Treatments involving monoclonal antibodies used in patients with metastatic colorectal cancer as a strategy to decrease drug resistance caused by mutations in the KRAS/NRAS genes. Protocol for systematic review
Creators: name: Emiliano Méndez, Liliana Edith
Publisher: name: Zenodo
Year: 2022
Subjects: Cancer
Colorectal
digestive system
chemotherapy
monoclonal antibodies
Cetuximab
Panitumumab
Bevacizumab
epidermal growth factor
Clinical study
KRAS
NRAS

description: Colorectal cancer (CRC) is the most common type of cancer that occurs in the digestive system. In recent years, the incidence of this type of cancer has increased significantly. Currently, most patients with this type of cancer are prescribed conventional cytotoxic drugs; these drugs are the main chemotherapeutic agents against cancer, however, they have serious side effects. For the treatment of CRC, the most common chemotherapeutic drugs are monoclonal antibodies (mAbs), such as Cetuximab, Panitumumab and Bevacizumab, which act by blocking epidermal growth factor signaling. The disadvantage is that these mAbs are usually very expensive, in addition, several patients with CRC show drug resistance when treated with these drugs [1]. Metastasis is the main cause of death in CRC patients. In recent years, the application of chemotherapy and molecular targeted therapies, including mAbs against epidermal growth factor receptor (EGFR) and mAbs against vascular endothelial growth factor, has improved the prognosis of patients with metastatic colorectal cancer (mCRC) [2]. As a first-line treatment, cetuximab in combination with chemotherapy has been recommended, however, drug resistance to cetuximab exists widely. Clinical studies show that cetuximab is effective for only about 10 % of patients with mCRC. Many efforts have been made to find biomarkers or drivers of cetuximab drug resistance in order to increase its efficacy and improve the treatment of mCRC. Drug resistance to cetuximab can be classified into acquired resistance, which often occurs 3 to 12 months after effective response to treatment. Mutations in the KRAS and NRAS genes are the most common causes of acquired resistance to cetuximab [2]. In 2019, E. Elez, et al. performed a phase 2 study where panitumumab plus irinotecan is used to improve EGFR-targeted therapy, this because the first treatment with irinotecan in the 46 patients with KRAS exon-2 wild-type had failed because they presented resistance to the drug. In this article, we aimed to evaluate the safety, overall survival (OS) and progression-free survival (PFS) of the treatment applied to the patients. [3].<br> Mutations in KRAS/NRAS are important biomarkers in mCRC that predict lack of benefit from epidermal growth factor receptor antibodies and occur in approximately 60% of mCRC cases. Identification of these alterations is important not only to avoid the potential toxicity of ineffective therapy, but RAS mutations may also predict a worse outcome after anti-EGFR treatment. Because of the strength of RAS mutations as a predictive biomarker, testing for these alterations has become essential prior to treatment with cetuximab or panitumumab [4]. Molecular profiling of colorectal tumors has better defined patients who may benefit from targeted therapy. In patients with KRAS wild-type (WT) tumors, treatment with cetuximab compared with supportive care significantly improved median OS 9.5 months vs. 4.8 months; hazard ratio 0.55; 95 % confidence interval (CI) 0.41 to 0.74; p&lt;0.001 [5]. While panitumumab plus irinotecan treatment presented a PFS of 3.8 months; 95 % CI 2.7 to 4.3 and a median OS of 12.5 months; 95 % CI 6.7 to 15.9 [3]. In 2021, A. Dharmaji, et al. conducted a study where they analyzed the survival rate in patients with CRC, where they concluded that the survival rate is less than 5 years and it depends on several factors such as age and pathology. Early diagnosis and the application of immediate treatment are of utmost importance to reduce mortality and morbidity in patients with CRC, and it is also necessary to find a treatment that increases the survival rate in these patients [6]. <strong>Research Question:</strong><br> Which treatment has a higher overall survival rate and progression-free survival in patients with metastatic colorectal cancer with drug resistance? <br> Inclusion Criteria:<br> - Clinical trial registries of metastatic colorectal cancer.<br> - Published registries with dates from 2017 onwards.<br> - Records involving RAS family genes (KRAS and NRAS).<br> - Records involving anti-EGFR monoclonal antibodies. <br> - Records that evaluate OS and PFS.<br> Exclusion criteria:<br> - Records in languages other than English. <br> - Records without full access by subscription.<br> - Records with information on cancer types other than colorectal cancer.<br> - Records that do not indicate approval by an ethics committee. <strong>General objective:</strong> To analyze the resistance presented by the drugs used as treatment in metastatic colorectal cancer and to determine which one gives the highest probability of survival (OS and PFS). <strong>Specific objectives:</strong> - To select registries showing treatment options against metastatic colorectal cancer. <br> - To study the resistance to some drugs used in the treatment of mCRC.<br> - To determine which monoclonal antibody treatments are used in patients with mCRC.<br> - To compare the mAbs used in the treatment of metastatic colorectal cancer.<br> - To determine which treatment has the highest overall survival and progression-free survival rate in patients with this disease. The relevance of this research lies in the search for treatment strategies in mCRC, which allow reducing the resistance to it and which provide a higher survival rate for patients with this cancer. It has been demonstrated that when a type of cancer metastasizes, the efficacy of treatments decreases notably and the disease progresses rapidly; the same happens in CRC at this stage. Also, it begins to create a drug resistance that is difficult to counteract. Therefore, it is of great importance to find a treatment that does not present adverse events or that achieves that they are minimal, and that is capable of increasing survival rates in patients with this type of cancer. Here, RAS mutations will be considered, since these mutations are present in 9 % to 30 % of all cancers, with KRAS mutations being the most prevalent (86 %), then NRAS (11 %) and HRAS infrequently (3 %) [7].<br> Based on the above, we intend to make a comparison between the most commonly used treatments in patients with mCRC who also have wild-type RAS; this in order to determine which treatment shows better survival rates (OS/PFS) and to evaluate the adverse events that these treatments present. <strong>Methods</strong> Selection of keywords. Selection of the databases that are available for the UACJ and declaration of which ones will be used. Proposed databases: PubMed, ScienceDirect and Nature. Definition of the strategy containing search terms and Booleans in the databases, the initial strategy proposed is: ("metastatic colorectal cancer" OR mCRC) AND (RAS) AND ("drug resistance") AND (anti-EGFR) AND (treatment OR therapy). Implementation of the search strategy in the databases. Elaboration of a PRISMA flow chart for the application of inclusion and exclusion criteria. Critical evaluation of the studies included in the review. Selection of the records to be studied and compared. Comparison of the adverse effects of the treatments used. Comparison of the results of overall survival and progression-free survival of the different treatments. Identification of the treatment that offers a higher OS and PFS rate, according to the findings.
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