Efficacy and immune mechanisms of cetuximab for the treatment of metastatic colorectal cancer

Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor and inhibits downstream intracellular signals. Research has shown that cetuximab can stimulate the autoimmune system and produce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity reactions, which can recruit cytotoxic lymphocytes to attack and kill cancer cells. Cetuximab is mainly indicated for patients with epidermal growth factor receptor-positive metastatic colorectal cancer who fail to respond to both irinotecan- and oxaliplatin-based regimens. The efficacy and safety of cetuximab as monotherapy or in combination with other treatment options were evaluated in a series of phase II and phase III trials. Identifying the clinical and molecular markers that can predict which patient groups may best benefit from cetuximab treatment is key to improving patient outcomes and avoiding unnecessary toxicities and costs. Herein, we discuss the mechanisms of action by which cetuximab exerts its antitumor effects, as well as the possible clinical and molecular markers that may help predict therapeutic benefits for patients with metastatic colorectal cancer.     

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。     

BEYOND KRAS: Other Markers and Potential Treatment Strategies for KRAS Mutant and Wild-type Patients

Despite the advances and new drug discoveries, the best drug in metastatic colorectal cancer (mcrc) is 5-fluorouracil. This drug is the backbone of FOLFOX and FOLFIRI which are the standard first line cytotoxic regimens in the metastatic setting. The efficacies of these two regimens are equivalent, and the selection of one over the other is largely based on the side effect profile. Bevacizumab is commonly added to each of these regimes in the first line setting. When a patient develops progression of disease on FOLFOX, then treatment with either single agent irinotecan, or FOLFIRI is a typical approach. If FOLFIRI-BEV is used in first line, the FOLFOX is typically given in second line. All patients with metastatic colorectal cancer have their tumor tested for the KRAS mutation in exon 2. If the tumor is KRAS wild-type then either cetuximab or panitumumab, with or without continued irinotecan, may be used. In patients whose tumors are symptomatic, and so requiring a rapid response, cetuximab or panitumumab may be incorporated into second line therapy instead of third line. There are no data supporting the use of cetuximab after progression on panitumumab or vice versa and use of one of these agents after failure on the other is not appropriate. Upon progression on the standard chemotherapies outlined above appropriate patients may be offered participation in a clinical trial. For patients whose tumors are KRAS mutant a clinical trial should be considered upon progression on oxaliplatin and irinotecan-based regimens. New agents and combinations of targeted therapies described below offer promising therapies for patients with both KRAS wild type and mutant tumors. As our molecular knowledge of mcrc advances future therapies will likely tailor an individualized approach based on tumor specific molecular markers.     

预测大肠癌化疗疗效的分子或基因指标

用于治疗大肠癌的药物主要有氟尿嘧啶、卡培他宾、依立替康、奥沙利铂、昔妥单抗、贝伐单抗,使大肠癌的化疗有效率明显提高,病人中位生存时间明显延长。但大肠癌化疗中原发和获得性耐药现象很普遍。一些分子或基因指标有可能预测大肠患者能否从辅助化疗或姑息化疗中获益。这篇综述主要回顾预测大肠癌化疗药物疗效的分子和基因指标,分析其联系,从而指导临床按个体化原则用药。     

Upfront Chemotherapy Regimens in Unresectable Disease: One, Two, or Three Cytotoxics?

Today, the upfront treatment of unresectable metastatic colorectal cancer (mCRC) may span from single-agent fluoropyrimidines to three and even four-drug regimens, currently under investigation in several trials. While clinical factors, including the crucial item of secondary resectability, certainly contribute to formulate the most appropriate strategy for each patient, also molecular markers are gaining increasing prominence in the decision-making process. This review aims at collecting our group??s point of view about the role of upfront combination regimens, both in patients pursuing a radical resection and in those unlikely to undergo a secondary surgery.     

