A review of prognostic and predictive biomarkers in breast cancer

Clinical and Experimental Medicine - Breast cancer (BC) is a common cancer all over the world that affects women. BC is one of the leading causes of cancer mortality in women, which today has...     

The impact of expression profiling on prognostic and predictive testing in breast cancer

Expression profiling has been extensively applied to the study of breast cancer and undoubtedly is changing the way breast cancer is perceived. Over the past few years, several groups have described prognostic "signatures" (gene lists) that are purported to be more accurate prognostic factors than well established clinical and pathological features. In addition, cDNA and oligonucleotide microarrays have also been used to devise predictive "signatures" in the setting of neoadjuvant chemotherapy setting. However, it seems that the enthusiasm with this new technology has led most of us to turn a blind eye to some serious methodological problems which are evident in landmark papers on breast cancer expression profiling. These issues include small and biased cohorts of patients, inappropriate statistical analysis and lack of thorough validation of the technology. In this review, we critically revisit the most relevant cDNA microarray studies on breast cancer prognosis and prediction published to date. Although the results are promising, further optimisation and standardisation of the technique and properly designed clinical trials are required before microarrays can reliably be used as tools for clinical decision making.     

Review of diagnostic,prognostic, and predictive biomarkers in melanoma

Melanoma is an aggressive cutaneous malignancy with rapidly rising incidence. Diagnosis of controversial melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges. Despite these challenges, multiple high throughput, nucleic-acid based biomarkers have been developed that can be assayed from histologic tissue specimens. FISH, CGH, Decision-Dx, and other multi-marker assays have been combined to improve overall predictability. This review discusses some of the most promising nucleic acid based assays that can be obtained from tissue specimens to assist with diagnosis, prognostication, and prediction of treatment response.     

Identification of potential prognostic biomarkers for breast cancer using WGCNA and PPI integrated techniques

In this study, we aimed to detect promising prognostic factors of breast cancer and interpreted the relevant mechanisms using an integrated bioinformatics analysis. RNA sequencing profile of breast cancer was downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, which were combined as a group (TCGA_GTEx). GSE70947 dataset was from Gene Expression Omnibus. Blue and turquoise modules, respectively identified in TCGA_GTEx database and GSE70947 dataset using weighted co-expression network analysis (WGCNA), were both notably associated with breast cancer. By comparing genes in the two significant modules with differentially expressed genes (DEGs), we obtained a set of 40 shared genes, which were mainly enriched in chromosome segregation and mismatch repair pathway. After protein-protein interaction (PPI) network and overall survival analysis, two hub genes EXO1 and KIF4A were extracted from the set of 40 shared genes, which were up-regulated and associated with the dismal outcome of breast cancer patients. There was a notable negative correlation between EXO1 and KIF4A expression and age of breast cancer patients, whereas a positive relationship with two another clinical traits stage and tumor category was detected. Univariate and multivariate Cox regression analysis revealed that the two hub genes could be independent prognostic factors of breast cancer. Mechanistically, gene correlation analysis suggested that EXO1 and KIF4A exerted their oncogenic role via promoting breast cancer cell proliferation. Overall, our findings identify two promising individual prognostic predictors of breast cancer and pave the new way for diagnosis and therapy strategy of breast cancer.     

Cell‐free microRNAs as diagnostic,prognostic, and predictive biomarkers for lung cancer

Lung cancer is the most common cancer worldwide, accounting for over 1.37 million deaths annually. The clinical outcome and management of lung cancer patients could be substantially improved by the implementation of non‐invasive biomarker assays for the early detection, prognosis as well as prediction and monitoring of treatment response. MicroRNAs (miRNAs) have been implicated in the regulation of virtually all signaling circuits within a cell and their dysregulation has been shown to play an essential role in the development and progression of cancer. Recently, miRNAs were found to be released into the circulation and to exist there in a remarkably stable form. Furthermore, various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell‐free miRNAs could serve as non‐invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets. Since that, a considerable effort has been devoted to decode the information carried by circulating miRNAs. In the current review, we give an insight into the mechanisms of miRNA release into the bloodstream, their putative functional significance and systematically review the studies focused on the identification of cell‐free miRNAs with the diagnostic, prognostic, and predictive significance in lung cancer and discuss their potential clinical utility. © 2012 Wiley Periodicals, Inc.     

