Prognostic relevance of receptor tyrosine kinase expression in breast cancer: A meta-analysis

Background

Receptor tyrosine kinases (RTKs) may facilitate tumor progression if activated aberrantly. The prognostic impact of human epidermal growth factor receptor 2 (HER2) overexpression and effectiveness of its therapeutic targeting is well established, but the effects on prognosis of overexpression of other RTKs is unknown. Here we evaluate the association of RTK expression and survival in breast cancer.

Methods

PubMed was searched to identify studies evaluating the association between expression of RTKs other than HER2 and survival of women with breast cancer. Published data were extracted and computed into odds ratios (OR) for death at 5 years with 95% confidence intervals (CI). Data were pooled in a meta-analysis using the Mantel–Haenszel random-effect model. For studies reporting data for more than one RTK the lowest and highest OR were used for separate analyses.

Results

Sixteen studies comprising 11,056 patients were included in the analysis. There was an association between overexpression of RTKs and decreased 5-year OS and this was highly significant when using highest ORs from studies reporting more than one RTK (OR = 2.42; 95% CI = 1.92–3.06, P < 0.001). Similar results were observed for 5-year BCSS. Worse OS was seen with overexpression of fibroblast growth factor receptor 2/3 (FGFR) (OR = 3.81; 95% CI = 1.79–8.11) and epidermal growth factor receptor (EGFR)/HER1 (OR = 2.45; 95% CI = 1.90–3.15).

Conclusion

Overexpression of various RTKs is associated with poor outcomes. This data suggests the clinical evaluation of combination of agents against RTKs or relevant oncogenic nodes.     

乳腺癌基因表达谱研究进展

乳腺癌是分子表达差异显著的一组疾病,乳腺癌临床异质性源自分子异质性.根据基因表达谱研究开发的分子标签,如70-基因标签、21-基因标签、乳腺癌分子分型标签等,在预测乳腺癌患者预后、指导临床治疗决策方面,表现出良好的应用价值和前景.     

Underutilization of gene expression profiling for early-stage breast cancer in California

Purpose

To describe the utilization of gene expression profiling (GEP) among California breast cancer patients, identify predictors of use of GEP, and evaluate how utilization of GEP influenced treatment of early-stage breast cancer.

Methods

All women diagnosed with hormone-receptor-positive, node-negative breast cancer reported to the California Cancer Registry between January 2008 and December 2010 were linked to Oncotype DX (ODX) assay results.

Results

Overall, 26.7 % of 23,789 eligible patients underwent the assay during the study period. Women age 65 or older were much less likely than women under age 50 to be tested (15.1 vs. 41.4 %, p < 0.001). Black women were slightly less likely and Asian women were slightly more likely than non-Hispanic white women to undergo GEP with the ODX assay (22.2 and 28.9 vs. 26.9 %, respectively, p < 0.001). Patients residing in low SES census tracts had the lowest use of the test (8.9 %), with the proportion increasing with higher SES category. Women with Medicaid health insurance were less likely than other women to be tested (17.7 vs. 27.5 %, p < 0.001). Receipt of adjuvant chemotherapy (ACT) was associated with the ODX recurrence score, although only 63 % of patients whose recurrence scores indicated a high benefit received ACT. Of patients not tested, 15 % received ACT.

Conclusions

Nearly three-fourths of eligible breast cancer patients in California during the 3-year period 2008 through 2010 did not undergo GEP. As a result, it is likely that many women unnecessarily received ACT and suffered associated morbidity. In addition, some high-risk women who would have benefited most from ACT were not identified.

