大肠癌药物疗效及预后预测的分子指标研究进展

大肠癌是人类最常见的恶性肿瘤之一,药物治疗在大肠癌的综合治疗中扮演重要的角色。化疗药物和靶向药物的联合使用,使大肠癌的药物治疗有效率明显提高,但仍有很大一部分患者对于化疗药物无反应。寻找化疗疗效预测以及预后的分子指标,选择能从化疗受益的优势人群就非常重要。本文就大肠癌药物治疗疗效预测及预后分子指标的研究进展做一综述。     

大肠癌化疗疗效及毒性预测分子的研究进展

大肠癌患者对化疗药物的反应和毒性具有明显的个体差异,这种差异是个体遗传多态性通过影响药物的代谢、转运和作用靶点等引起。治疗前对患者进行抗肿瘤药物疗效和（或）不良反应相关的基因检测,从而可以实现合理选择化疗药物,本文对大肠癌化疗疗效及毒性预测分子作一综述,以指导临床个体化用药。     

斑蝥酸钠维生素B6注射液联合FOLFOX4方案治疗晚期大肠癌疗效观察

新型药物和治疗方案的出现使晚期大肠癌的治疗效果得到一定提高,如贝伐珠单抗、西妥昔单抗等分子靶向药物与化疗药物的联合应用,但不可耐受的不良反应限制了其临床应用.目前,综合治疗已成为大肠癌治疗的指导原则.近年来,应用斑蝥酸钠维生素B6注射液联合化疗治疗晚期大肠癌取得了较好的疗效.     

复发转移大肠癌中K-Ras基因表达及其临床意义

目的 探讨K-Ras基因在复发转移大肠癌中的表达、临床意义及其对预后的预测价值。方法 收集2005年1月至2010年12月解放军总医院收治的复发转移大肠癌病例资料,回顾性分析所有患者临床病理特征、分子特征与预后的关系。结果 入选96例病例,K-Ras基因突变率为25％（24／96）,性别、年龄、病灶部位、病理类型、转移器官个数、转移部位与K-Ras基因突变无相关性。截至2010年12月31日,70例（72.9％）患者病情进展,29例（30.2％）死亡,中位总生存期（OS）为37.39个月,中位无进展生存期（PFS）为9.63个月,1、2、3年生存率分别为79％、57％和52％。单因素分析显示K-Ras基因状态（P=0.004）、肝转移（P=0.002）及辅助化疗（P=0.012）是影响PFS的预后因素,其他临床病理特征及一线治疗应用靶向药对PFS无明显影响;年龄（P=0.026）、肝转移（P=0.050）、腹腔转移（P=0.001）及全程用靶向药物（P=0.009）是影响OS的预后因素,其他临床病理特征、K-Ras基因状态以及辅助化疗对OS无影响。分层分析显示,K-Ras野生组中使用西妥昔单抗者较未使用者OS明显延长（P=0.019）。Cox多因素分析显示肝转移（P=0.002）和K-Ras基因状态（P=0.004）是PFS的独立预后因素;肝转移（P=0.003）、腹腔转移（P=0.000）和全程用靶向药物（P=0.007）是OS的独立预后因素。结论 复发转移大肠癌 K-Ras野生型患者能从西妥昔单抗治疗中获益,K-Ras基因检测是西妥昔单抗疗效的预测指标;K-Ras野生型患者对化疗的受益程度高于突变型患者,K-Ras基因状态可以预测化疗疗效。     