TIGIT and PD-1 may serve as potential prognostic biomarkers for gastric cancer

Gastric Cancer (GC) is the fifth leading cause of cancer-related death in the world, and in urgent need of specific therapeutic targets to acquire prominent effectiveness. T-cell immunoglobulin and immunoreceptor tyrosine–based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are identified to be abnormally overexpressed in various types of cancers including GC. This study aimed to investigate whether TIGIT and PD-1 could serve as potential prognostic biomarkers for GC. Firstly, TCGA GC dataset analysis and correlation analysis were utilized to inspect the relationship between expression of TIGIT, PD-1 and CD8 + T cells in GC and adjacent normal tissues. Then, flow cytometry was used to verify the data after collecting the peripheral blood, GC and adjacent normal tissues from 150 GC patients. Lastly, quantitative RT-PCR was performed to detect the expression of CD155, CD113, CD112 and TIGIT in six human GC cell lines and 631 GC patients in KM Plotter Database to conduct prognostic analysis. As results, we found that TIGIT and PD-1 were upregulated in GC tissues with high CD8 + T cells infiltration, while correlation analysis indicated they were in high-positive correlation. In addition, the flow cytometry analysis further showed that the high-expression of TIGIT in tumor microenvironment of GC could suppress the function of infiltrative CD8 + T cells, which leads to the escape of GC cells from immune killing. Furthermore, CD155 and CD112 were found abnormally upregulated in GC tissues and cell lines and the high expression of CD155, CD112 and TIGIT demonstrated poor prognosis results. In conclusion, these results provided potential therapeutic targets and prognostic biomarkers for treatment of GC in clinic.     

TRKB acts as a prognostic predictive marker in Her-2 positive breast cancer

Human epidermal growth factor receptor 2 (Her-2) positive breast cancer (BC) was associated with an increased risk for brain metastases. Tropomyosin receptor kinase (TRKB) is a specific binding receptor for brain-derived neurotrophic factor associated with brain metastases. However, TRKB was still unknown to be involved in Her-2 positive BC. A tissue microarray comprised of 60 Her-2 positive BC cases and 32 matched adjacent normal samples was analyzed for TRKB expression by immunohistochemical staining. Results were compared to clinicopathologic and survival data by univariate and multivariate analysis. Furthermore, we explored the co-expression genes and related functional proteins using GEPIA, Kaplan-Meier plotter, LinkedOmics and PPI. We found that TRKB protein expression levels were elevated in Her-2 positive BC, and high levels of TRKB expression were associated with vascular invasion, more lymph nodes metastases and more advanced TNM stage as well as poorer OS. TRKB was confirmed as an independent prognostic factor for Her-2 positive BC by univariate and multivariate analysis. Besides, enrichment analyses revealed that protein kinase B signaling was highly correlated to TRKB in Her-2 positive BC. Therefore, TRKB may act as a potential prognostic target and biomarker for Her-2 positive BC.     

Predictive and prognostic markers for invasive breast cancer

Breast cancer is one of the most serious carcinomas among women worldwide, yet there are now encouraging signs that improvements in the mortality rate may be possible. The use of hormone therapy and chemotherapy has been widely accepted as treatment for breast cancer. Predictive factors can be used to predict response or lack of response to a particular therapy, and prognostic factors can be useful in making decisions about which patients should receive adjuvant therapy. Histopathology remains the universal basis of diagnosis, with the identification of new surrogate markers for potential new treatments. These are aimed at blocking tumor cell proliferation, neutralizing growth factors, stimulating apoptosis and blocking metastasis, and represent an integral part of new approaches for improving clinical management of patients with breast cancer. We review the standard predictive and prognostic factors that are routinely available today, and also describe some of the new, potential markers that are currently under investigation.     

Diagnostic and prognostic molecular biomarkers for prostate cancer

Prostate cancer is the most common malignant tumour in men and is a major research focus of pathologists, urologists and uro-oncologists alike. The pathologist is confronted with an increasing number of biospsies, necessitating ancillary tests in morphologically challenging cases. Next to basal cell markers, additional positive markers that aid in the differential diagnosis are presented here. The clinical decision of urologists, whom and how to treat these men, is dependent predominantly on pathological parameters, but still the grid spanned by these is too wide to allow a sufficient prognostication of the individual case. Here, a brief and critical overview is given of recent developments of prognostic biomarkers in prostate cancer.     

An overview of assessment of prognostic and predictive factors in breast cancer needle core biopsy specimens

Needle core biopsy (NCB), as part of triple assessment for preoperative evaluation and diagnosis of breast cancer, is now considered as an established, highly accurate method for diagnosing breast cancer that has replaced either fine needle aspiration cytology or excisional biopsy as the initial diagnostic biopsy procedures in many institutions. In addition to its primary role in establishing an accurate histological diagnosis, NCB can potentially provide important additional pathological prognostic information which may be of direct clinical value in certain situations, such as patients being considered for preoperative (neoadjuvant) therapy. With this background in mind we briefly review the current role of NCB in breast cancer diagnosis and then concentrate this review on the usefulness and issues relating to use of this technique in providing accurate, reliable and clinically relevant preoperative prognostic and predictive information in patients with breast cancer.     