结直肠癌精准治疗发展趋势

 结直肠癌精准治疗是生物技术、信息技术等多种前沿技术在结直肠癌临床实践中的融合应用。随着循证医学的发展和越来越多分子标志物被发现,结直肠癌精准治疗将逐步渗透到外科治疗、化疗、放疗、靶向治疗及免疫治疗等各个方面,为不同生物学特征患者提供个体化治疗方案。       

Molecular predictors of response to EGFR antibodies in colorectal cancer

Cetuximab and panitumumab, antibodies against the epidermal growth factor receptor (EGFR), have been shown to be effective in treating irinotecan-resistant and chemorefractory metastatic colorectal cancer, respectively. However, these costly and potentially toxic treatments are effective in only a small proportion of patients. It is important to identify markers that can better define which patients will benefit from these treatments. The major potential molecular predictive markers of response to cetuximab or panitumumab are involved more or less directly in the EGF signaling pathway. Among them, KRAS mutations, EGFR gene copy number, and, more recently, expression of the PTEN protein and the epiregulin and amphiregulin genes appear to be the most relevant; these must be evaluated in future clinical trials before they are incorporated into the therapeutic strategy for colorectal cancer.     

Molecular predictors of response to EGFR antibodies in colorectal cancer

Cetuximab and panitumumab, antibodies against the epidermal growth factor receptor (EGFR), have been shown to be effective in treating irinotecan-resistant and chemorefractory metastatic colorectal cancer, respectively. However, these costly and potentially toxic treatments are effective in only a small proportion of patients. It is important to identify markers that can better define which patients will benefit from these treatments. The major potential molecular predictive markers of response to cetuximab or panitumumab are involved more or less directly in the EGF signaling pathway. Among them, KRAS mutations, EGFR gene copy number, and, more recently, expression of the PTEN protein and the epiregulin and amphiregulin genes appear to be the most relevant; these must be evaluated in future clinical trials before they are incorporated into the therapeutic strategy for colorectal cancer.     

The role of irinotecan in colorectal cancer

Irinotecan, also known as CPT-11, is a topoisomerase I inhibitor currently approved for use as a second-line agent in the treatment of advanced colorectal cancer. Preliminary reports from randomized studies exploring combinations of CPT-11 plus 5-fluorouracil have shown improved antitumor activity versus 5-fluorouracil-based treatments alone, and suggest a first-line role for these combination regimens. The role of CPT-11/5-fluorouracil regimens in the adjuvant setting is now being actively explored. Studies of single-agent CPT-11 in the first-line treatment of metastatic colorectal cancer have shown activity; however response rates do not appear to be superior to those seen with standard first-line 5-fluorouracil-based regimens. The use of specific molecular markers as prognostic indicators of response or resistance to specific chemotherapies may, however, permit the identification of a selected population of patients with tumor characteristics that would specifically favor consideration of up-front use of single-agent CPT-11.     

Prognostic and Predictive Markers in Colorectal Cancer

Prognostic and predictive biomarkers have revolutionized medicine by allowing individualized treatment decisions. Most notably in oncology, where treatment can be associated with significant toxicities and often unpredictable outcomes, there is a need to isolate patients that are likely to benefit from an intervention. In colorectal cancer, there are many markers being investigated but only a few that have sufficient evidence to warrant use in clinical practice. This paper will review these prominent biomarkers in both adjuvant and metastatic colorectal cancer and summarize the data regarding their utility. The markers reviewed include microsatellite instability, 18qLOH, gene profile assays such as ColoPrint and Oncotype DX, Kras, Braf, thymidylate synthase, and circulating tumor cells. The paper will also discuss optimal clinical trial design, with a focus on different validation strategies for emerging biomarkers. By highlighting the pertinent literature, the hope is to facilitate a personalized approach to colorectal cancer care.     

Current status of adjuvant therapy for colorectal cancer

Adjuvant therapy with chemotherapy and/or radiation therapy in addition to surgery improves outcome for patients with high-risk carcinomas of the colon or rectum. For colon cancer, fluorouracil (5-FU) combined with leucovorin is a current standard of care that improves long-term survival. A recent European trial (MOSAIC) has documented significant improvement in 3-year disease-free survival when oxaliplatin (Eloxatin) was added to infusional 5-FU and leucovorin in the FOLFOX regimen. Two US cooperative group trials will evaluate the addition of antiangiogenesis therapy with bevacizumab (Avastin) to chemotherapy. A third trial will evaluate FOLFOX, irinotecan (Camptosar) combined with infusional 5-FU and leucovorin (FOLFIRI), and the sequential use of FOLFOX followed by FOLFIRI. In rectal cancer, postoperative 5-FU-based chemotherapy combined with irradiation can improve both local tumor control and survival. The German Rectal Cancer Group has recently reported that preoperative combined-modality therapy is less toxic and more effective in preventing local tumor relapse compared to similar treatment given postoperatively. A coordinated pair of cooperative group clinical trials will evaluate oral capecitabine (Xeloda) as a radiation enhancer in the preoperative setting, and the FOLFOX and FOLFIRI regimens compared to 5-FU and leucovorin following surgery. Predictive and prognostic molecular markers will be studied in these new adjuvant therapy clinical trials for both colon and rectal cancer with the goal of developing future regimens tailored to individual patients. There has been a recent and dramatic increase in the pace of drug development for colorectal cancer which holds promise to further improve curative therapy as part of a multidisciplinary approach in the surgical adjuvant setting.     