p53基因与大肠癌辅助化疗

大肠癌为我国常见的恶性肿瘤之一.80年代末至今,其发病率呈逐年上升趋势.在大肠癌患者的治疗方案中,辅助化疗占有很重要的地位.以5-FU为主的化疗药物是治疗大肠癌的首选用药.然而,药物对肿瘤细胞的敏感性在不同个体中差别甚大,同一种药物对不同大肠癌患者的疗效各不相同;尤其对于进展期或复发性大肠癌患者,制订化疗方案更需考虑个体差异以提高疗效,但选用什么指标作为化疗药物筛选的标准目前尚无定论.随着分子生物学理论和技术的不断完善,在大肠癌方面的研究已达到分子水平,许多文献报道p53抑癌基因与患者预后及肿瘤化疗药敏有关.若能运用基因手段作为制订肿瘤化疗方案的一个指标,将对临床用药有较大的参考价值.为此.本文就p53基因对大肠癌患者的预后及辅助化疗中的影响这两方面的国内外最新进展作一综述.一、p53基因与大肠癌p53基因为一抑癌基因,在维持细胞生长、抑制恶性增殖过程中起重要作用.在正常细胞中,p53控制着生长停滞状态的静止期细胞从G_0期到G_1期的转变,并且在G_1期的生长限制点(restriction point)控制着细胞进入细胞周期的增殖.当细胞发生DNA损伤时,p53能使细胞分裂终止在G_1～S期,使其有足够时间修复损伤,恢复正常状态;若损伤不能修复,则启动细胞程序死亡导致细胞凋亡,保证有癌变倾     

大肠癌的靶向治疗

  阐述了贝伐单抗（BV）与西妥昔单抗（C225）治疗晚期或转移性大肠癌（CRC）的作用。分子靶向药物BV与C225能特异性阻断血管内皮生长因子（VEGF）和表皮生长因子受体（EGFR）的生物效应，临床应用治疗CRC有效且耐受良好，它与细胞毒药物不同，主要是抑制肿瘤生长，而不是缩小，与化疗联合应用可望增强疗效，延长生存期与改善生活质量。     

曲妥珠单抗原发耐药及继发性耐药的分子机制

曲妥珠单抗是目前治疗ＨＥＲ ２阳性乳腺癌的主要靶向药物,在乳腺癌的各阶段与化疗联合能够明显增加疗效,降低复发转移风险,延长患者生存期。但并非所有患者都获益,原因是存在初始治疗无效的原发性耐药和治疗过程中产生的继发性耐药。对曲妥珠单抗耐药机制的研究发现,ＨＥＲ-２分子空间结构及下游信号通路的改变均可能导致曲妥珠单抗的耐药。本文综述曲妥珠单抗可能的耐药机制,为下一步筛选出能够预测曲妥珠单抗疗效的生物学指标提供基础。     

西妥昔单抗治疗晚期结直肠癌研究进展

结直肠癌因早期诊断率低,大多数患者在发现时已处于中晚期,治疗难度大,预后极差,化疗已成为转移性或局部晚期结直肠癌主要的治疗手段,但是疗效不甚理想。西妥昔单抗（cetuximab,C225）作为一种重要的靶向药物,为晚期结直肠癌患者的生物治疗打开了一扇新的大门。西妥昔单抗在细胞水平、基因水平等多个层面上发挥着抗肿瘤作用,其作用靶点表皮生长因子受体(epithelial growth factor receptor, EGFR)在多种癌组织中高表达,尤其是结直肠癌中。根据FOLFIR I (伊立替康+亚叶酸钙+氟尿嘧啶 )、FOLFOX (奥沙利铂+亚叶酸钙+氟尿嘧啶 )、CapeOx（奥沙利铂+卡培他滨）等联合化疗药物临床试验结果,上述方案都是晚期结直肠癌患者可供选择的,每个方案各有利弊,有效率及适用指征略有不同。单药西妥昔单抗可用于耐受不了高强度化疗或已进行常规化疗后需要维持治疗的患者。目前有很多研究致力于探索具有临床应用前景的疗效预测指标如皮疹、EGFR表达、基因拷贝数（gene copy number,GCN)及基因多态性标志物等,其中大鼠肉瘤病毒癌基因同源物（kirsten rat sarcoma viral oncogene homolog, KRAS ）基因突变研究最为广泛和深入,多项临床试验证实KRAS基因检测可以预测西妥昔单抗的疗效并在临床上已开始应用。通过基因检测等手段找到敏感而特异的西妥昔单抗预后标志物是实现个体化治疗结直肠癌的一大趋势。     