Bench to bedside: research influencing clinical practice in breast cancer

Based on recent evidence derived from clinical trials and translational research, breast cancer pathology has witnessed a rapid increase in the utilization of predictive markers, companion diagnostics and molecular testing for tailored management of patients with breast cancer. New diagnostic entities with specific molecular phenotypes have also been included in the classification of breast cancer. Genomic assays including Oncotype DX®21-gene Recurrence Score (RS), Prosigna and EndoPredict are currently used in routine practice to guide adjuvant/neoadjuvant therapy. The analysis of established biomarkers such as ER and PR immunohistochemistry has been updated to recognize new categories with different clinical behaviour and significance, such as the ER low expressors and HER2 low carcinomas. PD-L1 testing and PIK3CA mutation have been introduced for advanced TNBC and recurrent ER positive breast cancer respectively. This review provides an update on the rapidly evolving field of predictive & prognostic markers, companion diagnostics, molecular and genomic testing of breast cancer.     

免疫评分在肝癌患者中的预后研究

目的　探讨免疫评分及PD-L1在肝癌组织的表达情况,分析肝癌患者的免疫评分与其临床病理特征及预后的关系。 方法　采用免疫组化检测免疫评分与PD-L1在61例肝癌患者中的表达,分析PD-L1、免疫评分与临床病理特征及预后之间的关系。 结果　肝癌中免疫评分较高的表达率为26.2%,较低的表达率为73.8%。统计分析发现免疫评分与AFP增高（P<0.05）及肝内复发（P>0.05）具有相关性;而与患者年龄、性别、肿瘤直径、分化程度、脉管癌栓等临床因素无相关性（P>0.05）。生存分析发现免疫评分较高患者的总生存期与无复发生存期显著高于免疫评分较低的患者（χ2=11.39,P<0.01;χ2=14.78,P<0.01）。肝癌组织PD-L1的阳性表达率为44.3%,对应癌旁低表达,具有统计学差异（χ2=7.313,P<0.01）。PD-L1阳性患者的总生存期与无复发生存期低于PD-L1阴性患者（χ2=5.598,P<0.05;χ2=10.90,P<0.01）。肝癌组织中PD-L1与免疫评分间具有负相关性（χ2=12.703,P<0.01）。 结论　免疫评分可作为患者预后的一个标志物,免疫评分高的患者预后较好,反之易早期复发且预后较差;肝癌组织PD-L1与免疫评分之间具有负相关性。     

癌胚抗原阴性的结、直肠癌检测和结直肠癌预后相关生物标记

目的探讨结直肠癌的发生、发展过程中患者血清质谱多肽蛋白图谱的变化,筛选与结直肠癌预后及癌胚抗原(CEA)阴性检测相关的肿瘤标记分子。方法用蛋白指纹图谱技术检测结直肠癌,结直肠管状腺瘤患者和健康者血清质谱多肽蛋白图谱。结果初步筛选出对结直肠癌有代表性的7个差异蛋白;2个与其淋巴结转移相关的差异蛋白;4个与其远处转移相关的差异蛋白;3个在其根治性切除后表达下降的差异蛋白;而由3398·3u、5477·1u和8453·9u组成的诊断模型对CEA阴性表达结直肠癌的阳性检测率为100%。结论蛋白指纹图谱技术可筛选出有意义的生物标记差异蛋白,这对结直肠癌预后判断、CEA阴性的结直肠癌检测和改变结直肠癌的进程具有重要意义。     

