Systemic treatment for metastatic colorectal cancer

Significant progress has been achieved in the treatment of metastatic colorectal cancer (mCRC) patients during the last 20 years. There are currently numerous treatments available for the first-line treatment of mCRC. Sophisticated molecular technologies have been developed to reveal novel prognostic and predictive biomarkers for CRC. The development of next-generation sequencing and wholeexome sequencing, which are strong new tools for the discovery of predictive molecular biomarkers to facilit...     

Novel targeting approaches and signaling pathways of colorectal cancer: An insight

Colorectal cancer(CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog(SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC. Targeted therapies necessitate information regarding the particular aberrant pathways. Advancements in gene therapies have resulted in the recognition of novel therapeutic targets related with these signal-transduction cascades. CRC is a stepwise process where mutations occur over the time and activation of oncogenes and deactivation of tissue suppressor genes takes place. Genetic changes which are responsible for the induction of carcinogenesis include loss of heterozygosity in tumor suppressor genes such as adenomatous polyposis coli, mutation or deletion of genes like p53 and K-ras. Therefore, many gene-therapy approaches like gene correction, virusdirected enzyme-prodrug therapy, immunogenetic manipulation and virotherapy are currently being explored. Development of novel strategies for the safe and effective delivery of drugs to the cancerous site is the need of the hour. This editorial accentuates different novel strategies with emphasis on gene therapy and immunotherapy for the management of CRC.     

Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer

Colorectal cancer is the second most leading cause of cancer related deaths in the western countries. One of the forms of colorectal cancer is hereditary non-polyposis colorectal cancer (HNPCC), also known as "Lynch syndrome". It is the most common hereditary form of cancer accounting for 5%-10% of all colon cancers. HNPCC is a dominant autosomal genetic disorder caused by germ line mutations in mismatch repair genes. Human mismatch repair genes play a crucial role in genetic stability of DNA, the inactivation of which results in an increased rate of mutation and often a loss of mismatch repair function. Recent studies have shown that certain mismatch repair genes are involved in the regulation of key cellular processes including apoptosis. Thus, differential expression of mismatch repair genes particularly the contributions of MLH1 and MSH2 play important roles in therapeutic resistance to certain cytotoxic drugs such as cisplatin that is used normally as chemoprevention. An understanding of the role of mismatch repair genes in molecular signaling mechanism of apoptosis and its involvement in HNPCC needs attention for further work into this important area of cancer research, and this review article is intended to accomplish that goal of linkage of apoptosis with HNPCC. The current review was not intended to provide a comprehensive enumeration of the entire body of literature in the area of HNPCC or mismatch repair system or apoptosis; it is rather intended to focus primarily on the current state of knowledge of the role of mismatch repair proteins in molecular signaling mechanism of apoptosis as it relates to understanding of HNPCC.     

基于COSMIC数据库的结直肠转移性癌的体细胞突变基因变化的研究

目的利用癌症体细胞突变目录（COSMIC）数据库,筛选结直肠原发性癌和结直肠转移性癌两类癌组织之间的具有显著差异的体细胞基因突变,并分析其可能的功能及通路。 方法从COSMIC数据库下载结直肠癌全外显子测序数据,在R 3.5.0环境下,利用卡方检验或Fisher确切概率法对结直肠原发性癌和结直肠转移性癌两类癌组织之间的差异体细胞突变基因进行挖掘,记录具有显著差异的体细胞突变基因并进行功能及通路富集分析,探索其可能生物学功能及通路。 结果共发现120个具有显著差异的体细胞突变基因,包括RHEB、RP11-368J21.2、AGAP10等,对其进行GO和KEGG富集分析显示,这些显著性差异体细胞突变基因可能与如脱氢酶活性、还原酶活性、细胞周期停滞、代谢途径、PI3K-Akt信号通路、细胞周期、细胞粘附分子、癌症中的转录失调、铂类耐药性等功能及通路相关。 结论挖掘结直肠原发性癌和结直肠转移性癌之间的显著差异体细胞突变基因可为研究结直肠癌的转移调控机制提供借鉴,显著差异体细胞突变基因可能作为结直肠癌转移诊断标志物或转移治疗靶点应用于临床。     

Molecular biomarkers for the detection of metastatic colorectal cancer cells

Approximately half of all patients with colorectal cancer develop local recurrence or distant metastasis during the course of their illness. Recently, the molecular detection of metastatic cancer cells in various types of clinical samples, such as lymph nodes, bone marrow, peripheral blood, and peritoneal lavage fluid, has been investigated as a potential prognostic marker. The prognostic value of molecular tumor cell detection was independent of the type of detection method used. As assays become more sensitive and quantitative, a more thorough assessment of the cancer status of patients will be based on molecular markers alone. At present, it is difficult to conclude that one specific molecular marker is superior to others. Comparative analyses are recommended to assess the prognostic impact of molecular analyses in the same patient and determine the biomarkers that provide the most accurate prognostic information.     

