The relationship between KRAS gene mutation and adenocarcinoma of the lung Gefitinib and Erlotinib p

 

Qiaogui Bin , born in 1969 in Yuci , General Hospital of Guangzhou Military Command of Thoracic Surgery , deputy director, deputy chief physician. 1993 graduated from the Fourth Military Medical University Medical undergraduate six-year , in 1996 graduated from the Graduate School of the Fourth Military Medical University , received a master's degree . 2001 Zhongshan Medical University doctoral students admitted in 2002, admitted to DAAD Scholarship ( DAAD scholarship ) to study at the University of Schleswig-Holstein , Germany , respectively, in 2004 and 2005 by China , Germany PhD. October 2005 by the "Hong Kong of Mainland Professionals Scheme introduced " funded work study at University of Hong Kong .

    Has been committed to breast cancer surgery based multidisciplinary treatment and transformation studies . Currently a member of the International Society for the Study of lung cancer , the Guangdong Provincial Committee of the Standing Committee of Association of lung cancer . Commitment to the National Natural Science Foundation of China , the Guangdong Provincial Natural Science Foundation and the army , the Guangdong Provincial Science & Technology of number of research projects . Has edited monographs 1 , deputy chief translator monograph 1 , monographs 4 , in the "Journal of the National Cancer Institute", "British Journal of Cancer" and "Cancer" and other domestic and foreign journals published more than 30 papers , received Shaanxi Provincial Science and Technology progress Award and the military and technological progress prize each one . For DNA repair with non- small cell lung cancer prognosis and prediction research was held in Barcelona in 2005, the 11th World Conference on Lung Cancer to speak communicate (oral presentation). Was a representative of the National Federation is currently China Youth Federation, the Ministry of Overseas Liaison Committee .

    3 Background

   Epidermal growth factor receptor (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitors (tyrosine kinase inhibitor, TKI) including Gefitinib and Erlotinib for advanced non-small cell lung cancer have a certain effect .

   Non-small cell lung cancer activating mutations in the EGFR gene can predict the efficacy of EGFR TKI .

   EGFR signaling pathways involved in the KRAS gene downstream , the study found 15% to 30% of lung adenocarcinoma KRAS mutations .

    4 Purpose

    Research KRAS gene mutation and EGFR TKI primary resistance relationship .

    5 Study Design

   Researches: researchers and patients are from Memorial Sloan-Kettering Cancer Center.

   Study subjects: Erlotinib and Gefitinib received treatment in patients with advanced non-small cell lung cancer .

   STUDY DESIGN : A retrospective clinical study , single center .

   Evaluation : The patients were divided into active and inactive EGFR TKI treatment groups , tissue samples were detected KRAS, EGFR gene mutations , to evaluate whether their mutations associated with efficacy .

    6 Results

    The results showed that 8 /38 ( 24% ) of EGFR TKI treatment failure in patients with KRAS mutations , and EGFR TKI effective in patients without KRAS mutations 0 / 21 ( 0% ) . 22 EGFR TKI treatment is effective in patients , 17 with EGFR mutations , 38 patients resistant to EGFR gene mutations were not found in Table 1. KRAS mutations suggested that EGFR TKI therapy .

    7 Conclusions

    Detect KRAS and EGFR gene mutation in favor TKI targeted crowd choice.

    8 Comments

    Lung cancer is currently the worldwide incidence and mortality of the first cancer , despite years of efforts , the overall treatment effect is still not optimistic. Into the twenty- first century, to EGFR -targeting molecular targeted drugs for the treatment of lung cancer appears to bring new hope and means to Gefitinib (ZD1839, Iressa , AstraZeneca ) and Erlotinib (OSI- 774 , Tarceva , Roche ) as the representative of TKI is currently approved and widely used in many countries progress or refractory non-small cell lung cancer targeted small molecule drugs. The initial clinical practice found that after failure of chemotherapy for non-small cell lung cancer patients TKI therapy total efficiency up to 10 %, while patients on TKI drugs effective in improvement of symptoms , lesion control and survival time gained significantly benefits . Further subgroup analysis also found that Asians , adenocarcinoma , women and non-smokers are the advantages of TKI therapy groups [ 1-3 ] , the choice of the crowd through this advantage can TKI drug's effectiveness was increased to 40 % or more. But can not be ignored is that these selective advantage for the clinical features of the crowd does not actually reflect the true nature of the tumor , the use of these clinical features of patient selection is able to obtain good results may be due to these clinical characteristics and biological characteristics of the tumor there is a close relationship between itself and therefore the choice of the crowd advantage TKI drugs might be more accurate to use biological indicators . 2004 , in "Science" and "New England Journal of Medicine" and other journals published several articles about TKI EGFR mutations and drug sensitivity Relationship [ 4-6 ] found that patients with EGFR mutations TKI effectiveness of drugs up to 71% to 100% , these results aroused great attention and crowd TKI therapy selection method in depth.