Expression of BRCA1 protein in breast cancer and its prognostic significance

BRCA1 is a tumor suppressor gene which, when mutated, is associated with the development of hereditary breast cancers. In sporadic tumors, although inherent gene mutations are rare, loss of BRCA1, resulting from reduced expression or incorrect subcellular localization, is postulated to be important. The purpose of the current study was to examine the expression and localization of BRCA1 protein and to assess its prognostic value, in a well-characterized series of unselected breast carcinomas. We have examined BRCA1 in a series of invasive breast carcinoma (1940 cases) using tissue microarray and immunohistochemistry, to evaluate its expression pattern and to correlate this with clinicopathologic variables and patient outcome. In breast cancer, complete loss of nuclear expression was observed in 223 cases (15%) and cytoplasmic expression was found in 541 breast cancers (36.6%). Absent or reduced nuclear BRCA1 expression was observed more frequently in ductal carcinoma of no special type and medullary-like carcinoma and less frequently in lobular and tubular mixed carcinomas. It was also associated with high-grade, advanced lymph node stage, larger size, vascular invasion, negative estrogen receptor, progesterone receptor and androgen receptor expression, and positive p53 and P-cadherin expression, and with the basal-like class of breast cancer. Altered BRCA1 was associated with shorter disease-free interval. Cytoplasmic expression was also associated with development of recurrence and positive EGFR and HER2 expression. It showed an inverse association with survival particularly in low-grade, small-size, and estrogen receptor-positive subgroups. In the grade 1 subgroup, multivariate analysis with adjustment for other prognostic factors showed that cytoplasmic expression of BRCA1 was an independent predictor of disease-free interval. BRCA1 alteration may play a significant role in the development and progression of breast cancer. Immunohistochemical assessment of BRCA1 expression could provide additional clinically relevant information in routine classification of breast cancer.     

Update on HER2 expression in breast cancer

Recent studies since the 2018 ASCO/CAP guideline update for HER2 testing in breast cancer have made novel discoveries in HER2-targeted therapy. These studies have elucidated a new subtype of breast cancer known as "HER2-low" breast cancers, which represents a distinct subgroup under what has been classified as HER2-negative breast cancer. Additionally, there is further understanding of alterations within the ERBB2 gene, including mutations in the tyrosine kinase domain, both de novo or as a resistance mechanism. Finally, better understanding of the HER2 immunohistochemistry (IHC) patterns in specific histologic subtypes of breast cancer, such as invasive micropapillary breast carcinoma, has allowed for more accurate classification of HER2 IHC. All of these findings have important implications for HER2-targeted therapy and overall outcomes.     

Update on sentinel node pathology in breast cancer

Pathologic examination of the sentinel lymph nodes (SLNs) in patients with breast cancer has been impacted by the publication of practicing changing trials over the last decade. With evidence from the ACOSOG Z0011 trial to suggest that there is no significant benefit to axillary lymph node dissection (ALND) in early-stage breast cancer patients with up to 2 positive SLNs, the rate of ALND, and in turn, intraoperative evaluation of SLNs has significantly decreased. It is of limited clinical significance to pursue multiple levels and cytokeratin immunohistochemistry to detect occult small metastases, such as isolated tumor cells and micrometastases, in this setting. Patients treated with neoadjuvant therapy, who represent a population with more extensive disease and aggressive tumor biology, were not included in Z0011 and similar trials, and thus, the evidence cannot be extrapolated to them. Recent trials have supported the safety and accuracy of sentinel lymph node biopsy (SLNB) in these patients when clinically node negative at the time of surgery. ALND remains the standard of care for any amount of residual disease in the SLNs and intraoperative evaluation of SLNs is still of value for real time surgical decision making. Given the potential prognostic significance of residual small metastases in treated lymph nodes, as well as the decreased false negative rate with the use of cytokeratin immunohistochemistry (IHC), it may be reasonable to maintain a low threshold for the use of cytokeratin IHC in post-neoadjuvant cases. Further recommendations for patients treated with neoadjuvant therapy await outcomes data from ongoing clinical trials. This review will provide an evidence-based discussion of best practices in SLN evaluation.     

Comparison of the expression of prognostic biomarkers between primary tumor and axillary lymph node metastases in breast cancer

The prognosis and prediction of axillary lymph node (ALN) metastases in breast cancer is traditionally based upon the biomarkers status of the primary tumor. Some retrospective studies showed significant discordance in receptor expression between primary and metastatic tumors. We aim to prospectively assess the incidence of discordant biomarkers status in primary tumor and ALN metastases and to evaluate the role of ALN biopsies for the reassessment of receptor status. Tissue arrays were constructed from 54 breast cancer patients with ALN metastases diagnosed. Arrays were immuno-stained to compare protein expression of four biomarkers including estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 by immunohistochemistry. The kappa value of consistency in the primary tumor and the metastatic lymph nodes were 0.465 for ER, 0.445 for PR, and 0.706 for HER2. Good consistency was shown for Ki67 expression in primary and metastases regions with T test. No significant difference is existed between primary tumor and ALN metastases. It is concluded that the good consistency is present for ER, PR, HER2 and Ki67 between the primary tumor and the metastatic lymph nodes, suggesting that ER, PR, HER2, or Ki67 status in primary tumors could reflect their status in ALN metastases.