Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy

AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers(m CRCs) addicted to epidermal growth factor receptor(EGFR) signalling.METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting m CRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of Pub Med, Medline and Web of Science to identify eligible papers until March 21 st, 2016 using these following terms: ‘‘colorectal cancer', "predictive biomarkers' ', "anti-EGFR therapy", "KRAS", "NRAS', "PIK3CA", "TP53", "PTEN", ‘‘EGFR", "MET", "HER2", "epiregulin", "amphiregulin", "prognostic biomarkers", "BRAF", "miR NA" and "antibody-dependent cell-mediated cytotoxicity(ADCC) activity". Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion. RESULTS: The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mC RCs. Nevertheless, it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30%. Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers. So far the identification of predictive biomarkers have generated interesting, though preliminary and, at times, conflicting data on the importance of tumour mR NA levels of EGFR ligands, of activating mutations in other genes such as NRAS and PIK3 CA. The prognostic value of selected micro RNAs level and ADCC activity is under investigation, while the prognostic impact of BRAF status remains controversial.CONCLUSION: This review focuses on the personalized treatment of m CRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy.     

Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer

AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage Ⅰ-Ⅲ CRC and examined associations of these mutations with disease-free survival(DFS) and overall survival(OS) using uni- and multivariate Cox proportional hazards models.RESULTS: KRAS and BRAF mutations were detected in 312(38%) of 812 and 40(5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males(P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender(P = 0.006), proximal tumor location(P 0.001), mucinous or poorly differentiated histology(P 0.001), and MSI-high tumors(P 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS(HR = 1.35; 95%CI: 1.03-1.75) and OS(HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS(HR = 2.20; 95%CI: 1.19-4.06) and OS(HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, inJapanese patients with curatively resected CRC.     

表皮生长因子受体靶向治疗结直肠癌的临床进展

当今,靶向治疗成为肿瘤治疗模式里越来越重要的因子,而靶向治疗中研究最多的是关于表皮生长因子受体(epidermal growth factor receptor,EGFR)靶向治疗药物.随着临床的深入研究,EGFR分子靶向药物的临床应用利弊也成为关注的焦点.此文就EGFR在结直肠癌靶向治疗中的研究进展作一综述.     

EGFR靶向治疗在结直肠癌中的研究进展

表皮生长因子受体酪氨酸激酶(EGFR)家族的异常表达和活化,与肿瘤的发生和进展、肿瘤转移关系密切,抑制受体活性可以有效的抑制肿瘤.EGFR信号在结直肠癌形成中具有重要的作用, 随着对肿瘤分子生物学的深入研究,针对EGFR的分子靶向药物已进入结直肠癌治疗的临床研究阶段,此文就EGFR在结直肠癌靶向治疗中的研究进展作一综述.     

KRAS和表皮生长因子受体突变基因与原发性非小细胞肺癌的相关性

目的 研究KRAS和表皮生长因子受体(EGFR)基因在原发性非小细胞肺癌(NSCLC)中的突变状态以及其与靶向治疗效果的相关性。方法 收集郑州大学第一附属医院收治的150例经病理证实的NSCLC患者原发肿瘤及受累的淋巴结标本,进行KRAS和EGFR突变基因序列分析。150例中12例患者纵隔淋巴结转移灶经DNA序列分析发现EGFR基因突变后给予吉非替尼进行术前辅助治疗。结果150对（分别为原发灶和受累淋巴结）标本中,2例原发肿瘤和10例淋巴结转移灶中检测到KRAS突变基因,35例原发肿瘤和44例淋巴结转移灶中检测到EGFR突变基因。KRAS和EGFR基因在原发灶和转移灶中不一致的比率分别为6.7％ (10/150)和8.7％ (13/150)。1例原发肿瘤无EGFR突变的患者接受吉非替尼治疗后效果不佳。结论 NSCLC患者原发灶和转移灶中KRAS和EGFR基因突变状态不一致,这对于应用酪氨酸激酶抑制剂靶向治疗NSCLC具有重要的参考意义。     