    This study published in 2005 by the United States, Memorial Sloan-Kettering Cancer Center , in 2004, they found that mutations in EGFR TKI drugs for lung cancer patients have a good reactivity [ 6 ] . Perhaps realizing RAS gene downstream of EGFR signal transduction pathway is important regulator , or is recognized KRAS and EGFR mutations in a tumor tissue of the same are mutually exclusive , meaning that KRAS and EGFR gene may play in the progression of lung cancer equally important role , so the study was to investigate the KRAS gene mutation and TKI therapy relationship between lung cancer susceptibility . The study collected a total of 60 cases of lung adenocarcinoma patients , all patients underwent Gefitinib or Erlotinib treatment , corresponding with the patient specimens were collected from TKI treatment . The results of the study found , KRAS mutations in lung adenocarcinoma patients Gefitinib or Erlotinib monotherapy primary drug resistance are closely related. In 38 cases against TKI -insensitive patients in nine cases the patient's tumor KRAS mutations exist in the organization , and in 21 patients with objective response in one case there is no KRAS mutations ; addition , 77% of patients sensitive to the presence of EGFR mutant , but not sensitive to the presence in patients without EGFR mutations . Therefore, the researchers believe that patients should be accompanied by select TKI therapy judge EGFR and KRAS mutations in two genes , TKI targeted therapy to improve the hit rate and reduce unnecessary " over-treatment ." The clinical significance of this research in the following areas : ( a ) further confirmed the EGFR TKI treatment effect on the predicted effect , found 17 cases of patients with EGFR mutations all sensitive to TKI therapy . ( 2 ) discussed earlier KRAS mutations and primary resistance to TKI drugs relationship changed in the past solely used for predicting the outcome of EGFR situation that no mutation of the patients to EGFR TKI therapy may refer to the need for KRAS status . ( 3 ) found that KRAS exon 2 mutations in lung adenocarcinoma with primary resistance against TKI drugs closely related tumors with KRAS mutations after treatment by Gefitinib or Erlotinib no tumor shrinkage . ( 4 ) on the TKI drug-sensitive patients were without KRAS mutations .

    As an exploratory study of the transformation (translational research), the study in terms of sample size , the choice of cases and controls , and many other aspects of the setting deficiencies , but because of the institute is obtained with or without findings ( 21 cases no one case sensitive KRAS mutations exist ) , it will increase the reliability of the results and to continue further research is necessary . In fact, in some of the subsequent large-scale studies have also confirmed the results of the study . Through the study of BR21 patient specimens collected for testing, the results are found in patients KRAS mutations effective therapeutic Erlotinib is low, but also significantly shorter survival ( hazard ratio 1.63, P = 0.03) [7] . BR21 data suggest , KRAS mutations in lung cancer patients with primary resistance to TKI drugs related to the use of genetic testing for KRAS TKI therapy patient screening provides an important reference. In another named TRIBUTE large randomized controlled studies have reached similar results [ 8 ] , through the study of the collected specimens TRIBUTE detection and analysis , the study found that received standard chemotherapy plus Erlotinib -treated patients , If there KRAS mutations are significantly shorter survival , suggesting that KRAS mutations that affect drug efficacy TKI unfavorable factors .

    Now there are many large medical centers are used for detection of EGFR TKI therapy patient selection , proved by EGFR TKI allows the detection efficiency up to 80%. We believe that through joint detection of KRAS gene TKI therapy will further improve the hit rate , save medical costs. Based on the above evidence , in 2008 also pointed NCCN treatment guidelines for lung cancer with EGFR mutations ( or copy number ) , without KRAS mutations and non-smoking patients with advanced non-small cell lung cancer Erlotinib can be used for first-line treatment .

    Currently, in addition to EGFR and KRAS gene prediction performance on TKI prospective study , there are a number of studies are exploring the PTEN, Raf and PI3K-Akt pathway activation downstream of EGFR and other TKI treatment effect on the predicted effect. Some U.S. agencies have also jointly established the " non-small cell lung cancer molecular analysis working group (The Molecular Assays in NSCLC Working Group)", in order to TKI therapy for genetic testing to develop standardized processes . In addition, there are still some research being explored by testing serum or skin endures weeks of EGFR and other tumor markers to predict the level of TKI treatment.

    9 Notes

    This study is a retrospective single- group study , level of evidence is low. Later ISEL, Interest and other tests failed to confirm KRAS and EGFR gene mutation EGFR TKI therapy predicted effect, therefore, the relevant mutations in KRAS and EGFR TKI therapy 's role needs to be further explored.