Mutational characteristics determined using circulating tumor DNA analysis in triple-negative breast cancer patients with distant metastasis.
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ABSTRACT:
SUBMITTER: Rong G
PROVIDER: S-EPMC7743003 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
Mutational characteristics determined using circulating tumor DNA analysis in triple-negative breast cancer patients with distant metastasis.
Rong Guohua G Yi Zongbi Z Ma Fei F Guan Yanfang Y Xu Yaping Y Li Lifeng L Xu Binghe B
Cancer communications (London, England) 20201003 12
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Project description:BackgroundCirculating tumor cells (CTCs) represent a temporal "snapshot" of a patient's cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer.MethodsWe used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice.ResultsStaining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency.ConclusionPDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.
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Project description:BackgroundTriple-negative breast cancer is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible.Methodology/principal findingsClinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated by oligonucleotide microarrays. Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI) 1.04-5.06, Cox P=0.04), outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-? signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer.Conclusions/significanceGene expression data and recurrence information of triple-negative breast cancer were collected and analyzed in this study. A novel set of 45-gene signature was found to be statistically predictive in disease recurrence of triple-negative breast cancer. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of distant recurrence for early-stage triple-negative patients.
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Project description:This microarray dataset contains 51 triple-negative breast cancers, 25 normal breast tissues, and 106 luminal breast cancers (reanalyzed data from Series GSE24124, GSE9309, and GSE17040). Keywords: Expression profiling by array Specimens of breast cancer tissue were collected and snap-frozen from breast cancer patients who had surgery between 1995 and 2008 at National Taiwan University Hospital (NTUH, Taipei, Taiwan). Clinicopathological information was obtained for all breast cancer patients along with informed consent. The AJCC/UICC TNM system was used for breast cancer staging classification.
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Project description:Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, accounting for 10-20% of breast cancers with high intrinsic heterogeneity. Its unique immune microenvironment, including high expression of vascular endothelial growth factors, tumor infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a dual role in the occurrence, growth, and metastasis of TNBC. Understanding the TNBC microenvironment is of great significance for the prognosis and treatment of TNBC. In this article, we describe the composition and function of immune cells in the TNBC microenvironment and summarize the major cytokine growth factors and chemokines in the TNBC microenvironment. Finally, we discuss the progress of TNBC, cytokine-induced killer cell therapy, and immune checkpoint therapy.
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2014-01-02 | E-GEOD-53752 | biostudies-arrayexpress
Project description:Distinguishing malignant cells from non-neoplastic ones is a major challenge in triple-negative breast cancer (TNBC) treatment. Here, we developed a complementary targeting strategy that uses precisely matched, multivalent ligand-receptor interactions to recognize and target TNBC tumors at the primary site and metastatic lesions. We screened a panel of cancer cell surface markers and identified intercellular adhesion molecule-1 (ICAM1) and epithelial growth factor receptor (EGFR) as optimal candidates for TNBC complementary targeting. We engineered a dual complementary liposome (DCL) that precisely complements the molecular ratio and organization of ICAM1 and EGFR specific to TNBC cell surfaces. Our in vitro mechanistic studies demonstrated that DCLs, compared to single-targeting liposomes, exhibited increased binding, enhanced internalization, and decreased receptor signaling. DCLs consistently exhibited substantially increased tumor targeting activity and antitumor efficacy in orthotopic and lung metastasis models, indicating that DCLs are a platform technology for the design of personalized nanomedicines for TNBC.
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Project description:AimsThis study investigates the association between circulating tumor cells (CTCs) and breast cancer metastasis.MethodsA retrospective study was conducted using patients with histologically confirmed breast cancer recruited from the First Affiliated Hospital of Nanjing Medical University during the period of August 2017-October 2020. We used adjusted logistic regression, the random forest algorithm, and sensitivity analysis to study the association between CTC enumeration and tumor metastasis. Further, we performed next-generation sequencing (NGS) on the CTCs obtained from two patients with breast cancer brain metastasis.ResultsA total of 41 out of 116 enrolled patients were identified with tumor metastasis. CTC enumeration was significantly higher in patients with liver metastasis than in those without liver metastasis. Patients with CTCs ≥ 5 exhibited a higher risk of tumor metastasis than those with CTCs < 5 in the adjusted model (odds ratios (OR) = 6.25, 95% confidence interval (CI) = 2.63-15.58). The random forest model identified CTC enumeration as a significant metastasis-related variable with the highest mean decrease accuracy and mean decrease Gini score. No significant association was found between CTCs and visceral metastasis with an OR of 1.29 (95% CI = 0.98-2.05, p = 0.232). Upon further investigating organ-specific metastasis, we found that patients with high CTC levels were more likely to develop liver metastasis (OR = 4.87, 95% CI = 1.34-20.17, p = 0.021). The NGS study of CTCs identified a total of 120 indel mutations (e.g., CNGB1, NTSR1, ZG16). The enriched biological processes were mechanoreceptor differentiation and macrophage activation involved in the immune response. The enriched KEGG pathways included focal adhesion, the PI3K-Akt signaling pathway, and microRNAs involved in cancer.ConclusionsOur study revealed that CTCs ≥ 5 are a risk factor for tumor metastasis in breast cancer patients. In addition, we reported that CTCs ≥ 5 might be associated with a higher risk of liver metastasis in patients with metastatic breast cancer. We have provided the mutational profiles of CTCs based on next-generation sequencing.
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Project description:Circulating tumor cells (CTCs) are cardinal intermediaries in the metastatic cascade, particularly in triple-negative breast cancer (TNBC), owing to their high-affinity interactions that bolster survival and dissemination. Addressing this pivotal mechanism, we have developed APEVs@DOX, a pioneering biomimetic delivery system. Utilizing activated platelet membranes as a scaffold, APEVs@DOX recapitulates the natural affinity between platelets and CTCs, enabling targeted delivery of doxorubicin. Our results, substantiated by meticulous in vitro and in vivo experimentation, revealed 78 % reduction in lung metastasis nodules in murine models relative to controls, affirming APEVs@DOX's proficiency in CTCs capture and eradication. This study not only illuminates the potential of CTCs-targeted therapies in the precision medicine armamentarium for TNBC but also contributes empirical data to guide the strategic design of anti-metastatic interventions. The therapeutic impact of APEVs@DOX in curtailing metastatic spread offers a beacon of hope for advancing TNBC treatment paradigms.
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