晚期大肠癌化学治疗的新进展

近10年先后批准了6个新药用于治疗晚期大肠癌，包括伊立替康、卡培他滨、奥沙利铂、贝伐单抗、西妥昔单抗和帕妥尼单抗，新的治疗方案也不断涌现。与单用氟尿嘧啶一样，晚期大肠癌患者同样可从这3个细胞毒药物和3个靶向药物中获益。大量研究证实，随着这些新的药物和方案的应用，晚期大肠癌的中位生存期可以从最好支持治疗的6～8个月延长到联合化疗加靶向药物的30个月以上。本文试对晚期大肠癌化学治疗的新进展进行一个综述性评价。     

2008年转移性结直肠癌个体化治疗进展回顾

含草酸铂或伊立替康的化疗方案作为晚期结直肠癌的标准治疗方案,使得患者总生存期超过20个月,靶向治疗药物西妥昔单抗和贝伐单抗的加入进一步提高了疗效.2008年结直肠癌治疗的重要进展是确定KRAS基因状态与抗EGFR抗体疗效的相关性.CRYSTAL、OPUS和CELIM等随机研究显示,通过K-ras检测可筛选出能从分子靶向治疗药物中获益的人群,西妥昔单抗无论是联合以奥沙利铂为基础、还是联合以伊立替康为基础的一线化疗方案,都能使KRAS野生型患者疗效显著提高,显示出西妥昔单抗在mCRC一线治疗中的优势.     

Individualized chemotherapy based on genetic and genomic profiling

The treatment of colorectal cancer has evolved over the past few years to multidrug therapy including 5-fluouracil (5-FU), irinotecan (CPT-11), and oxaliplatin combination regimens. The addition of novel agents such as bevacizumab and cetuximab has added to the efficacy of chemotherapy in this disease. Identification of molecular determinants of 5-FU, irinotecan, and oxaliplatin efficacy and toxicity is of critical importance for the development of more efficient and less toxic treatment strategies for patients with colon cancer. Markers have been identified that may predict response, survival and toxicity to 5-FU, CPT-11, and platinum-based chemotherapy in patients with advanced colorectal cancer. This review explores these markers as well as potential new markers that have been identified for irinotecan and targeted therapy.     

RAS/RAF突变与MSI状态在结直肠癌治疗中的研究进展

近几年,结直肠癌中的分子研究取得了相当大的进展,对如何通过分子表达的不同来选择最佳治疗方案也有了更深的认识。RAS/RAF基因是染色体不稳定性(CIN)通路中最重要的组成部分之一。最近的研究显示RAS/RAF突变的患者有机会接受靶向MAP激酶信号传导通路中的EGFR-KRAS/BRAF-MEK抑制剂的联合治疗,从而为预后不良的RAS/RAF突变患者提供一种新的治疗方式。日前,微卫星不稳定性(MSI)已经被确认为结直肠癌患者接受PD-1治疗的分子标志物。但是MSI对患者是否应接受免疫治疗的预测仍存在些许偏差,相信更为完美的预测靶点肿瘤突变负荷(TMB)将在不久的将来应用于指导临床进行免疫治疗。RAS/RAF突变及MSI状态的研究进展,为改善结直肠癌患者的预后提供了美好前景。     

Evolving Treatment of Advanced Colorectal Cancer

Advances in colorectal cancer treatment have led to improved outcomes for patients. A number of cytotoxic agents, alone and in combination, have shown activity. The addition of the newer, so-called “targeted” agents to standard chemotherapy drugs and regimens has also modestly improved outcomes. Progress in our knowledge and understanding of molecular pathways has led to the identification of markers critical in determining response or nonresponse to some of the targeted agents. This review discusses the available therapies in metastatic colorectal cancer and describes some of the molecular markers implicated in activity and resistance to current targeted therapies.     

