The Genomic Landscape of Lobular Breast Cancer

• Main Authors: Amy E. McCart Reed, Samuel Foong, Jamie R. Kutasovic, Katia Nones, Nicola Waddell, Sunil R. Lakhani, Peter T. Simpson
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Cancers
• Subjects: invasive lobular carcinoma; breast cancer; lobular; genomics; sequencing; precision oncology
• Online Access: https://www.mdpi.com/2072-6694/13/8/1950

Invasive lobular carcinoma (ILC) is the second most common breast cancer histologic subtype, accounting for approximately 15% of all breast cancers. It is only recently that its unique biology has been assessed in high resolution. Here, we present a meta-analysis of ILC sequencing datasets, to provide a long-awaited ILC-specific resource, and to confirm the prognostic value and strength of association between a number of clinico-pathology features and genomics in this special tumour type. We consider panel (<i>n</i> = 684), whole exome (<i>n</i> = 215) and whole genome sequencing data (<i>n</i> = 48), and review histology of The Cancer Genome Atlas cases to assign grades and determine whether the ILC is of classic type or a variant, such as pleomorphic, prior to performing statistical analyses. We demonstrate evidence of considerable genomic heterogeneity underlying a broadly homogeneous tumour type (typically grade 2, estrogen receptor (ER)-positive); with genomes exhibiting few somatic mutations or structural alterations, genomes with a hypermutator phenotype, and tumours with highly rearranged genomes. We show that while <i>CDH1</i> (E-cadherin) and <i>PIK3CA</i> mutations do not significantly impact survival, overall survival is significantly poorer for patients with a higher tumour mutation burden; this is also true for grade 3 tumours, and those carrying a somatic <i>TP53</i> mutation (and these cases were more likely to be ER-negative). Taken together, we have compiled a meta-dataset of ILC with molecular profiling, and our analyses show that the genomic landscape significantly impacts the tumour’s variable natural history and overall survival of ILC patients.