NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

Abstract

Inflammatory breast cancer (IBC) is the most pro‐metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non‐IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next‐generation sequencing (tNGS) and array‐comparative genomic hybridization (aCGH) to 57 IBC and 50 non‐IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non‐IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor‐positive (HR+)/HER2−, HER2+, and triple‐negative] were 68%, 15%, and 17% in non‐IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non‐IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non‐IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non‐IBC. Ninety‐seven percent of IBCs displayed at least one AGA. This percentage was higher than in non‐IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non‐IBC. The genomic landscape of IBC is different from that of non‐IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.

Genetic Variants Detected Using Cell-Free DNA from Blood and Tumor Samples in Patients with Inflammatory Breast Cancer

“…Genes involved in DNA repair were found more frequently altered in IBC than in non-IBC breast cancer [36]. TP53 was found to be the most frequently altered gene in IBC and its rate of mutation in IBC was found to be significantly higher than in non-IBC patients [36][37][38]. Matsuda et al found that TP53 was altered in 75% of IBC (18/24 patients) and in 28.2% (106/376 patients) of non-IBC patients [38].…”

“…Deficient DNA repair and control of cell cycle would contribute to disease progression. In a recent study of 101 untreated primary IBC tumors aggregated from four public datasets, Bertucci et al showed that the genomic profile of IBC is different from non-IBC breast cancer [36]. Genes involved in DNA repair were found more frequently altered in IBC than in non-IBC breast cancer [36].…”

“…In a recent study of 101 untreated primary IBC tumors aggregated from four public datasets, Bertucci et al showed that the genomic profile of IBC is different from non-IBC breast cancer [36]. Genes involved in DNA repair were found more frequently altered in IBC than in non-IBC breast cancer [36]. TP53 was found to be the most frequently altered gene in IBC and its rate of mutation in IBC was found to be significantly higher than in non-IBC patients [36][37][38].…”

Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling

“…The rarity of the disease, misdiagnosis, and difficulty in sample collection before treatment have resulted in a limited number of published molecular studies [ 2 , 5 , 9 , 10 ]. Transcriptome profiling analyses revealed that IBC is highly heterogeneous, showing the same molecular subtypes of non-IBC, with a higher proportion of HER2-positive and triple-negative (TNBC: negativity for estrogen receptor: ER, progesterone receptor: PR, and HER2) subtypes [ 2 , 5 , 11 , 12 , 13 ].…”

“…Copy number alterations (CNAs) have been reported in a few studies using both low-resolution techniques (such as restriction fragment length polymorphism or microsatellite markers) and more robust methodologies (array-comparative genomic hybridization and next-generation sequencing (NGS) [ 10 , 14 , 15 , 16 , 17 , 18 ]. CNA data also failed in distinguishing IBC from non-IBC cases.…”