Does CSE1L Overexpression Affect Distant Metastasis Development in Breast Cancer?

Cell–cell communication proteins Eph and ephrin constitute the largest family of receptor tyrosine kinases (RTKs). They are distinguished by the fact that both receptors and ligands are membrane-bound, and both can drive intracellular signaling in their respective cells. Ever since these RTKs have been found to be involved in cancer development, strategies to target them therapeutically have been actively pursued. However, before this goal can be rationally achieved, the contributions of either Eph receptors or their ephrin ligands to cancer development and progression should be scrutinized in depth. To assess the clinical pertinence of this concern, we performed a systematic review and meta-analysis of the prognostic/predictive value of EphB2 and its multiple cognate ephrin ligands in breast cancer. We found that EphB2 has prognostic value, as indicated by the association of higher EphB2 expression levels with lower distant metastasis-free survival (DMFS), and the association of lower EphB2 expression levels with poorer relapse-free survival (RFS). We also found that higher EphB2 expression could be a prognostic factor for distant metastasis, specifically in the luminal subtypes of breast cancer. EFNB2 showed a marked correlation between higher expression levels and shorter DMFS. EFNA5 or EFNB1 overexpression is correlated with longer RFS. Increased EFNB1 expression is correlated with longer OS in lymph node (LN)-negative patients and the luminal B subtype. Higher levels of EFNB2 or EFNA5 are significantly correlated with shorter RFS, regardless of LN status. However, while this correlation with shorter RFS is true for EFNB2 in all subtypes except basal, it is also true for EFNA5 in all subtypes except HER2+. The analysis also points to possible predictive value for EphB2. In systemically treated patients who have undergone either endocrine therapy or chemotherapy, we found that higher expression of EphB2 is correlated with better rates of RFS. Bearing in mind the limitations inherent to any mRNA-based profiling method, we complemented our analysis with an immunohistochemical assessment of expression levels of both the EphB2 receptor and cognate ephrin ligands. We found that the latter are significantly more expressed in cancers than in normal tissues, and even more so in invasive and metastatic samples than in ductal carcinoma in situ (DCIS). Finally, in an in vitro cellular model of breast cancer progression, based on H-Ras-transformation of the MCF10A benign mammary cell line, we observed dramatic increases in the mRNA expression of EphB2 receptor and EFNB1 and EFNB2 ligands in transformed and invasive cells in comparison with their benign counterparts. Taken together, these data show the clinical validity of a model whereby EphB2, along with its cognate ephrin ligands, have dual anti- and pro-tumor progression effects. In so doing, they reinforce the necessity of further biological investigations into Ephs and ephrins, prior to using them in targeted therapies.

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Incorporation of biologic factors for the staging of de novo stage IV breast cancer

npj Breast Cancer ◽

10.1038/s41523-020-00186-5 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Zhen-Yu He ◽

Chen-Lu Lian ◽

Jun Wang ◽

Jian Lei ◽

Li Hua ◽

...

Keyword(s):

Breast Cancer ◽

Risk Score ◽

Distant Metastasis ◽

De Novo ◽

Stage Iv ◽

Staging System ◽

Sensitivity Analyses ◽

Operating Characteristics ◽

Prognostic Analysis ◽

Stage Iv Breast Cancer

Abstract This study aimed to investigate the prognostic value of biological factors, including histological grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status in de novo stage IV breast cancer. Based on eligibility, patient data deposited between 2010 and 2014 were collected from the surveillance, epidemiology, and end results database. The receiver operating characteristics curve, Kaplan–Meier analysis, and Cox proportional hazard analysis were used for analysis. We included 8725 patients with a median 3-year breast cancer-specific survival (BCSS) of 52.6%. Higher histologic grade, HER2-negative, ER-negative, and PR-negative disease were significantly associated with lower BCSS in the multivariate prognostic analysis. A risk score staging system separated patients into four risk groups. The risk score was assigned according to a point system: 1 point for grade 3, 1 point if hormone receptor-negative, and 1 point if HER2-negative. The 3-year BCSS was 76.3%, 64.5%, 48.5%, and 23.7% in patients with 0, 1, 2, and 3 points, respectively, with a median BCSS of 72, 52, 35, and 16 months, respectively (P < 0.001). The multivariate prognostic analysis showed that the risk score staging system was an independent prognostic factor associated with BCSS. Patients with a higher risk score had a lower BCSS. Sensitivity analyses replicated similar findings after stratification according to tumor stage, nodal stage, the sites of distant metastasis, and the number of distant metastasis. In conclusion, our risk score staging system shows promise for the prognostic stratification of de novo stage IV breast cancer.