     

Altered gene expression in breast cancer liver metastases

We previously developed a highly aggressive cell line from heart metastases of 4T1 breast carcinoma (designated 4THM), which produced liver metastases (designated 4TLM). In this study, gene array analysis (GAEA) compared gene expression profiles in 4TLM with profiles in 4T1 and 4THM primary tumors. GAEA demonstrated that 4T1 and 4THM tumors differed in about 250 genes. Over 1,000 genes, however, were expressed differently in 4TLM compared with primary tumors. A cohort of 16 genes showed significantly decreased expression in 4THM tumors, which decreased even further in 4TLM. Many of these genes have been implicated in breast cancer, and many are involved in cell adhesion and junctional complexes. Expression of multiple tight and adherence junction proteins was either downregulated or disappeared in 4TLM; downregulation of claudin 4, claudin 7 and γ‐catenin was confirmed by quantitative polymerase chain reaction, immunoblot, and immunocytochemical (ICC) analyses. At the protein level, intact ZO‐1 was also observed in 4T1 tumors, but was not expressed in 4THM or 4TLM tumors. ICC demonstrated expression of γ‐catenin at the plasma membrane with 4T1 tumors, whereas staining appeared to be nuclear/perinuclear in 4THM tumors. Claudin 7 staining was also seen in monocyte/pmacrophage‐like cells in liver around metastatic lesions by ICC, and it appeared that larger 4TLM tumors apparently reexpressed claudin 7 RNA and protein. Our results demonstrate that decreased or abnormal expression of a number of cell adhesion/junctional proteins, including claudin 4, 7, ZO‐1 and γ‐catenin, correlates with liver metastases, and that cell adhesion molecules in the microenvironment are also altered. © 2008 Wiley‐Liss, Inc.     

Cyclooxygenase-2 gene expression in human breast cancer

Expression of the inducible isoform of the cyclooxygenase gene (PGHS-2, COX-2) which codes for the enzyme that catalyzes formation of prostaglandins, was detected in 13/13 human breast tumors of high grade but not in samples of normal breast tissue. There was a statistically significant linear association between COX-2 gene expression and high (>50%) tumor cell density (p<0.01), with COX-2 protein localized to tumor cells. These results indicate that COX-2 gene expression may be useful as a molecular biomarker for human breast tumors and may also predict sensitivity to treatment with nonsteroidal anti-inflammatory drugs.     

ImmunoPET of the differential expression of CD146 in breast cancer

With advancement in antibody engineering, the development and characterization of new cancer-specific molecular targets are in the forefront of this PET-antibody combination “revolution”. Overexpression of CD146 in different types of tumors, including breast tumor, has been associated with tumor progression and poor prognosis. Non-invasive detection of CD146 with a monoclonal antibody may provide a noninvasive diagnostic tool with high specificity and accountability. Methods: Herein, we have developed a CD146-specific monoclonal antibody (YY146), radiolabeled it with ⁵²Mn and ⁸⁹Zr and identified its capability in acting as a non-invasive imaging agent that specific targets CD146 in different murine breast cancer models. CD146 expression was first screened in different breast tumor cell lines through Western Blot and confirmed its binding ability to YY146 using Flow Cytometry. Serial immunoPET images were carried out after intravenous administration of ⁵²Mn or ⁸⁹Zr labeled YY146. In addition, we also performed in vivo fluorescence imaging in animals injected with YY146 conjugated with Cy5.5. Results: Western Blot results show that MDA-MB-435 cell line had greater levels of CD146 expression when compared to the other cell lines investigated. Flow cytometry confirmed binding ability of YY146. PET images revealed well correlated uptake between tumor uptake and CD146 expression levels, confirmed by biodistribution studies and fluorescence imaging. Conclusion: PET imaging, for up to 7 days, of mice bearing three different breast tumors were carried out and revealed radiotracer uptake in tumors that strongly (r² = 0.98, P < 0.01), correlated with CD146 expression levels, as confirmed by in vitro and ex vivo studies.     

MicroRNA gene expression deregulation in human breast cancer

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.     

Found in transcription: gene expression and other novel blood biomarkers for the early detection of breast cancer

Early detection of a growing breast tumor is of key importance for patient survival. Despite limitations, mammography screening has improved the detection of breast tumors, however many tumors are not detected. This is especially true for younger women and women with high breast density. Novel diagnostic blood biomarkers either generated by the tumor and released into the blood, or generated by nontumor cells as a response to the tumor presence, can now potentially help improve the accuracy of early-stage breast cancer detection. They include multicomponent biomarkers, circulating tumor cells and RNA expression of peripheral blood. These novel biomarkers and their potential use will be presented and discussed in this review, with special emphasis on gene expression-based markers.     

