Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Taxanes for advanced non-small cell lung cancer

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.     

Has bevacizumab (Avastin) given extra therapeutic gain in metastatic colorectal cancer and malignant brain gliomas? Systematic review answering this question

During the last decade, the development of new drugs known as targeted therapies was the result of a better understanding of the processes involved in the transformation of normal cells into cancer. The term targeted therapy refers to drugs that selectively target specific molecular pathways involved in tumourigenesis or tumour progression. Angiogenesis is important for tumour growth and metastasis and is an important target for new biological agents. Bevacizumab is a humanised recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumour growth. On February 26, 2004, the FDA (Food and Drug Administration) approved Bevacizumab as first-line treatment for patients with metastatic colorectal cancer. The integration of targeted therapies in the treatment of colon cancer has resulted in significant improvements in efficacy outcomes. Bevacizumab was the first antiangiogenic therapy approved for use in cancer and received accelerated FDA approval for the treatment of recurrent glioblastoma multiform in 2009. The efficacy of Bevacizumab in the treatment of metastatic colorectal cancer and recurrent glioblastoma multiform is presented in this review article. The structural characteristics and selectivity profiles of this antiangiogenic drug and those disclosed in related patent applications are also summarised in this article.     

Antiangiogenic therapy in malignant glioma: promise and challenge

Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are currently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.     

Efficacy of trebananib (AMG 386) in treating epithelial ovarian cancer

Introduction: Epithelial ovarian cancer (EOC) is the leading cause of death among gynecologic cancers. The majority of women are diagnosed with advanced stage disease. It is considered a chemosensitive cancer with a high initial response rate to first-line platinum and taxane-based chemotherapy. However, most patients with advanced EOC will relapse with subsequent resistance to conventional chemotherapy and ultimately succumb to their disease. Therefore, new therapeutic agents and strategies are desperately needed to improve the outcomes in patients with advanced EOC.

Areas covered: This review focuses on the use of Trebananib (a non-VEGF-dependent angiogenesis pathway inhibitor) in EOC. Angiogenesis has been recognized as an important process promoting EOC growth and metastasis. Targeting angiogenesis in EOC have been developed and studied with demonstrated clinical efficacy. Bevacizumab, a humanized monoclonal antibody, that targets vascular endothelial growth factor A (VEGF-A), has been the most well evaluated molecular targeted therapy in the treatment of advanced and recurrent EOC with proven clinical efficacy. However, VEGF-dependent angiogenesis pathway inhibitors are often associated with serious toxicities and drug resistance ultimately develops. Hence, new therapeutic approach targeting the angiopoietin-Tie-2 complex pathway (a non-VEGF-dependent angiogenesis pathway) has gained interest over the past few years as an alternative strategy to overcome VEGF-dependent anti-angiogenesis-related toxicity and resistance.

Expert opinion: Targeting angiopoietin-Tie-2 pathway represents a promising alternative approach to tumor anti-angiogenesis with a distinct toxicity profile from the VEGF-dependent pathway inhibitors. However, there are still many questions to be answered regarding the optimal treatment schedules, maintenance regimens, duration of maintenance therapy, and the best combination strategy.

Currently there is no reliable surrogate molecular, cellular, or genetic marker that would definitively predict response to anti-angiogenic therapy. Identification of certain relevant and predictive biomarkers in the future may optimize treatment’s efficacy by distinguishing the subset group of patients with EOC that would derive the most benefit from existing antiangiogenic treatment regimens.     

Prospect of combination of anti-PD-1/PD-L1 therapy and other therapeutics for treatment of lung cancer