ERCC1 mRNA表达与结直肠癌标准方案化疗临床预后的相关性研究

目的:探讨结直肠癌石蜡组织中切除修复交叉互补基因 (excision repair cross-complementing group 1,ERCC1) mRNA表达水平与接受标准方案化疗的结直肠癌患者临床病理的关系以及其预后意义。方法:采用实时荧光定量 RT-PCR检测福尔马林固定－石蜡包埋的结直肠癌组织中DNA修复基因ERCC1 mRNA的表达水平,并比较其表达水平与接受标准方案化疗的结直肠癌患者的临床病理及生存期之间的关系。结果:ERCC1 mRNA表达与结直肠癌临床病理特征无相关性(P＞0.05)。将ERCC1 mRNA在96例大肠癌患者中的表达量（相对于β-actin）分为低表达组与中高表达组（≤5.21为低表达组,＞5.21为中高表达组）,样本总生存期呈正态分布,中高表达组平均总生存期为68.52月（95%CI:63.06-76.06）,低表达组平均总生存期为56.63月（95%CI:44.45-68.80）,从生存曲线上看中高表达组患者总生存时间明显长于低表达组,两者有统计学差异(P=0.049)。样本无进展生存期呈偏态分布,中高表达组的中位生存时间30.98月（95%CI:0-18.65）,低表达组的中位生存时间8.48月（95%CI:6.37-10.60）,两者之间差别无统计学意义（P=0.575）。Cox多因素回归分析发现性别（P=0.023）、分期（P＜0.001）、以肠梗阻或肠穿孔起病（P=0.046）是患者总生存期的独立影响因素,年龄（P=0.043）、分期（P＜0.001）、脉管侵犯（P=0.002）是患者无进展生存期的独立影响因素。结论:ERCC1 mRNA的表达水平可能是使用标准方案化疗的结直肠癌患者预后的影响因素,性别、分期、以肠梗阻或肠穿孔起病、年龄、脉管侵犯是影响结直肠患者预后的独立影响因素。     

Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) patients carrying KRAS mutated tumors do not benefit from epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies. Indeed, the mutational status of KRAS is currently a validated predictive biomarker employed to select mCRC patients for EGFR targeted drugs. When patients fail standard 5-fluorouracil-, oxaliplatin-, irinotecan- and bevacizumab-based therapies, EGFR-targeted salvage therapy can be prescribed only for those individuals with KRAS wild-type cancer. Thus, clinicians are now facing the urgent issue of better understanding the biology of KRAS mutant disease, in order to devise novel effective therapies in such defined genetic setting. In addition to KRAS, recent data point out that BRAF and PIK3CA exon 20 mutations hamper response to EGFR-targeted treatment in mCRC, potentially excluding from treatment also patients with these molecular alterations in their tumor. This review will focus on current knowledge regarding the molecular landscape of mCRC including and beyond KRAS, and will summarize novel rationally-developed combinatorial regimens that are being evaluated in early clinical trials.     

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.     

Current therapies for advanced colorectal cancer

Significant advances have been made in the treatment of advanced colorectal cancer over the past 5 years, namely due to the introduction of three novel cytotoxic agents-capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin)-and the recent approval of two biologic agents-bevacizumab (Avastin) and cetuximab (Erbitux). During this time period, the median survival of patients with advanced, metastatic disease has gone from 10 to 12 months to nearly 24 months. Intense efforts have focused on identifying novel targeted therapies that target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. Recent clinical trial results suggest that the anti-VEGF antibody bevacizumab can be safely and effectively used in combination with each of the active anticancer agents used in colorectal cancer. Despite the development of active combination regimens, significant improvements in the actual cure rate have not yet been achieved. Combination regimens with activity in advanced disease are being evaluated in the adjuvant and neoadjuvant settings. The goal is to integrate these targeted strategies into standard chemotherapy regimens so as to advance the therapeutic options for the treatment of advanced colorectal cancer. Finally, intense efforts are attempting to identify the critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/or the drug-specific side effects. The goal of such studies is to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with colorectal cancer.     

