Dataset Information

Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis.

ABSTRACT:

Background

Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.

Methods and findings

Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival.

Conclusions

This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.

SUBMITTER: Lefebvre C

PROVIDER: S-EPMC5189935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHigh tumor heterogeneity contributes to breast cancer recurrence and metastasis. However, the lack of indicators to serve as precise and reliable means of predicting breast cancer prognosis has yet to be addressed. This study aims to reveal the prognostic relevance of mutations in metastatic breast cancer (MBC) by large-scale circulating tumor DNA (ctDNA) analysis in China.MethodsWe performed ctDNA panel-captured sequencing of 958 blood samples from MBC patients including 494 hormone receptor (HR)-positive cases, 130 human epidermal growth factor receptor 2-positive cases, and 177 triple-negative breast cancer (TNBC) cases. The somatic mutations and potential targets were assessed. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method.ResultsIn 801 of the 958 MBC blood samples, 663 mutated genes and 5,829 nonsynonymous alterations were identified. Mutated genes of the highest frequency were tumor protein p53 (TP53, 54%), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA, 41%), estrogen receptor 1 (ESR1, 12%), myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3, 11%), DNA (cytosine-5)-methyltransferase 3A (DNMT3A, 10%), erb-b2 receptor tyrosine kinase 2 (ERBB2, 10%), GATA binding protein 3 (GATA3, 8%), FAT atypical cadherin 1 (FAT1, 7%), phosphatase and tensin homolog (PTEN, 6%), and mitogen-activated protein kinase kinase kinase 1 (MAP3K1, 6%). Enriched mutations and driver genes in MBC varied across stages and in multiple subtypes. Moreover, TP53, ERBB2, or coexisting TP53/PIK3CA mutations in MBC were remarkably related with shorter PFS. Mutated DNA damage response (DDR) genes were significantly associated with tumor mutation burden and mutant-allele tumor heterogeneity score, as well as with worse clinical outcome.ConclusionsOur findings indicate that the mutations of TP53, PIK3CA, ERBB2, and in particular, DDR genes, in MBC might be relevant indicators of unfavorable prognosis in MBC.