Molecular markers of chemotherapeutic response and toxicity in colorectal cancer

Outcomes in colorectal cancer have improved over the last 15 years; this is in part due to the optimization of 5-fluorouracil schedules and the introduction of new and effective chemotherapeutic agents, such as irinotecan and oxaliplatin. However, not all patients respond to these agents and a proportion may suffer severe side effects from particular chemotherapy drugs. These observations have resulted in a concerted research effort to identify markers of chemotherapy efficacy and toxicity. Here we review the evidence for using molecular markers to individualize chemotherapy treatment in colorectal cancer.     

Molecular markers of chemotherapeutic response and toxicity in colorectal cancer

Outcomes in colorectal cancer have improved over the last 15 years; this is in part due to the optimization of 5-fluorouracil schedules and the introduction of new and effective chemotherapeutic agents, such as irinotecan and oxaliplatin. However, not all patients respond to these agents and a proportion may suffer severe side effects from particular chemotherapy drugs. These observations have resulted in a concerted research effort to identify markers of chemotherapy efficacy and toxicity. Here we review the evidence for using molecular markers to individualize chemotherapy treatment in colorectal cancer.     

结直肠癌微卫星不稳定（MSI）与其发病及预后的关系

抑癌基因及癌基因之间的相互作用是结直肠癌发病主要发病原因,近年研究发现微卫星不稳定成为结直肠癌发病另一重要机制,尤其是遗传性非息肉病性结直肠癌（hereditary non-polyposis colorectal cancer,HNPCC）及部分散发性结直肠癌发生的重要原因。微卫星不稳定的结直肠患者具有独特的临床病理特征,如低分化、黏液腺癌、多位于右半结肠、淋巴细胞浸润明显等。化疗是结直肠癌患者手术后重要治疗手段,氟尿嘧啶类药物为结直肠癌患者化疗的基本药物,因此结直肠癌患者对于氟尿嘧啶类药物敏感性成为患者能否从化疗中获益的重要因素,也成为各位学者的研究热点。近年来有学者提出微卫星不稳定及其他分子标记物可预测结直肠癌患者化疗敏感性,同时也可成为判断预后的指标。微卫星不稳定将来可成为结直肠癌患者的预后及化疗敏感性的判断因素,也可为个体化治疗提供理论依据,但目前尚需大样本的前瞻性临床试验进一步证实。结直肠癌目前在国内外发病率均逐渐升高,成为危害人类生命的重要疾病,且遗传倾向明显,是目前人类恶性肿瘤中遗传变化最明显的肿瘤。对于结直肠癌的发病研究表明,染色体不稳定（chromosome instability）为结直肠癌发病的主要原因,其机制仍未完全阐明。近年的研究发现微卫星不稳定（microsatelite instability）为结直肠癌发病的另一重要机制,是遗传性非息肉病性结直肠癌（heredi? tary non-polyposis colorectal cancer,HNPCC）及部分散发性结直肠癌发生的重要原因。目前关于微卫星不稳定的研究不仅于发病机制上,与结直肠癌预后的关系也成为目前研究的热点。      

Prognostic and predictive markers in liver limited stage IV colorectal cancer

Colorectal cancer is the third most commonly diagnosed cancer among both men and women. Personalised treatment options remain complex, although there is broad agreement over which patients with colorectal liver metastases (CRLM) should and should not be offered resection. Decisions on an optimal management strategy involves careful assessment of both technical and oncological factors. In this review we aim to summarise current prognostic biomarkers for metastatic colorectal cancers, specifically patients considered for resection.A number of clinico-pathological factors have been identified as prognostically important with good internal validity, but limited external validity. Furthermore, these prognostic scoring systems do not take factor in modern chemotherapeutic agents and the disease modification these agents produce. Histopathological response to chemotherapy is of significant prognostic importance.Molecular markers can help predict the efficacy of a biological agent. An important prognostic factor of liver metastasis is the recognition that location of the primary colorectal cancer impacts on metastatic phenotype and represents difference in genotype, i.e. proximal tumours are more aggressive than distal tumours with an increased likelihood of disease progression.Several mutational molecular markers identified include microsatellite instability, BRAF, and KRAS/NRAS and combination mutations, which confer poorer outcomes.Accurate prognostication in patients with liver limited colorectal metastases remains crucial, as this allows tailoring treatment options to each disease and improving outcomes. Access to tissue before treatment remains a limitation although advances in ability to assess tumour biology by non-invasive methods are promising.     

