KRAS mutation as the biomarker of response to chemotherapy and EGFR-TKIs in patients with advanced non-small cell lung cancer: clues for its potential use in second-line therapy decision making.

OBJETIVE: In patients with non-small cell lung cancer (NSCLC), knowledge of the epidermal growth factor receptor (EGFR) mutation status is fundamental for selecting the treatment involving EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Little information is available regarding the response and progression-free survival (PFS) in platinum-based chemotherapy (CT) versus EGFR-TKIs in the presence or absence of KRAS mutation, particularly in patients without EGFR mutation. METHODS: From 2007 to 2010, 353 patients with NSCLC were treated with first-line CT, EGFR-TKIs were used in the second or third line of treatment. Tests were performed for EGFR and KRAS mutation and the results of the mutations were obtained 3 to 4 months after the start of the treatment. We analyzed clinical characteristics, mutation profile, response and PFS to CT and EGFR-TKIs, and overall survival. The protocol is registered with ClinicalTrials.gov, number NCT01023828. RESULTS: Presence of the wild-type (WT) KRAS was independently associated with increased response rate to first-line CT when compared with KRAS mutation (41.4% vs. 14.7%; P=0.001). The EGFR mutation (57.8% vs. 11.7%; P<0.001) and WT-KRAS (39.6% vs. 3.3%; P=0.001) were associated with the EGFR-TKIs response. PFS of patients with WT-EGFR and KRAS mutation treated with EGFR-TKIs was shorter when compared with patients with WT-EGFR and WT-KRAS (P<0.001). CONCLUSIONS: KRAS mutation status is a good biomarker for response to EGFR-TKIs in patients with NSCLC. KRAS mutational status could impact the decision to give CT or EGFR-TKIs as a second line of treatment to patients with NSCLC, particularly in patients with WT-EGFR.

Emergence of HA mutants during influenza virus pneumonia.

During the influenza pandemic of 2009, the number of viral pneumonia cases showed a marked increase in comparison with seasonal influenza viruses. Mutations at amino acid 222 (D222G mutations) in the virus hemagglutinin (HA) molecule, known to alter the receptor-recognition properties of the virus, were detected in a number of the more severely-affected patients in the early phases of the pandemic. To understand the background for the emergence of the mutant amino acid D222G in human lungs, we conducted histological examinations on lung specimens of patients from Mexico who had succumbed in the pandemic. Prominent regenerative and hyperplastic changes in the alveolar type II pneumocytes, which express avian-type sialoglycan receptors in the respiratory tract of severely affected individuals, were observed in the Mexican patients. An infection model utilizing guinea pigs, which was chosen in order to best simulate the sialic acid distribution of severe pneumonia in human patients, demonstrated an increase of D222G mutants and a delay in the diminution of mutants in the lower respiratory tract in comparison to the upper respiratory tract. Our data suggests that the predominance of avian-type sialoglycan receptors in the pneumonic lungs may contribute to the emergence of viral HA mutants. This data comprehensively illustrates the mechanisms for the emergence of mutants in the clinical samples.

Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure.

HYPOTHESIS: Although smoking is the major risk factor for non-small-cell lung cancer (NSCLC), other factors are also associated with lung carcinogenesis, such as wood-smoke exposure (WSE). This article has been aimed at suggesting that lung cancer related to cigarette smoking and lung cancer related to WSE have different clinical and genetic characteristics. EXPERIMENTAL DESIGN: A cohort of 914 lung cancer patients was prospectively studied; they had been treated at Mexico's National Cancer Institute between 2007 and 2010. The associations of WSE and cigarette smoking with clinical characteristics, mutation profile, response to chemotherapy, and epidermal growth factor receptor tyrosine kinase inhibitors were analyzed, and overall survival (OS) rate was calculated. The trial was registered with ClinicalTrials.gov: NCT01023828. RESULTS: Of the lung cancer patients studied, 95.1% were classified as coming within the NSCLC histology subtype; 58% of the patients smoked cigarettes, 35% had a background of WSE (exposure to both cigarette smoke and wood smoke was documented in 12.1% of all patients), and 19.4% patients had no smoke-exposure background. WSE was associated with NSCLC and adenocarcinoma histology, and was also more frequently associated with epidermal growth factor receptor-mutations than cigarette-smoking patients were (50.0% cf. 19.4%), whereas KRAS mutations were less common in WSE patients (6.7%) than in smokers (21%). WSE patients had a higher epidermal growth factor receptor tyrosine kinase inhibitor response rate (39.7%) than smokers (18.8%). The NSCLC patient WSE group's OS was longer (22.7 months) than that for smokers (13.8 months). CONCLUSION: NSCLC patients who smoked tobacco/cigarettes differed from those having a background of WSE regarding tumor histology, mutation profile, response rate, and OS, indicating that different carcinogenic mechanisms were induced by these two types of smoke exposure.