Macroscale genomic alterations in histomolecular invasive lobular carcinoma compared to other breast cancer subtypes.

Abstract

1049 Background: Although invasive lobular carcinoma (ILC) is often classified as a separate breast cancer (BC) subtype with distinct molecular features, options for diagnosis and treatment remain similar to other BCs. Using an integrated histomolecular approach to classify 617 BC samples into either histomolecular ILC (hmILC) or histomolecular no special type (hmNST) subsets, we compared their macroscale genomic alterations to describe biological traits of the ILC BC subtype, which may lead to improved approaches in BC therapies. Methods: A total of 617 BC FFPE samples were subject to whole-exome and bulk RNA sequencing analysis. hmILC subset was defined based on CDH1 truncation/deletion or low CDH1 expression (z-score < -2.5×MAD), while all other samples were classified as hmNST. Copy number variations (CNVs) were assessed using Sequenza to detect recurrent amplifications/gains and deletions; homologous recombination deficiency (HRD) scores were calculated based on large-scale state transitions and loss-of-heterozygosity events; tumor mutational burden (TMB) scores were evaluated as percent of mutations per megabase; and mutational signatures were deconvoluted using maftools R package. Results: Genome-wide CNV analysis revealed distinct patterns in hmILC compared to hmNST. hmILC showed hallmark deletions at regions harboring CDH1 (16q), while gains were observed significantly more frequently at regions harboring FCGR3A (1q) compared to hmNST. Elevated APOBEC activation signature expression was found in 32% hmILC vs. 19% hmNST samples (p = 0.002, chi-squared test). HRD-positive cases were less frequent in the hmILC subset (25%) compared to hmNST (42%) (p = 0.001). In contrast, hmILC tumors more frequently demonstrated high TMB scores compared to hmNST (10% vs. 2%, p = 0.0003). Moreover, TMB-positive hmILC samples were mostly HRD-negative.Genetic alterations in genes like FANCA , FANCD2 and PALB2 were more frequently enriched in hmILC tumors compared to hmNST (p < 0.1). Furthermore, hmILC subset with high HRD scores frequently harbored additional DNA repair gene mutations (e.g., BRCA2 ) compared to the subset with low HRD scores (p = 0.02). Conclusions: This study revealed macroscale genomic alterations, such as unique CNV patterns, altered distributions of HRD- and TMB-positive cases and increased APOBEC-driven mutational processes, in the hmILC BC subset. These distinct genomic architectures highlight the need for innovative trials using inhibitors of DNA repair and related pathways for hmILC BC patients, particularly in those with high HRD-high tumors.