Abstract
BackgroundInflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Using a custom-made breast cancer gene sequencing panel, we investigated somatic mutations in IBC to better understand the genomic differences compared with non-IBC and to consider new targeted therapy in IBC patients.MethodsTargeted next-generation sequencing (NGS) of 91 candidate breast cancer-associated genes was performed on 156 fresh-frozen breast tumor tissues from IBC patients. Mutational profiles from 197 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as non-IBC controls for comparison analysis. The mutational landscape of IBC was correlated with clinicopathological data and outcomes.ResultsAfter genotype calling and algorithmic annotations, we identified 392 deleterious variants in IBC and 320 variants in non-IBC cohorts, respectively. IBC tumors harbored more mutations than non-IBC (2.5 per sample vs. 1.6 per sample, p < 0.0001). Eighteen mutated genes were significantly different between the two cohorts, namely TP53, CDH1, NOTCH2, MYH9, BRCA2, ERBB4, POLE, FGFR3, ROS1, NOTCH4, LAMA2, EGFR, BRCA1, TP53BP1, ESR1, THBS1, CASP8, and NOTCH1. In IBC, the most frequently mutated genes were TP53 (43.0%), PIK3CA (29.5%), MYH9 (8.3%), NOTCH2 (8.3%), BRCA2 (7.7%), ERBB4 (7.1%), FGFR3 (6.4%), POLE (6.4%), LAMA2 (5.8%), ARID1A (5.1%), NOTCH4 (5.1%), and ROS1 (5.1%). After grouping 91 genes on 10 signaling pathways, we found that the DNA repair pathway for the triple-negative breast cancer (TNBC) subgroup, the RTK/RAS/MAPK and cell cycle pathways for the HR–/HER2+ subgroup, the DNA repair, RTK/RAS/MAPK, and NOTCH pathways for the HR+/HER2– subgroup, and the DNA repair, epigenome, and diverse pathways for the HR+/HER2+ subgroup were all significantly differently altered between IBC and non-IBC. PIK3CA mutation was independently associated with worse metastasis-free survival (MFS) in IBC since the median MFS for the PIK3CA mutant type was 26.0 months and for the PIK3CA wild type was 101.1 months (p = 0.002). This association was observed in TNBC (p = 0.04) and the HR–/HER2+ subgroups (p = 0.0003), but not in the HR+/HER2– subgroup of IBC.ConclusionsBreast cancer-specific targeted NGS uncovered a high frequency of deleterious somatic mutations in IBC, some of which may be relevant for clinical management.
Highlights
Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer
Criteria for the diagnosis of IBC were the simultaneous presence of diffuse erythema and edema involving at least one-third of the breast with or without a measurable breast mass [1]
We aim to explore whether the frequent unknown pathogenic mutations of Receptor tyrosine kinase (RTK) on ERBB4, FGFR3, EGFR, and ERBB2 reported in the present study are potential therapeutic targets
Summary
Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Using a custom-made breast cancer gene sequencing panel, we investigated somatic mutations in IBC to better understand the genomic differences compared with non-IBC and to consider new targeted therapy in IBC patients. IBC is rare, constituting 1–5% of breast cancer cases, it harbors aggressive behavior with poor a prognosis and accounts for roughly 10% of breast cancer mortality annually [2]. Compared to non-IBC, IBC frequently presents resistance to conventional therapies and early recurrence. Therapeutic progress in the past two decades in the context of non-IBC has had a positive impact in women with IBC, with a more than 22-month improvement in median breast cancer-specific survival (BCSS) and a 14% improvement in 2-year BCSS [3], IBC is still a challenge for breast cancer physicians because of poor survival and lack of specific treatment. We urgently need to identify how and why IBC is distinct from non-IBC
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