FOLFOX4 in the treatment of metastatic colorectal cancer in elderly patients: A prospective study

Elderly patients constitute a subpopulation with special characteristics that differ from those of the general population and have been under-represented in clinical trials. We, prospectively, analyzed the toxicity and efficacy of the original FOLFOX4-regimen in the treatment of elderly patients affected by metastatic (m) colorectal cancer (CRC). Thirty-six consecutive patients aged 67-82 years (median age 72 years), 22 males and 14 females, with mCRC and measurable disease, were enrolled in the study. The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. A total of 36 patients, aged 67-82 years were included. Twenty-two and 14 patients were male and female, respectively. The median age was 72 years (range 67-82). The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The overall response rate (ORR) was 44.4% and similar to original study. Median progression-free survival (PFS) was 7.5 months and median overall survival (OS) was 16 months. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. Tolerability, however, was manageable and no toxic death occurred. FOLFOX4-regimen maintains its efficacy, and safety ratio in elderly patients with mCRC and good performance status. It would be considered the treatment of choice in the treatment of this particular setting of patients.     

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.     

Role of cetuximab in first-line treatment of metastatic colorectal cancer

The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.     

The role of salvage treatment in advanced colorectal cancer

The selection of salvage therapy after first-line treatment failure for metastatic colorectal cancer patients has become more complex with the development of several active drugs in this setting. The addition of oxaliplatin and irinotecan to 5-fluorouracil in the first-line therapy has conditioned the election of the regimen used in second-line, becoming a standard of care the switch between both schedules at the time of disease progression. The recent introduction of new targeted drugs has complicated the scenario even more, allowing different possible combinations in first-, second-, third- and even fourth-line therapy. The role of hepatic arterial infusions has been reconsidered with the availability of new and more active cytotoxic drugs and has become an approach to be taken in mind in the management of these patients. With the possibility of active salvage therapy, surgery rescue approaches should be taken in account during all the course of the patients’ disease.     

Options for metastatic colorectal cancer beyond the second line of treatment

Colorectal cancer is the third most common cancer, with recent advances in the management of unresectable metastatic lesions. The aim of this review is to discuss the remaining options for heavily pretreated patients with unresectable metastatic colorectal cancer. Beyond second-line treatment, two epidermal growth factor receptor (EGFR) inhibitors, cetuximab and panitumumab, have a demonstrated clinical interest in patients with KRAS wild-type tumours. However, few data exist in patients pretreated with an anti-EFGR and who are being rechallenged with anti-EGFR drugs. Reintroduction of chemotherapy should be considered. In September 2012, regorafenib, a multi-kinase inhibitor was approved by the US Federal Drug Administration for patients refractory to other standard treatments. In the case of metastases limited to the liver, transarterial chemoembolization, hepatic artery infusion and radioembolization could also be discussed in selected patients. With the multiplication of therapeutic options in first-line, second-line treatment, and beyond, the concept of subsequent lines of chemotherapy should be replaced by a multiline strategy, dependent on the patient and on tumour biology. A better understanding of the tumour biology and predictive factors for the response to these therapies is needed, and further strategic trials are urgently warranted.     

Neuroendocrine differentiation:The mysterious fellow of colorectal cancer

Neuroendocrine differentiation in sporadic colorectal cancer has been recognized since decades, but its clinical impact is still controversially discussed. Detailed parameter analyses hint at the possibility that probablynot neuroendocrine differentiation itself, but its association with poor grade of tumor differentiation, lymph node metastases, distant metastases and other unfavorable features contribute to worse clinical outcome. However, other studies deny a relationship between neuroendocrine differentiation and prognosis of colorectal cancer. This review elucidates, whether new insights into the origin of neuroendocrine differentiation in the intestinal epithelium, its regulation by m TOR pathway components and its possible link to the intestinal stem cell compartment could determine a role of neuroendocrine cells as prognostic marker and putative therapeutic target in sporadic colorectal cancer.     

Irinotecan,a key chemotherapeutic drug for metastatic colorectal cancer

Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer(CRC) at the end of the last century,survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil,oxaliplatin and several molecularly-targeted anticancer drugs,resulting in the extension of overall survival to longer than 30 mo. Severe,occasionally life-threatening toxicity occurs sporadically,even in patients in relatively good condition who have a low risk of chemotherapyinduced toxicity,often causing the failure of irinotecanbased chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDPglucuronosyltransferase 1A1 gene. The large interand intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38,with the ultimate goal of achieving personalized irinotecan-based chemotherapy.     

