Establishment of a Novel Method for Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Mutations in Lung Cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Drug resistance to targeted therapies occurs in lung cancer, and resistance mechanisms related to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are continuously being discovered. We aimed to establish a novel method for highly parallel multiplexed detection of genetic mutations related to EGFR TKI-resistant lung cancer using Agena iPLEX chemistry and matrix-assisted laser desorption ionization time-of-flight analysis on the MassARRAY mass spectrometry platform.</p><p><b>METHODS</b>A review of the literature revealed 60 mutation hotspots in seven target genes (EGFR, KRAS, PIK3CA, BRAF, ERBB2, NRAS, and BIM) that are closely related to EGFR TKI resistance to lung cancer. A total of 183 primers comprised 61 paired forward and reverse amplification primers, and 61 matched extension primers were designed using Assay Design Software. The detection method was established by analyzing nine cell lines, and by comparison with LungCarta™ kit in ten lung cancer specimens. EGFR, KRAS, and BIM genes in all cell lines and clinical samples were subjected to Sanger sequencing for confirming reproducibility.</p><p><b>RESULTS</b>Our data showed that designed panel was a high-throughput and robust tool, allowing genotyping for sixty hotspots in the same run. Moreover, it made efficient use of patient diagnostic samples for a more accurate EGFR TKIs resistance analysis. The proposed method could accurately detect mutations in lung cancer cell lines and clinical specimens, consistent with those obtained by the LungCarta™ kit and Sanger sequencing. We also established a method for detection of large-fragment deletions based on single-base extension technology of MassARRAY platform.</p><p><b>CONCLUSIONS</b>We established an effective method for high-throughput detection of genetic mutations related to EGFR TKI resistance based on the MassARRAY platform, which could provide more accurate information for overcoming cancers with de novo or acquired resistance to EGFR-targeted therapies.</p>

Insight into early-phase trials for lung cancer in the United States / 癌症

<p><b>INTRODUCTION</b>Few data have been published comparing early-phase trials for lung cancer between China and the United States (US). This study was to investigate the differences of phase 1 trials for lung cancer between these two countries.</p><p><b>METHODS</b>In 2014, a cross-sectional survey was conducted to compare phase 1 trials for lung cancer between the Guangdong Lung Cancer Institute (GLCI), the University of Wisconsin Carbone Cancer Center (UWCCC), and the University of Texas MD Anderson Cancer Center (MDACC).</p><p><b>RESULTS</b>We found that the GLCI had a lower percentage of phase 1 lung cancer trials than the MDACC in December 2014 (23.8% [5/21] vs. 59.8% [28/47], P = 0.006) and the UWCCC in September 2014 (16.7% [3/18] vs. 34.8% [8/23], P = 0.345). Descriptive analyses were performed for early-phase trials conducted by the Cancer Therapy Evaluation Program at the National Cancer Institute (CTEP/NCI), the MDACC, and the Chinese Thoracic Oncology Group (CTONG). There were 149 ongoing early-phase trials in the Department of Investigational Cancer Therapeutics (Phase 1 program) at the MDACC in October 2014. In contrast, no phase 1 trials had been initiated by the CTONG since its establishment in 2007.</p><p><b>CONCLUSIONS</b>These data suggest that a significantly higher percentage of phase 1 trials for lung cancer were conducted in the US than in China. Early-phase oncology trials with robust preclinical data had a higher chance of being approved by the Investigational Drug Branch at the CTEP/NCI. Given the importance of early-phase oncology trials in developing innovative cancer medicines, such studies should be highly encouraged and strategically funded in China.</p>

Impact of smoking status and pathologic type on epidermal growth factor receptor mutations in lung cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Epidermal growth factor receptor (EGFR) mutations in lung carcinomas can make the disease more responsive to the treatment with tyrosine kinase inhibitors. We aimed to evaluate the prevalence of EGFR mutations in a large series of lung carcinomas.</p><p><b>METHODS</b>We examined 1195 consecutive lung cancer patients for EGFR mutations in exons 18, 19, and 21 using direct sequencing of polymerase chain reaction products. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit > 1 year ago), or current smokers (quit < 1 year ago).</p><p><b>RESULTS</b>There were EGFR mutations in 9 (4.5%) of 201 squamous carcinomas, in 1 (2%) of 50 large cell carcinomas, and in 1 (2.3%) of 44 small cell carcinomas that were investigated. Three hundred and twenty-seven mutations were found in the series of 858 adenocarcinomas (38.1%). Among 858 lung adenocarcinomas, we detected EGFR mutations in 250 (48.6%) of 514 never smokers, 39 (33.9%) of 115 former smokers, and 38 (16.6%) of 229 current smokers. Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P = 0.0002) or stopped smoking less than 15 years ago (P = 0.033) compared with individuals who never smoked.</p><p><b>CONCLUSIONS</b>Adenocarcinoma is the most frequent EGFR mutation pathologic type in lung cancer. The likelihood of EGFR mutations in exons 18, 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 15 years ago. These data can assist clinicians in assessing the likelihood of exons 18, 19, or 21 EGFR mutations in Chinese patients with lung cancer when mutational analysis is not feasible.</p>