A Critical Review of Second-generation anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer

2020 ◽  
Vol 21 ◽  
Author(s):  
Daniel Sur ◽  
Andrei Havasi ◽  
Alecsandra Gorzo ◽  
Claudia Burz
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Metastatic Colorectal Cancer ◽  
Second Generation ◽  
Current Data ◽  
Braf Mutations ◽  
Durable Response ◽  
Ongoing Research

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

scholarly journals Update in Antiepidermal Growth Factor Receptor Therapy in the Management of Metastatic Colorectal Cancer

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Herbert H. Loong ◽  
Brigette B. Ma ◽  
Anthony T. C. Chan
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Ongoing Research ◽  
Historical Progress ◽  
Predictors Of Response ◽  
Epidermal Growth

The approval of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC) has expanded the armamentarium against this disease. This paper will review the historical progress and recent clinical developments of anti-EGFR therapies in the treatment of metastatic CRC. Novel strategies of targeting the EGFR pathway to improve efficacy as well as ongoing research in identifying specific molecular predictors of response will be discussed.

Use of HER2 gene amplification to identify patients with metastatic colorectal cancer resistant to anti-EGFR monoclonal antibodies.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 474-474 ◽  
Author(s):  
Cecilia Barbara ◽  
Vittoria Martin ◽  
Francesca Molinari ◽  
Lorenza Landi ◽  
Alice Riva ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Metastatic Colorectal Cancer ◽  
Gene Amplification ◽  
Objective Response ◽  
Chromosome 17 ◽  
Her2 Gene ◽  
Braf Mutations ◽  
Her2 Gene Amplification ◽  
Gene Status

474 Background: KRAS mutation represents the only validated biomarker used in clinical practice for selection of metastatic colorectal cancer (mCRC) candidates for therapy with the anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies. Previous studies conducted in small cohorts of patients suggested that HER2, the major EGFR partner, could modify the sensitivity to anti-EGFR agents. Aim of the present study was to investigate the role of HER2 gene status in a cohort of mCRC patients treated with cetuximab or panitumumab. Methods: 266 chemorefractory mCRC patients treated with cetuximab or panitumumab alone or in combination with chemotherapy were collected in an international consortium effort. HER2 gene status was analyzed using the dual-color FISH assay LSI HER2/neu-CEP17 (PATHVYSION, Abbott) in one central lab, whereas KRAS/BRAF mutations were investigated locally. HER2 gene amplification was defined as the presence of a ratio between HER2 gene and chromosome 17 centromere > 2. Results: An objective response to anti-EGFR therapy (complete or partial response according to RECIST criteria) was observed in 79/266 (29%) of patients. Twelve cases (4.5%) showed the classical pattern of HER2 gene amplification (R>2) in the whole tissue (>80% of tumor cells). By matching HER2 gene status with clinical response we observed that HER2 gene amplification was significantly related to therapy resistance (p<0.0001). Moreover, analysis of follow-up data indicated that HER2 gene amplification was significantly associated with a worse progression free survival (PFS, p=0.0025) and with a trend for a worse overall survival (p=0.062). Similar associations were also observed in the KRAS/BRAF wild-type patients. Conclusions: Data from this large retrospective study suggest that HER2 gene status evaluated by FISH may represent an additional marker useful for the prediction of mCRC patients’ response to EGFR-targeted therapies, in line with very recent evidence. In particular, patients with HER2 gene amplification seem to be resistant and show a shorter PFS. Future studies are needed to deeply investigate the clinical and biological meaning of HER2 gene status deregulation in mCRC.

scholarly journals OPTIMAL SEQUENCES AND COMBINATION OF CHEMOTHERAPY AND MONOCLONAL ANTIBODIES IN THE TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER

2018 ◽  
Vol 8 (2) ◽  
pp. 50-59
Author(s):  
M. Yu. Fedyanin ◽  
S. A. Tjulandin
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Targeted Therapy ◽  
Metastatic Colorectal Cancer ◽  
Metastatic Colon Cancer ◽  
Clinical Factors ◽  
Therapy Choice ◽  
The Impact

In this review we analyzed results of studies concerning the choice of first and subsequent lines of therapy in patients with metastatic colon cancer. We discussed data of various combinations of monoclonal antibodies with different chemotherapeutic regimens. Also we discussed modern preclinical and clinical trials concerning strategy of choice of targeted therapy sequence in patients with metastatic disease. We considered the impact of various molecular and clinical factors on the effectiveness of drugs and determined their application for therapy choice for colon cancer.

scholarly journals Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Suk-young Lee ◽  
Sang Cheul Oh
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Chemotherapeutic Agents ◽  
Biologic Agents ◽  
Main Stream ◽  
Improved Outcomes ◽  
Endothelial Growth Factor

Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review.

scholarly journals Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance

2020 ◽  
Vol 8 (3) ◽  
pp. 179-191 ◽  
Author(s):  
Qing-Hai Li ◽  
Ying-Zhao Wang ◽  
Jian Tu ◽  
Chu-Wei Liu ◽  
Yu-Jie Yuan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Signaling Pathways ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Clinical Activity ◽  
Braf Mutations ◽  
Insulin Growth Factor

Abstract Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

scholarly journals Baseline and Kinetic Circulating Tumor Cell Counts Are Prognostic Factors in a Prospective Study of Metastatic Colorectal Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 502
Author(s):  
Virgílio Souza e Silva ◽  
Emne Ali Abdallah ◽  
Angelo Borsarelli Carvalho de Brito ◽  
Alexcia Camila Braun ◽  
Milena Shizue Tariki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Prospective Study ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Predictive Biomarkers ◽  
Multi Drug Resistance ◽  
Cell Counts ◽  
Potential Clinical Benefit ◽  
A Prospective Study

The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2−CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.

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