基因突变与结直肠癌靶向治疗的新进展

KRAS基因突变作为表皮生长因子受体(epidermal growth factor receptor,EGFR)单抗疗效预测指标的发现,给转移性结直肠癌(metastatic colorectal cancer,mCRC)的治疗带来了巨大的改变.然而,结直肠癌(colorectal cancer,CRC)的发生涉及到多个癌基因、抑癌基因和信号传导通路的改变,而不同的信号传导通路之间存在着千丝万缕的联系,形成了复杂的信号传导网络.如何寻找使用抗EGFR单抗的适合人群,从而避免不必要的不良反应和无效治疗是目前研究的热点.本文就目前国内外研究较多的预测抗EGFR单抗疗效的生物靶标及相应对策进行综述.     

Immunotherapy in colorectal cancer: Available clinical evidence,challenges and novel approaches

In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyteassociated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.     

Personalizing medicine for metastatic colorectal cancer:Current developments

Metastatic colorectal cancer(mCRC)is still one of the tumor types with the highest incidence and mortality.In 2012,colorectal cancer was the second most prevalence cancer among males(9%)and the third among females(8%).In this disease,early diagnosis is important to improve treatment outcomes.However,at the time of diagnosis,about one quarter of patients already have metastases,and overall survival of these patients at 5-years survival is very low.Because of these poor statistics,the development of new drugs against specific targets,including the pathway of angiogenesis,has witnessed a remarkable increase.So,targets therapies through epidermal growth factor and its receptor and also KRAS pathways modulation acquired a main role whether in association with standard chemotherapy and radiotherapy.With the current knowledge in the field of molecular biology,including genetic mutations and polymorphisms,we know better why patients respond so differently to the same treatments.So,in the future we can develop increasingly personalized treatments to the patient and not the disease.This review aims to summarize some molecular pathways and their relation to tumor growth,as well as novel targeted developing drugs and recently approved for mCRC.     

EGFR靶向药物在结直肠癌中的研究进展

结直肠癌是常见的消化系恶性肿瘤,传统的化疗和放疗效果均不甚理想.表皮生长因子受体(EGFR)q%号转导通路在结直肠癌细胞的增殖、血管生成、侵袭、转移等方面有重要作用.因此,针对EGFR的靶向药物已陆续开发,并应用于结直肠癌治疗的临床实践.本文就EGFR靶向药物在结直肠癌中的研究现状及其相关问题进行综述.     

年龄对转移性结直肠癌不同治疗方法的影响及预后研究

目的探讨年龄与转移性结直肠癌（mCRC）的治疗方式选择和预后的相关性。 方法我们从美国国家癌症数据库（NCDB）中选择了2004~2014年mCRC的患者,总数为43 977人,将患者分为三个年龄组：18~49岁、50~75岁和＞75岁。分别描述了每个治疗类别的患者百分比,包括仅原发性肿瘤切除术（PTR）、仅化疗和PTR加化疗。在调整人口统计学和临床因素后,计算并比较不同年龄组和治疗组的限制平均生存时间（RMST）。 结果18~49岁年龄组的大多数患者（61.8%）接受PTR联合化疗,50~75岁年龄组约有53.3%的患者接受PTR联合化疗,＞75岁年龄组大约有34.7%接受PTR联合化疗。在研究期间,所有年龄组的mCRC患者,PTR加化疗组呈下降趋势,而仅化疗组呈上升趋势。与其他治疗方法相比,PTR加化疗在所有年龄组中的生存率最高。除了18~49岁组的患者外,化疗与仅PTR相比具有更高的生存时间。在接受PTR加化疗治疗的患者中,与其他治疗相比,18~49和50~75岁组的围手术期化疗的患者可以获得更长的生存期,但＞75岁组的化疗与否和生存期无关。 结论尽管mCRC患者PTR加化疗呈下降趋势,但是其在所有年龄组中显示出最大的生存获益。不同的年龄组在接受特定的MDT治疗后的获益存在差异。     

结直肠癌k-ras基因检测及其靶向治疗的研究现状

越来越多的研究表明,EGFR单抗对k-ras基因野生型结直肠癌患者治疗有效.k-ras基因编码的K-ras蛋白为EGFR信号通路下游区的一种小分子G蛋白,k-ras基因发生突变后,导致该信号通路异常活化,从而对EGFR单抗治疗无效.因此,检测k-ras基因状态对指导结直肠癌患者靶向治疗十分重要.本文就k-ras基因检测...     

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.