J Campbell, Christos Sotiriou. Characterization and clinical relevance of the genomic alterations defining lobular breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-05.