Lung cancer is the leading cause of cancer death worldwide, mainly because it has no obvious symptoms at the early stage and it is usually diagnosed at the advanced stage. Surgery and chemotherapy are the main common treatment options for lung cancer patients. During the past 25 years, great progress has been made in the treatment of lung cancer. Novel materials such as nanoparticles have shown therapeutic potential for lung cancer as they can selectively enter tumor cells due to their small size and surface modifiability. However,the prognosis of patients with lung cancer is still unsatisfactory. Targeted immunotherapy has shown potential for the treatment of lung cancer. The anti-tumor immunotherapy has been widely concerned as immune escape plays an important role in the occurrence and development of tumors. In particular, agents targeting PD-1/PD-L1 have been widely studied and some anti-PD-1/PD-L1 agents have been approved for the treatment of lung cancer by FDA since they have shown significant anti-tumor activity in lung cancer patients. Nevertheless, not all patients response to this therapy and the immune-related adverse events have emerged. The immune-related adverse events mainly involve the gut, skin, endocrine glands, liver,lung and other tissues. With the development of this field, combination therapy has been regarded as a promising strategy to improve the safety and efficacy of antiPD-1/PD-L1 therapy. Studies have shown that the radiotherapy, chemotherapy, oncolytic virus, antiangiogenic agents and indoleamine 2,3-dioxygenase(IDO) inhibitors may improve the efficacy and reduce the incidence of adverse events of anti-PD-1/PD-L1 therapy. Radiotherapy can not only kill tumor cells, but also stimulate the immune system by releasing tumor antigens. Chemotherapy may induce the tumor-specific adaptive immune response.Oncolytic virotherapy, which is a form of immunotherapy,can kill tumors directly and induce the host immune response to tumour cells. Angiogenic factors have immunosuppressive effect, thus the antiangiogenic drugs may improve anti-tumor activity of anti-PD-1/PD-L1 agents in the treatment of lung cancer. Researches on IDO inhibitors in combined with other therapies are active and this combination may have good safety. In this review, we summarized the mechanisms and advantages of the combination therapy based on anti-PD-1/PD-L1 therapy,providing basis for its further clinical application.     

State of the art and up-and-coming angiogenesis inhibitors for ovarian cancer

ABSTRACT

Angiogenesis inhibitors have clearly shown activity in ovarian cancer in various settings; however, preliminary data did not reflect significant survival benefit. Bevacizumab has been extensively studied and is approved for use in ovarian malignancy. However, the efficacy of bevacizumab is modest and most treated patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Newer therapies are being evaluated and their role of these newer therapies is upcoming and promising. Recent research focuses on the role of this drug group in frontline, maintenance and recurrent settings. Combination of PARP inhibitors with angiogenesis inhibitors has recently shown to improved survival rates. Potential strategies need to be devised for selecting patients most likely to benefit from such therapy.     

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.     

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.     

立体定向放射治疗在寡转移性非小细胞肺癌治疗中的联合应用

寡转移性非小细胞肺癌( NSCLC)不同于广泛转移的晚期 NSCLC,针对寡转移灶局部治疗可获得潜在治愈的可能。立体定向放射治疗( SBRT)作为有效的局部治疗手段,联合化疗、络氨酸激酶抑制剂( TKIs)、免疫检查点抑制剂( ICIs)、抗血管生成等可以为晚期 NSCLC病人带来生存获益。该文回顾了 SBRT在寡转移性 NSCLC的研究,从 SBRT对寡转移性 NSCLC的治疗效果、 SBRT联合 TKIs和 SBRT联合 ICIs的临床研究进展展开综述。     

晚期非小细胞肺癌治疗的新趋势

当今肺癌研究的热点是以与肿瘤发生、发展相关的驱动基因为靶点,研发新的药物,进行有针对性的个体化分子靶向治疗,从而改善患者预后。靶向药物、新型化疗药物、抗血管新生药物以及治疗性疫苗等各种治疗手段在晚期非小细胞肺癌(NSCLC)患者的治疗中均取得了显著的进展。其中表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)对于EGFR突变阳性NSCLC患者无论在一线、维持还是二线治疗中疗效均得到肯定;替吉奥胶囊有望成为晚期NSCLC一线、二线治疗新的选择;克唑替尼是棘皮动物微管结合蛋白4与间变淋巴瘤激酶融合基因(EML4-ALK)阳性患者治疗的新标准;抗血管新生药物在NSCLC的治疗疗效得到了进一步证实;EGF疫苗在晚期NSCLC治疗中的结果值得期待。这些成果将会改变目前晚期NSCLC的治疗策略,而基于患者临床特点及分子分型的个体化治疗将成为晚期非小细胞肺癌治疗的新趋势。     

Vascular endothelial growth factor-targeted therapy for the treatment of renal cell carcinoma

