Introduction: Before anti-EGFR therapy is given to patients with colorectal cancer, it is required to determineKRASmutation status in tumor. When tumor tissue is not available, cell-free DNA (liquid biopsy) is commonly used as an alternative. Due to the low abundance of tumor-derived DNA in cell-free DNA samples, methods with high sensitivity were preferred, including digital polymerase chain reaction, amplification refractory mutation system and next-generation sequencing. The aim of this systemic review and meta-analysis was to investigate the accuracy of those methods in detectingKRASmutation in cell-free DNA sample from patients with colorectal cancer.Methods: Literature search was performed in Pubmed, Embase, and Cochrane Library. After removing duplicates from the 170 publications found by literature search, eligible studies were identified using pre-defined criteria. Quality of the publications and relevant data were assessed and extracted thereafter. Meta-DiSc and STATA softwares were used to pool the accuracy parameters from the extracted data.Results: A total of 33 eligible studies were identified for this systemic review and meta-analysis. After pooling, the overall sensitivity, specificity, and diagnostic odds ratio were 0.77 (95%CI: 0.74–0.79), 0.87 (95%CI: 0.85–0.89), and 23.96 (95%CI: 13.72–41.84), respectively. The overall positive and negative likelihood ratios were 5.55 (95%CI: 3.76–8.19) and 0.29 (95%CI: 0.21–0.38), respectively. Area under curve of the summarized ROC curve was 0.8992.Conclusion: Digital polymerase chain reaction, amplification refractory mutation system, and next-generation sequencing had overall high accuracy in detectingKRASmutation in cell-free DNA sample. Large prospective randomized clinical trials are needed to further convince the accuracy and usefulness ofKRASmutation detection using cfDNA/liquid biopsy samples in clinical practice.Trial registration: PROSPERO CRD42020176682;https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176682.

Introduction: Cetuximab and panitumumab have been used clinically to treat metastatic colorectal cancer for more than 15 years. Before the treatment is given, it is required to determine the KRAS mutation status since it would lead to drug resistance. Tumor tissue sample is traditionally used for cancer genotyping. In recent years, liquid biopsy sample has been intensively investigated as a surrogate for tumor tissue sample due to its non-invasiveness and better presentation of tumor heterogeneity. The aim of this study is to systematically summarize the accuracy of KRAS mutation measurement in colorectal cancer using cell-free DNA in liquid biopsy samples, with tumor tissue sample as reference (gold standard).Methods and analysis: We will search literatures in the following databases: Pubmed, Embase, and Cochrane Library. Systemic review and meta-analysis will be performed to summarize the accuracy of KRAS mutation measurement in colorectal cancer using liquid biopsy sample, and subgroup analysis will be performed on different testing platforms, and on metastatic and non-metastatic colorectal cancer.Timeline: This study will start on June 1, 2020, and is expected to be finished by November 1, 2020.Ethics and dissemination: Ethical approval will not be required since the data obtained and analyzed in this study will not be on individual patients. Study results will be disseminated as an official publication in a peer-reviewed journal.Registration:PROSPERO CRD42020176682