基因表达谱在乳腺癌中的意义

乳腺癌的发生发展具有很强的个体特异性,利用基因表达谱可鉴别这种肿瘤异质性.现综述基因表达谱在乳腺癌诊断、预后和化疗等方面中的潜在应用.     

Identification and meta-analysis of a small gene expression signature for the diagnosis of estrogen receptor status in invasive ductal breast cancer

In breast cancer, the determination of estrogen receptor (ER) expression is crucial for the decision on therapeutic strategies. Current ER expression analysis is based on immunohistochemical (IHC) staining of ER on formalin fixed tissue sections. However, low levels of ER expression frequently escape detection because of varying sensitivities of routine histopathological laboratories. Moreover, in estimating ER by IHC the receptor protein only is tested instead of the complex underlying ER pathway, which reflects its biological activity. To overcome this limitation, we have used the microarray technology to study 56 samples of invasive ductal carcinoma. We infer a robust and reliable signature of 10 genes, which is associated with ER expression and presumably therapeutically relevant biological processes. In a meta-analysis, the signature was tested on 3 further independent microarray gene expression data sets, covering different laboratories, array platforms, and clinics. The classification based on the signature showed a very low misclassification rate. In summary, the expression of few genes is sufficient to determine ER status. Future decisions on antiestrogen based therapy in breast cancer could be based on this signature rather than on immunostaining alone.     

CCDC8基因在乳腺癌中的表达

目的 探讨CCDC8在乳腺癌组织中的表达及其与乳腺癌临床病理特征的关系.方法 采用定量反转录聚合酶链反应（qRT-PCR）分析CCDC8在40例乳腺癌组织和22例良性乳腺肿瘤组织中的表达情况;以及CCDC8的表达与年龄、肿块大小、临床分期、雌激素受体（ER）、孕激素受体（PR）、CerbB2、p53 、Ki-67、nm23之间的关系.结果 CCDC8基因在乳腺良性肿瘤中的表达量（1685±755）明显高于乳腺癌组织中的表达量（502.1±223.2）;CCDC8基因的表达量在年龄＞50岁（789.8±367）乳腺癌组织中的表达高于年龄≤50岁（452.5±170.3）的乳腺癌组织;CCDC8的表达与ER、PR、CerbB2、p53、Ki-67、临床分期之间差异无统计学意义（P＞ 0.05）;CCDC8的表达与nm23的表达差异有统计学意义（P=0.044）;CCDC8与nm23呈负相关（Correlation Coegicient=-0.400,P=0.039＜ 0.05）.结论 CCDC8在乳腺肿瘤组织中有表达,恶性组织表达量低于良性组织,CCDC8的表达与年龄、肿块大小、nm23有相关性,CCDC8可能是乳腺癌的一个抑癌基因影响乳腺癌的发生、发展.     

Prognostic significance of VEGF-C immunohistochemical expression in breast cancer: a meta-analysis

Vascular endothelial growth factor-C (VEGF-C) is considered as a prime mediator of lymphangiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF-C protein overexpression with the clinical outcome in patients with breast cancer but yielded conflicting results. Electronic databases updated to April 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF-C overexpression and survival of patients with breast cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 11 studies (n?=?1,357 patients) that evaluated the correlation between VEGF-C overexpression detected by immunohistochemistry and survival in patients with breast cancer. Combined hazard ratios suggested that VEGF-C overexpression was not associated with poor prognosis of disease-free survival (HR [hazard ratio]?=?0.80, 95 % CI [confidence interval]: 0.51–1.09), overall survival (OS) (HR?=?1.08, 95 % CI: 0.37–1.78) in patients with breast cancer. In the stratified analysis by patient source, significantly risks were not found among Asians or non-Asians. No significant heterogeneity was observed among all studies. VEGF-C overexpression was not associated with poor disease-free survival or overall survival in breast cancer.