Vascular endothelial growth factor (VEGF)-targeted agents have rapidly been adopted into standard-of-care treatment for renal cell carcinoma (RCC). However, a substantial proportion of patients fail to respond to these agents or experience considerable toxicity. This article reviews the benefits and limitations of currently approved anti-VEGF agents in advanced and metastatic RCC, and the role for newly approved and developmental agents. Sunitinib and bevacizumab plus interferon (IFN)-α have demonstrated significant improvements in progression-free survival (PFS) compared with IFNα in treatment-na?ve patients. A PFS benefit has also been shown with sorafenib versus placebo second-line to cytokine therapy. However, no anti-VEGF agent has shown a significant overall survival benefit. Anti-VEGF therapy is generally well tolerated, but a number of key adverse events, including dermatological, mucosal and constitutional symptoms, may limit treatment compliance and success. Pazopanib is a recently approved, highly selective anti-VEGF agent that shows benefit in PFS over IFNα, with low rates of treatment-related adverse events and, therefore, may be better tolerated than other currently approved agents. The advent of VEGF-targeted therapy for RCC has greatly improved prospects for patients with advanced or metastatic disease, but more efficacious agents are required that demonstrate a clear survival advantage. Ongoing trials evaluating novel anti-VEGF therapies could establish whether the increased potency and selectivity of these agents results in improved efficacy and tolerability in RCC patients, further improving their prognosis.     

The role of antiangiogenetic agents in the treatment of breast cancer

Angiogenesis is known to be essential for the development and progression of cancer. Vascular endothelial growth factor (VEGF) is a critical mediator in tumor angiogenesis for many solid malignancies, including breast cancer. Increased levels of VEGF have been associated with poor clinical outcomes, including reduced survival. VEGF has become an attractive target for cancer therapy in view of its pivotal role in angiogenesis. The primary approaches for inhibiting angiogenesis have focused on inhibiting the activity of VEGF, either by targeting the VEGF ligand itself with monoclonal antibodies (mAbs) or by interfering with the signaling events downstream of VEGF through the use of tyrosine kinase inhibitors (TKIs). Bevacizumab is a recombinant, humanized monoclonal IgG1, anti-VEGF antibody that has demonstrated significant clinical benefit in several solid tumors. Bevacizumab has been approved for use in combination with paclitaxel for the first line treatment of patients with metastatic breast cancer (MBC) based on the results of the randomized phase III E2100 trial in which it improves response rate and time to progress when administered with weekly paclitaxel until disease progression. Several trials to define the role of bevacizumab in different setting of disease and in combination with different chemotherapy regimens and targeted therapy in breast cancer patients are ongoing. Other small molecule inhibitors of VEGF tyrosine kinase activity (TKIs) such as sunitinib, vandetanib and sorafenib are being tested in MBC. This review will focus on bevacizumab and on the developements of the main antiangiogenic agents in the treatment of breast cancer.     

Sorafenib for lung cancer: is the "Battle" still open?

In the recent years, the improved understanding of the biological relevance of angiogenesis as a major cancer hallmark led to the development of a heterogeneous group of agents targeting this key process. Among the anti-angiogenic drugs (including monoclonal antibodies such as Bevacizumab, and other molecules with different mechanism of action, such as the vascular disrupting agents Vadimezan), the tyrosine kinase inhibitors (TKIs, Sorafenib, Sunitinib, Pazopanib, and Axitinib), are commonly thought to inhibit angiogenesis through a most rational and promising approach. In this regard, many tyrosine kinase inibitors, such as Sorafenib, are multi-targeted, which allows for the inhibition of those multiple functional pathways which are considered to be critical for both tumor development and progression. Besides, this multi-targeted activity may theoretically increase efficacy but also toxicity. As a member of this group, Sorafenib has already been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma not suitable for locoregional treatment, and it is currently under investigation for advanced non small cell lung cancer (NSCLC), either alone or in combination with other biological/cytotoxic agents.     

Molecularly-targeted therapies for non-small cell lung cancer

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.     

Molecularly-targeted therapies for non-small cell lung cancer

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.     

