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Therapeutic landscape in mutational triple negative breast cancer.

ABSTRACT: Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scarce. Very few recurrent mutations, including TP53 and PI3KCA mutations, together with a long tail of individually rare mutations occur in TNBC. These combined effects of genomic alterations drive TNBC progression. Given the complexity and heterogeneity of TNBC, clinical interpretation of the genomic alterations in TNBC may pave a new way for the treatment of TNBC. In this review, we summarized the germline and somatic mutation profiles of TNBC and discussed the current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics.

SUBMITTER: Shi Y

PROVIDER: S-EPMC6046102 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Therapeutic landscape in mutational triple negative breast cancer.

Shi Yaqin Y Jin Juan J Ji Wenfei W Guan Xiaoxiang X Guan Xiaoxiang X

Molecular cancer 20180714 1

Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scar ...[more]

PMID: 30007403

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Project description:Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer that represents 15-20% of breast tumors and is more prevalent in young pre-menopausal women. It is the subtype of breast cancers with the highest metastatic potential and recurrence at the first 5 years after diagnosis. In addition, mortality increases when a complete pathological response is not achieved. As TNBC cells lack estrogen, progesterone, and HER2 receptors, patients do not respond well to hormone and anti-HER2 therapies, and conventional chemotherapy remains the standard treatment. Despite efforts to develop targeted therapies, this disease continues to have a high unmet medical need, and there is an urgent demand for customized diagnosis and therapeutics. As immunotherapy is changing the paradigm of anticancer treatment, it arises as an alternative treatment for TNBC patients. TNBC is classified as an immunogenic subtype of breast cancer due to its high levels of tumor mutational burden and presence of immune cell infiltrates. This review addresses the implications of these characteristics for the diagnosis, treatment, and prognosis of the disease. Herein, the role of immune gene signatures and tumor-infiltrating lymphocytes as biomarkers in TNBC is reviewed, identifying their application in patient diagnosis and stratification, as well as predictors of efficacy. The expression of PD-L1 expression is already considered to be predictive of response to checkpoint inhibitor therapy, but the challenges regarding its value as biomarker are described. Moreover, the rationales for different formats of immunotherapy against TNBC currently under clinical research are discussed, and major clinical trials are highlighted. Immune checkpoint inhibitors have demonstrated clinical benefit, particularly in early-stage tumors and when administered in combination with chemotherapy, with several regimens approved by the regulatory authorities. The success of antibody-drug conjugates and research on other emerging approaches, such as vaccines and cell therapies, will also be addressed. These advances give hope on the development of personalized, more effective, and safe treatments, which will improve the survival and quality of life of patients with TNBC.

Project description:PurposeTriple-negative breast cancer (TNBC) does not have defined therapeutic targets and is currently treated with chemotherapy only. Kinase dysregulation triggers cancer cell proliferation and metastasis and is a crucial therapeutic target for cancer. In this study, targeted kinome sequencing of TNBC tumors was performed to assess the association between kinome gene alterations and disease outcomes in TNBC.MethodsA kinome gene panel consisting of 612 genes was used for the targeted sequencing of 166 TNBC samples and matched normal tissues. Analyses of the significantly mutated genes were performed. Genomic differences between Asian and non-Asian patients with TNBC were evaluated using two Asian TNBC datasets (from Seoul National University Hospital [SNUH] and Fudan University Shanghai Cancer Center [FUSCC]) and three non-Asian TNBC datasets (The Cancer Genome Atlas [TCGA], METABRIC, and Gustave Roussy). The prognostic value of kinome gene mutations was evaluated using tumor mutational burden (TMB) and oncogenic pathway analyses. Mutational profiles from the TCGA were used for validation.ResultsThe significantly mutated genes included TP53 (60% of patients), PIK3CA (21%), BRCA2 (8%), and ATM (8%). Compared with data from non-Asian public databases, the mutation rates of PIK3CA p.H1047R/Q were significantly higher in the SNUH cohort (p = 0.003, 0.048, and 0.032, respectively). This was verified using the FUSCC dataset (p = 0.003, 0.078, and 0.05, respectively). The TMB-high group showed a trend toward longer progression-free survival in our cohort and the TCGA TNBC cohort (p = 0.041 and 0.195, respectively). Kinome gene alterations in the Wnt pathway in patients with TNBC were associated with poor survival in both datasets (p = 0.002 and 0.003, respectively).ConclusionComprehensive analyses of kinome gene alterations in TNBC revealed genomic alterations that offer therapeutic targets and should help identify high-risk patients more precisely in future studies.

Project description:PurposeTriple-negative breast cancer (TNBC) is an aggressive tumor with poor prognosis, it has higher recurrence and metastatic rates than other breast cancer subtypes. This study aims to investigate biomarkers and potential targets for TNBC related to ferroptosis through data mining and bioinformatics analysis. The findings may provide new insights for treating TNBC.MethodsThe TNBC patients' data from the Cancer Genome Atlas (TCGA) database were extracted for differential expression and prognosis analysis. Consensus genes obtained by intersecting differential expressed and ferroptosis-related genes was used to establish the prognostic model by the univariate and multivariate Cox analyses. Besides, TNBC data from the Gene Expression Omnibus (GEO) database was used to confirm the reliability of the prognosis model. Moreover, clinical information was analyzed by multifactorial independent analysis to identify independent prognostic factors. The expression of genes constituting the prognostic model was further validated using the Human Protein Atlas (HPA) database. Finally, the Comparative Toxicogenomic Data (CTD) database was used to explore possible treatment drugs for TNBC.ResultsWe obtained 13,245 differential expressed genes, and 177 consensus genes. 98 genes with prognostic implication were obtained by univariable Cox. Then, a prognostic model including 12 ferroptosis-related genes was constructed by multivariable Cox. The area under curve (AUC) value of the prognostic model for TNBC was 0.82. The GEO database validated that the model (AUC = 0.77) could predict the patient outcomes. The staining results of 10 out of 12 prognostic model genes in HPA database showed that their expression was consistent with our predictions. Clinical risk analysis indicated that risk score of patients could act as an independent prognostic factor. Finally, six drugs that may have interaction with 12 ferroptosis-related genes were obtained using the CTD database.ConclusionThe prognostic model composed of 12 ferroptosis-related genes could predict the prognosis of TNBC patients, and seven genes (ASNS, LAMP2, CAV1, DPP4, HELLS, TF, ZFP69B) could be potential new therapeutic targets for TNBC, and two drugs (1-methyl-3-isobutylxanthine, rosiglitazone) could act as potential therapeutic drugs for the treatment of TNBC.

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Therapeutic landscape in mutational triple negative breast cancer.

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Therapeutic landscape in mutational triple negative breast cancer.

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