Lung cancer is currently the number one malignant tumor in terms of incidence and mortality worldwide, and despite years of efforts, the overall treatment effect is still not optimistic. Since the 21st century, the emergence of molecularly targeted drugs targeting the epidermal growth factor receptor (EGFR) has brought new hope and means for the treatment of lung cancer, with Gefitinib (ZD1839, Erythroid, AstraZeneca) and Erlotinib (OSI- 774, Roche), Tyrosine kinase inhibitors (TKI), are small molecule targeted drugs currently approved in multiple countries and widely used in progressive or refractory non-small cell lung cancer. Initial clinical practice found that patients with chemotherapy-naïve non-small cell lung cancer had an overall efficacy rate of more than 10% for TKI therapy, and patients who were effective on TKI drugs experienced significant benefits in terms of symptom improvement, lesion control, and survival time. Further subgroup analyses also identified Eastern ethnicity, adenocarcinoma, women, and nonsmoking as superior populations for TKI drug therapy, and this selection of superior populations could increase the effectiveness of TKI drugs to more than 40%. However, it should not be overlooked that the clinical characteristics used to select the superior population do not really reflect the nature of the tumor, and the good results achieved by using these clinical characteristics may be due to the close relationship between these clinical characteristics and the biological characteristics of the tumor itself, so the selection of the superior population for TKI drugs may be more accurate by biological indicators. In 2004, several studies on the relationship between EGFR mutations and TKI drug sensitivity were published in journals such as “Science” and “New England Journal of Medicine”, and the effectiveness of TKI drugs in patients with EGFR mutations was found to be as high as 71-100%. These results have attracted great attention and in-depth discussion on the selection methods of TKI drug treatment populations. This study, published in 2005, came from the Memorial Sloan-Kettering Cancer Center in the United States, which found in 2004 that lung cancer patients with EGFR mutations had good responsiveness to TKI drugs [6]. Perhaps the realization that the RAS gene is an important regulator downstream of the EGFR signaling pathway or that KRAS and EFGR gene mutations are mutually exclusive in the same tumor tissue implies that KRAS and EFGR genes may play equally important roles in lung cancer progression, so this study investigated the relationship between KRAS gene mutations and the sensitivity of TKI drugs for lung adenocarcinoma. relationship. A total of 60 lung adenocarcinoma patients were collected in this study, all of whom were treated with Gefitinib or Erlotinib, and specimens corresponding to the patients were collected from before TKI treatment. Results This study found that KRAS gene mutations were strongly associated with primary resistance to Gefitinib or Erlotinib monotherapy in lung adenocarcinoma patients. KRAS mutations were present in tumor tissue in 9 of 38 patients who were not sensitive to TKI, while none of the 21 patients in objective remission had KRAS mutations; in addition, EGFR mutations were present in 77% of sensitive patients, while none of the insensitive patients had EGFR mutations. Therefore, the investigators concluded that both EGFR and KRAS mutations should be determined during patient selection for TKI therapy to improve the hit rate of TKI-targeted therapy and to reduce unnecessary “overtreatment”. The clinical implications of this study are as follows: 1. The predictive effect of EGFR on TKI treatment was further confirmed, and all 17 patients with EGFR mutations were found to be sensitive to TKI treatment. 2. 2. The relationship between KRAS mutations and primary resistance to TKI drugs was explored earlier, which changed the previous situation of using EGFR alone for efficacy prediction and suggested that the status of KRAS could be referred to whether TKI therapy was needed for patients without EGFR mutations. 3. Mutations in exon 2 of KRAS were found to be closely associated with primary resistance to TKI drugs in lung adenocarcinoma, and tumors with KRAS gene mutations did not show tumor shrinkage after treatment with Gefitinib or Erlotinib. 4. None of the patients sensitive to TKI drugs had KRAS gene mutations. As an exploratory translational research, this study has shortcomings in terms of sample size, case selection, and control settings, but since the results of this study were either yes or no (none of the 21 susceptible patients had KRAS mutation), this certainly increases the credibility of the results and the need for further research. necessary. In fact, the results of this study have been confirmed in several subsequent large studies. The BR21 data suggest that KRAS mutations are associated with primary resistance to TKI drugs in lung cancer patients, and that the use of KRAS genetic testing may provide a useful tool for the treatment of patients with TKI drugs. could provide an important reference for the screening of patients treated with TKI drugs. Similar results were obtained in another large randomized controlled study called TRIBUTE [8], which found that the presence of KRAS mutations in patients treated with standard chemotherapy plus Erlotinib resulted in significantly shorter survival times, suggesting that KRAS mutations are a This suggests that KRAS mutations are a detrimental factor in the efficacy of TKI drugs. Many large medical centers are now using EGFR testing to select patients for TKI treatment, and EGFR testing has been shown to increase the efficiency of TKI to over 80%. It is believed that the combination of KRAS genetic testing will further improve the hit rate of TKI drug therapy and save medical costs. Based on the above evidence, the 2008 NCCN guidelines for the treatment of lung cancer also indicate that Erlotinib may be used as first-line therapy for patients with advanced non-small cell lung cancer who have EGFR mutations (or increased copy number), no KRAS mutations and are non-smokers. In addition to prospective studies on the predictive efficacy of EGFR and KRAS genes on TKI, several studies are currently examining the predictive role of activation of EGFR downstream pathways such as PTEN, Raf and PI3K-Akt on the efficacy of TKI therapy. The Molecular Assays in NSCLC Working Group has been formed by a group of U.S. institutions to standardize the process of genetic testing in TKI therapy. In addition, several studies are currently investigating the use of tumor markers such as EGFR in serum or peripheral tissues such as skin to predict TKI efficacy.