Prognostic value of epidermal growth factor expression in breast cancer

A series of 198 female breast cancer biopsies were analysed immunohistochemically for the expression of epidermal growth factor (EGF), with special emphasis on its prognostic significance. A total of 67/198 tumours (33.8%) were EGF-positive, 24 (12%) of which showed strong expression of EGF. EGF was usually expressed in the cytoplasm of the cancer cells but, in 22 cases, the normal ducts adjacent to the cancer showed positive staining as well. Strong EGF expression was related to distant metastases at diagnosis (P=0.04). Oestrogen(ER)- and progesterone-receptor(PR)-negative tumours showed EGF positivity with equal frequency (P=0.05 in both). Axillary lymph node status, histological type, tumour size, histological grade, S-phase fraction, mitotic index or cancer recurrence did not show any statistical correlation with EGF expression. Tumour size (P=0.007), axillary lymph node involvement (P=0.003) and ER content (P=0.03) were independent prognostic factors in multivariate survival analysis, whereas EGF positivity, as an independent factor, had no effect on survival. In univariate analysis, however, EGF positivity predicted a more favourable outcome in axillary-lymph-node-positive tumours (P=0.04). The results suggest that immunohistochemical assessment of EGF expression has hardly any clinical significance in addition to the well-established prognostic factors in breast cancer.Abbreviations EGF epidermal growth factor - EGFR EGF receptor     

Targeting the epidermal growth factor receptor in metastatic colorectal cancer

Although significant advances have been made in the treatment of metastatic colorectal cancer (CRC), prognosis remains poor, with a 5-year survival of less than 10%. Monoclonal antibodies that target the epidermal growth factor receptor (EGFR) have shown clinical benefit as single agents and in combination with standard chemotherapy in the refractory setting, with tolerable toxicity. This article will discuss the role of the EGFR pathway in the pathogenesis of CRC, the data supporting the current use of cetuximab and panitumumab in the treatment of CRC, and clinical trials of EGFR tyrosine kinase inhibitors in CRC. Novel strategies of targeting the EGFR pathway to improve efficacy, as well as ongoing research in identifying molecular predictors of response to anti-EGFR agents, will also be reviewed.     

Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer

Administration of monoclonal antibodies(mAbs)against epidermal growth factor receptor(EGFR)such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer(mCRC).However,the efficacy of these mAbs is limited due to genetic variation among patients,in particular K-ras mutations.The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC.Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF,MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors.Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation,our understanding of their mode of action is limited.Rational drug development based on stringent preclinical data,biomarker validation,and proper selection of patients is of paramount importance in the treatment of mCRC.In this review,we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFRRas-ERK and PI3K signalings.     

The epidermal growth factor receptor as a target for cancer therapy

Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-alpha on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G(1) phase, and was due to upregulation of p27(Kip1), resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.     

EGFR在结直肠癌组织中的表达及其意义

目的:探讨结直肠癌患者肿瘤组织中表皮生长因子受体(epidermal growth factor,EGFR)过表达与临床病理特征及其预后的关系和意义.方法:收集2004-01/2010-04在中国人民解放军南京军区福州总医院手术切除的结直肠癌组织标本1 228例,选择其中资料完整的病例1 100例,采用EliVisio...     

Correlation of human epidermal growth factor receptor protein expression and colorectal cancer

AIM: To investigate the correlation between human epidermal growth factor receptor (HER-2) protein expression and colorectal cancer (CRC) using a case-control study and meta-analysis.METHODS: Tumor tissue specimens from 162 CRC patients were selected for the case group. Fifty cases were randomly selected, and normal CRC tissue at least 10 cm away from the tumor margins of these cases was used to generate the control group. The expression of the HER-2 protein in the 162 CRC tissue samples and the 50 adjacent normal mucosa tissue samples was detected via immunohistochemistry. The experimental data were analyzed using SPSS 18.0 software, and R software version 3.1.0 was utilized for further verification.RESULTS: The expression of HER-2 protein in the 162 CRC tissue samples was significantly higher than in the normal tissue specimens. The data showed that the expression of HER-2 in CRC was related to the Dukes’ stage, the depth of invasion and lymph node metastasis. The HER-2-positive patients had lower 3- and 5-year OS rates than the HER-2-negative patients, but there was no significant difference. However, there was a statistically significant difference in the 3- and 5-year disease-free survival (DFS) rates of HER-2-positive and HER-2-negative patients. The results of the meta-analysis showed that the expression of HER-2 in CRC patients was statistically significantly increased over that of healthy people. The 3-year DFS rate in HER-2-positive patients was markedly lower than that in HER-2-negative patients.CONCLUSION: Down-regulation of HER-2 expression might be a dependable strategy for CRC therapy.     