Epidermal growth factor receptor inhibitors: an update on their development as cancer therapeutics

Therapeutic agents targeting the epidermal growth factor receptor (EGFR) have recently been approved for use in patients based on the results of large-scale phase II studies involving patients with advanced refractory non-small-cell lung cancer (NSCLC). Disappointingly, results from phase III trials of gefitinib in combination with standard chemotherapy regimens for the treatment of NSCLC were negative. While results from phase III trials with other agents such as erlotinib and cetuximab will be reported in the next 12 to 18 months, the early results raise a number of questions regarding the development of these agents, including patient selection (e.g., disease, stage, prior therapy, EGFR or other biomarker expression) and combinations with standard treatment regimens as well as hormonal agents, radiation or other novel agents which will require further elucidation. Early data suggest a number of potential roles for these agents in the modulation of resistance and in combination with other inhibitors of signal transduction.     

Bevacizumab as first-line treatment for advanced non-small cell lung cancer

Bevacizumab is a humanized monoclonal antibody (mAb) to vascular endothelial growth factor (VEGF), a major proangiogenic factor in advanced solid tumors. Phase I and II trial results suggested that this agent was well tolerated and could be combined with standard regimens in various solid tumors. An initial randomized phase II trial in advanced non-small cell lung cancer (NSCLC) yielded positive results regarding the potential efficacy of this agent in combination with carboplatin and paclitaxel (CbP). It also identified a safety signal in patients with squamous histology, who appear to have a higher rate of serious and potentially life-threatening pulmonary hemorrhage. Because of this observation, patients with predominantly squamous histology were excluded from the pivotal phase III trials, as were patients with brain metastases and a history of significant hemoptysis. Two phase III trials comparing a standard platinum-based doublet with or without bevacizumab have been reported in advanced NSCLC, both of which met their primary endpoints. The trial reported by the Eastern Cooperative Oncology Group (ECOG 4599) was the first to show an overall survival benefit, as well as a benefit in response rates and progression-free survival resulting from the addition of bevacizumab to CbP. Certain toxicities were increased when bevacizumab was added to CbP, including neutropenia, febrile neutropenia, thrombocytopenia, bleeding (including pulmonary hemorrhage), hypertension and proteinuria. Bevacizumab is the first targeted therapeutic agent to improve survival in advanced NSCLC when added to standard chemotherapeutic regimens.     

射频联合紫衫醇＋卡铂方案治疗晚期非小细胞肺癌的临床观察

目的：观察多极射频消融（RFA）联合紫衫醇＋卡铂方案（PC）治疗晚期非小细胞肺癌（NSCLC）的临床效果。方法：30例晚期NSCLC（Ⅲ、Ⅳ期）采用RFA联合PC方案治疗,并与28例单纯PC方案化疗进行比较。结果：以疗效、生活质量评分及生存时间等指标评价,RFA联合PC方案治疗组明显优于单纯PC方案化疗组,疗效差异有显著意义,P〈0.01。结论：RFA联合PC方案化疗明显提高晚期NSCLC治疗效果,可作为晚期NSCLC的综合治疗方法。     

Beyond bevacizumab: new anti-VEGF strategies in colorectal cancer

Introduction: Treatment of colorectal cancer (CRC) has changed dramatically over the past decade, mainly due to the advent of molecularly targeted agents. In particular, an improved understanding of the role of the angiogenesis pathway in CRC has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic CRC (mCRC) and at present is the only antiangiogenesis agent approved for the treatment of this cancer.

Areas covered: In this review, the authors outline the most recent data on the VEGF signaling pathway and on new therapeutic reagents that target it, provide insight into their mechanisms, and describe results from recent clinical trials.

Expert opinion: In the new decade of ‘modern therapy', an increasing number of antiangiogenic agents for the treatment of mCRC are being tested in preclinical models, and dozens of studies on these drugs are ongoing. Presently, eight novel antiangiogenic agents are in Phase III trials and a wide range of other candidates are being tested in Phase I/II trials. Given the preliminary positive results of two recent Phase III trials, aflibercept and regorafenib, probably, will be new-targeted agents approved for the treatment of mCRC. Furthermore, the list of potentially approved agents seems to increase in the next years and to maximize their potential clinical impact, is critically important to introduce efficient molecular diagnostic methodologies into the drug development process to indentify the subset of patients who would benefit most from their use.