Molecular Biomarkers of Colorectal Cancer and Cancer Disparities: Current Status and Perspective

This review provides updates on the efforts for the development of prognostic and predictive markers in colorectal cancer based on the race/ethnicity of patients. Since the clinical consequences of genetic and molecular alterations differ with patient race and ethnicity, the usefulness of these molecular alterations as biomarkers needs to be evaluated in different racial/ethnic groups. To accomplish personalized patient care, a combined analysis of multiple molecular alterations in DNA, RNA, microRNAs (miRNAs), metabolites, and proteins in a single test is required to assess disease status in a precise way. Therefore, a special emphasis is placed on issues related to utility of recently identified genetic and molecular alterations in genes, miRNAs, and various “-omes” (e.g., proteomes, kinomes, metabolomes, exomes, methylomes) as candidate molecular markers to determine cancer progression (disease recurrence/relapse and metastasis) and to assess the efficacy of therapy in colorectal cancer in relation to patient race and ethnicity. This review will be useful for oncologists, pathologists, and basic and translational researchers.     

Effects of molecular markers on the treatment decision and prognosis of colorectal cancer: a narrative review

ObjectiveTo summarize the effects of molecular markers on the treatment decision and prognosis of colorectal cancer.BackgroundColorectal cancer is a highly heterogeneous disease. Even colorectal cancers of the same pathological type and clinical stage may have significant differences in treatment efficacy and prognosis. There are three main molecular mechanisms for the occurrence and development of colorectal cancer: chromosomal instability (CIN) pathway, microsatellite instability (MSI), and CpG island methylate phenotype (CIMP). There are multiple molecular markers distributed on each pathway.MethodsWe performed a literature search on the PubMed database for studies published in English (from the date of initiation of the database to the year of 2020) using the following subject terms: “colon cancer”, “rectal cancer”, “colorectal cancer”, “molecular markers”, “biomarkers”, “treatment strategies”, and “prognosis”.ConclusionsThe different expression states of molecular markers have a significant impact on the treatment decision and prognosis of colorectal cancer. Main colorectal cancer molecular markers include MSI and some important genes. Individualized treatments for tumors with different molecular phenotypes have improved the treatment effectiveness for colorectal cancer. The rational use of molecular markers is valuable for treatment decision-making and the prognosis of patients with colorectal cancer.     

The use of carcinoembryonic antigen in the clinical management of patients with colorectal cancer

It has taken approximately 18 years to define the clinical utility of carcinoembryonic antigen (CEA) as a marker in patients with colorectal cancer. Hopefully, the use of CEA as a prototype and the knowledge of the many clinical studies designed to define its use in patients with colorectal cancer will help avoid the need for 18 years of studies in determining the biologic and clinical applicability of the many promising new candidate tumor markers now being developed. In this paper we will review our own studies which have helped to define the clinical utility of CEA in the care of patients with colorectal cancer.     

Role of Circulating Tumor Cells in Metastatic Colorectal Cancer: Clinical Challenges and Opportunities

Circulating tumour cells (CTCs) have been presumed critical to the metastatic process since 1800. These epithelial cells are disseminated from the primary or metastatic tumor site and can be identified in the peripheral blood of patients. Nowadays, technical advances have rendered it easier to reproducibly and repeatedly sample this population of cells with an acceptable degree of accuracy. Therefore, these cells could become an attractive surrogate for phenotypic and genotypic markers in correlation with the development of molecular targeted therapies. In metastatic colorectal cancer several prospective studies have demonstrated the independent prognostic significance of CTCs and identified the number of CTCs before and during treatment as a predictor for overall survival and disease free survival. However, the underlying molecular characteristics of CTCs associated with outcome remain largely unknown. In this review, the role of CTCs in metastatic colorectal cancer is discussed. The variety of assays that can be used for enrichment and detection steps in CTC detection will be described and the clinical utility of these cells for assessing prognosis and monitoring response to therapy will be analyzed. We will also address the shortcomings of current detection methods that fail to identify a mesenchymal subgroup of CTCs, and briefly address how characterization of these cells can help elucidate the biology of cancer metastases.     

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.