Current status of predictive biomarkers for neoadjuvant therapy in esophageal cancer

Neoadjuvant therapy has been proven to be extremely valuable and is widely used for advanced esophageal cancer. However, a significant proportion of treated patients(60%-70%) does not respond well to neoadjuvant treatments and develop severe adverse effects. Therefore, predictive markers for individualization of multimodality treatments are urgently needed in esophageal cancer. Recently, molecular biomarkers that predict the response to neoadjuvant therapy have been explored in multimodal approaches in esophageal cancer and successful examples of biomarker identification have been reported. In this review, promising candidates for predictive molecular biomarkers developed by using multiple molecular approaches are reviewed. Moreover, treatment strategies based on the status of predicted biomarkers are discussed, while considering the international differences in the clinical background. However, in the absence of adequate treatment options related to the results of the biomarker test, the usefulness of these diagnostic tools is limited and new effective therapies for biomarker-identified nonresponders to cancer treatment should be concurrent with the progress of predictive technologies. Further improvement in the prognosis of esophageal cancer patients can be achieved through the introduction of novel therapeutic approaches in clinical practice.     

Prognostic and predictive response factors in colorectal cancer patients: Between hope and reality

Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers worldwide. It is the second leading cause of cancer death in Western Countries. In the last decade the survival of patients with metastatic CRC has improved dramatically. Due to the advent of new drugs (irinotecan and oxaliplatin) and target therapies (i.e., bevacizumab, cetuximab and panitumab), the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently. Many questions needing of right collocations and more clearness still exist regarding the prognostic factors and the predictive factors of response to therapy. Despite advances in dosing and scheduling of chemotherapy in both adjuvant and advanced settings, and a greater emphasis on early detection, the outlook still remains poor for most patients. Molecular analyses have shown that the natural history of all CRCs is not the same. Individual patients with same stage tumours may have different long term prognosis and response to therapy. In addition, some prognostic variables are likely to be more important than others. Here we review the role of prognostic factors and predictive factors according to the recently published English literature.     

吉非替尼治疗表皮生长因子受体基因突变的晚期非小细胞肺癌患者疗效的meta分析

目的非小细胞肺癌（NSCLC）是恶性程度和死亡率极高的肿瘤,吉非替尼（gefitinib）是近年来研发的一种新的分子靶向药物,本文旨在系统评价吉非替尼治疗表皮生长因子受体（EGFR）基因突变的晚期NSCLC的有效性。方法计算机检索维普数据库（2000-2011．06）、万方数据库（2000-2011．06）、CNKI（2000-2011．06）、OVID（2000-2011．06）、Karger Online Jounals（2000-2011．06）。两名评价者独立评价纳入研究的质量、提取资料并交叉核对,研究采用RevMan5．1软件进行rneta分析。结果共纳入10个研究,包括941例,meta分析结果显示,吉非替尼治疗晚期NSCLC患者,EGFR基因突变者相比较于非突变者而言,疾病总有效率明显增加（RR=4．42,95％CI：3．49-5．60）,疾病控制率明显增加（RR=1．79,95％CI：1．23-2．61）,疾病进展率明显降低（RR=0．24,95％CI：0．18-0．32）。结论吉非替尼治疗EGFR基因突变的晚期NSCLC有一定的优势,可作为治疗EGFR基因突变的晚期NSCLC患者的常规药物。     

非小细胞肺癌表皮生长因子受体基因突变的临床意义

表皮生长因子受体(epidermal growth factor receptor,EGFR)是一种具有酪氨酸激酶活性的跨膜糖蛋白,可介导细胞的增殖、分化、凋亡抑制及血管生成等多种细胞过程.在多种人类恶性肿瘤中.均存在EGFR表达上调的现象,其中约70%的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者表现为EGFR过表达.另外,在亚洲非吸烟的女性肺腺癌患者中,EGFR的基因突变率达40%以上,表明EGFR的异常表达与NSCLC的发生及发展有密切关系.本文主要就近年来关于EGFR过表达和基因突变与NSCLC发生及转移关系的研究作一综述.     

Expression of epidermal growth factor receptor (EGFR) in colorectal cancer: An immunohistochemical study

Background and study aim

The epidermal growth factor receptor (EGFR) plays an important role in tumourigenesis and tumour progression of colorectal cancer (CRC) and leads to the activation of intracellular signaling pathways. The use of anti-EGFR-targeted therapy has increased for patients with metastatic CRC. Today, the clinical utility of immunohistochemistry has remained somewhat inconclusive. It is based on EGFR screening methods using paraffin-embedded tumour specimen to select patients eligible for treatment. There is still lack of agreement on reproducible scoring criteria for EGFR immunohistochemistry has in various clinical trials.