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.
Highlights
Inflammatory breast cancer (IBC) is the most aggressive clinical form of breast cancer (Dawood et al, 2011)
IBCs were associated with more unfavorable prognostic features than noninflammatory breast cancer (non-IBC): younger age, prevalent ductal type, higher American Joint Committee on Cancer (AJCC) stage, higher pathological grade, and more frequent HER2+ and TN subtypes
Our study confirms the hypothesis that IBC is distinct from non-IBC at the genomic level, independently from the molecular subtypes and disease stage
Summary
Inflammatory breast cancer (IBC) is the most aggressive clinical form of breast cancer (Dawood et al, 2011). Despite therapeutic progresses, ~ 50% of patients die from metastatic relapse. The distinct clinical presentation and aggressive behavior have not translated in design of differential treatment that remains similar to that of stage 3 noninflammatory breast cancer (nonIBC). Identification of new therapeutic targets and better understanding of the pathophysiology are crucial (Charafe-Jauffret et al, 2008). Because of the scarcity of disease, ‘omics’ studies remain rare in IBC (Bertucci et al, 2014a). The largest series reported to date is the one that we had collected within the International IBC Consortium (Bertucci et al, 2014b; Masuda et al, 2013; Van Laere et al, 2013), in which we notably showed the overrepresentation of aggressive molecular subtypes (basal, HER2-enriched, luminal B) when compared with non-IBC, justifying the need to stratify the IBC/ non-IBC comparison upon the molecular subtypes (Van Laere et al, 2013)
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