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A gene signature for late distant metastasis in breast cancer identifies a potential mechanism of late recurrences

Molecular Oncology ◽

10.1016/j.molonc.2013.07.006 ◽

2013 ◽

Vol 7 (5) ◽

pp. 987-999 ◽

Cited By ~ 23

Author(s):

Lorenza Mittempergher ◽

Mahasti Saghatchian ◽

Denise M. Wolf ◽

Stefan Michiels ◽

Sander Canisius ◽

...

Keyword(s):

Breast Cancer ◽

Distant Metastasis ◽

Gene Signature ◽

Potential Mechanism

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Predicting distant metastasis in breast cancer using ensemble classifier based on context-specific miRNA regulation modules

2012 IEEE International Conference on Bioinformatics and Biomedicine ◽

10.1109/bibm.2012.6392717 ◽

2012 ◽

Cited By ~ 3

Author(s):

Xionghui Zhou ◽

Juan Liu ◽

Jianghui Xiong

Keyword(s):

Breast Cancer ◽

Distant Metastasis ◽

Ensemble Classifier ◽

Mirna Regulation ◽

Context Specific

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Breast cancer subtypes and the risk of distant metastasis at initial diagnosis: a population-based study

Cancer Management and Research ◽

10.2147/cmar.s176763 ◽

2018 ◽

Vol Volume 10 ◽

pp. 5329-5338 ◽

Cited By ~ 34

Author(s):

Weikai Xiao ◽

Shaoquan Zheng ◽

Anli Yang ◽

Xingcai Zhang ◽

Yutian Zou ◽

...

Keyword(s):

Breast Cancer ◽

Distant Metastasis ◽

Population Based ◽

Initial Diagnosis ◽

Breast Cancer Subtypes ◽

Population Based Study ◽

Cancer Subtypes

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Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

BMC Cancer ◽

10.1186/1471-2407-8-339 ◽

2008 ◽

Vol 8 (1) ◽

Cited By ~ 37

Author(s):

Andrew Tutt ◽

Alice Wang ◽

Charles Rowland ◽

Cheryl Gillett ◽

Kit Lau ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Patients ◽

Distant Metastasis ◽

Risk Estimation ◽

Breast Cancer Patients ◽

Rt Pcr ◽

Node Negative ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

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Factors Predictive of Distant Metastases in Patients With Breast Cancer Who Have a Pathologic Complete Response After Neoadjuvant Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2005.11.124 ◽

2005 ◽

Vol 23 (28) ◽

pp. 7098-7104 ◽

Cited By ~ 78

Author(s):

Ana M. Gonzalez-Angulo ◽

Sean E. McGuire ◽

Thomas A. Buchholz ◽

Susan L. Tucker ◽

Henry M. Kuerer ◽

...

Keyword(s):

Breast Cancer ◽

Regression Analysis ◽

Neoadjuvant Chemotherapy ◽

Distant Metastasis ◽

Cox Regression ◽

Clinical Stage ◽

Pathologic Complete Response ◽

Distant Metastases ◽

Complete Response ◽

Cox Regression Analysis

Purpose To identify clinicopathological factors predictive of distant metastasis in patients who had a pathologic complete response (pCR) after neoadjuvant chemotherapy (NC). Methods Retrospective review of 226 patients at our institution identified as having a pCR was performed. Clinical stage at diagnosis was I (2%), II (36%), IIIA (27%), IIIB (23%), and IIIC (12%). Eleven percent of all patients were inflammatory breast cancers (IBC). Ninety-five percent received anthracycline-based chemotherapy; 42% also received taxane-based therapy. The relationship of distant metastasis with clinicopathologic factors was evaluated, and Cox regression analysis was performed to identify independent predictors of development of distant metastasis. Results Median follow-up was 63 months. There were 31 distant metastases. Ten-year distant metastasis-free rate was 82%. Multivariate Cox regression analysis using combined stage revealed that clinical stages IIIB, IIIC, and IBC (hazard ratio [HR], 4.24; 95% CI, 1.96 to 9.18; P < .0001), identification of ≤ 10 lymph nodes (HR, 2.94; 95% CI, 1.40 to 6.15; P = .004), and premenopausal status (HR, 3.08; 95% CI, 1.25 to 7.59; P = .015) predicted for distant metastasis. Freedom from distant metastasis at 10 years was 97% for no factors, 88% for one factor, 77% for two factors, and 31% for three factors (P < .0001). Conclusion A small percentage of breast cancer patients with pCR experience recurrence. We identified factors that independently predicted for distant metastasis development. Our data suggest that premenopausal patients with advanced local disease and suboptimal axillary node evaluation may be candidates for clinical trials to determine whether more aggressive or investigational adjuvant therapy will be of benefit.

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