Individualization of therapy based on clinical and molecular parameters

Cancers arising from the colonic mucosa are one of the most common causes of cancer-related deaths in the United States. In 2008, an estimated 148,810 new cases will be diagnosed and 49,960 patients will die from this disease. The current therapeutic options for patients with metastatic colorectal cancer are 5-fluorouracil-based therapy regimens in combination with irinotecan or oxaliplatin. Targeted agents, such as cetuximab and bevacizumab, have significantly increased the efficacy of chemotherapeutic regimens. However, there are only a few clinical and potential molecular markers available that can predict clinical outcome in colorectal cancer. Thus, the development of validated molecular predictive and prognostic markers may be helpful in identifying patients who are likely to be responsive to a specific drug and will serve a critical role in developing more efficient treatment strategies.     

Chemotherapy for colorectal cancer

With effective chemotherapy as adjuvant treatment, the survival benefit is clearly achieved for certain (stage III) colorectal cancer patients, though there still exist many unsettled issues including the controversies in the treatment of stage II disease. Advances in the development of a new generation of cytotoxic agents in the past several years have allowed us to move forward from the "fluorouracil-only era" in the treatment of advanced/metastatic colorectal cancer. It is still not very clear how best to minimize toxicity without compromising efficacy of the combination therapy with newer agents, or how to maximize the benefit of chemotherapy (concurrent versus sequential). There are many current ongoing clinical trials designed to address these issues. With better understanding of the signal transduction and molecular biology characteristics of colorectal cancer, and the development of biologic and molecular target agents, the outcomes of patients with colorectal cancer will be improved further. Future clinical trials should be focused on optimizing and individualizing therapy for patients based on their molecular profiles to achieve maximal clinical benefit.     

Prognostic and predictive relevance of microsatellite instability in colorectal cancer

Microsatellite instability (MSI) is the phenotypic hallmark of a deficient DNA mismatch-repair system, observed in 10-20% of sporadic colorectal cancers (CRC). Since the prognostic and predictive value of this genetic alteration has been assessed mainly in non-randomised, uncontrolled studies, we investigated the potential of MSI to predict patient survival and response to adjuvant chemotherapy in tumour specimens from a randomised trial of the Swiss Group for Clinical Cancer Research (SAKK) that tested the value of 5-fluorouracil/mitomycin adjuvant chemotherapy. MSI status was determined in matched normal and tumour tissue samples from 160 patients using a panel of 9 microsatellite markers. There was no correlation between high frequency MSI (MSI-H) and overall (OS) or disease-free survival (DFS) in the untreated control group of patients (HR=1.13, p=0.80; and HR=0.89, p=0.81, respectively). Furthermore, MSI-H phenotype did not predict for a larger benefit of adjuvant chemotherapy on OS or DFS (HR=0.49, p=0.41; HR=0.49, p=0.41, respectively), making a potential value of this molecular marker as a predictive factor in CRC unlikely. Our data do not confirm the prognostic relevance of MSI-H status in colorectal cancer patients found in some other studies. In addition, microsatellite instability did not correlate with the extent of chemotherapy benefit, although we observed a statistically non-significant favourable impact of 5-FU-based treatment in the MSI-H group compared to MSI-L/MSS patients. Larger prospective randomised trials are required to conclusively establish a potential clinical significance of MSI in colorectal cancer.