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• W2040923265 abstract "In non–small-cell lung cancer (NSCLC) besides the common exons 19 and 21 EGFR-activating mutations (>90%), exon 18-point mutations (mainly p.G719X) are rare (4%).1Massarelli E Johnson FM Erickson HS Wistuba II Papadimitrakopoulou V Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance.Lung Cancer. 2013; 80: 235-241Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar They are associated with a favorable response rate to EGFR tyrosine kinase inhibitors (EGFR-TKI),2Wu JY Yu CJ Chang YC Yang CH Shih JY Yang PC Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer.Clin Cancer Res. 2011; 17: 3812-3821Crossref PubMed Scopus (381) Google Scholar,3Keam B Kim DW Park JH et al.Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer.Int J Clin Oncol. 2014; 19: 594-600Crossref PubMed Scopus (90) Google Scholar but are lower than common mutations.4Watanabe S Minegishi Y Yoshizawa H et al.Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q.J Thorac Oncol. 2014; 9: 189-194Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar More than one mutation per sample represents complex mutations. Their clinical significance is uncertain, because they are rare (3.4–6.9%).2Wu JY Yu CJ Chang YC Yang CH Shih JY Yang PC Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer.Clin Cancer Res. 2011; 17: 3812-3821Crossref PubMed Scopus (381) Google Scholar,3Keam B Kim DW Park JH et al.Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer.Int J Clin Oncol. 2014; 19: 594-600Crossref PubMed Scopus (90) Google Scholar Here, we present two cases of NSCLC with rare complex mutation that respond differently to EGFR-TKI. In July of 2012, an Asian, 52-year-old male smoker presented with a right cervical lymph node. A stage IV adenocarcinoma in the right lung; lymphangitis carcinomatosis; mediastinal, cervical, and sus-clavicular lymph nodes; and sacrum and hip bone osteoblastic metastases were diagnosed. Two-point mutations in exon 18 of the EGFR, p.I706T, and p.G719A were detected. Gefitinib treatment started in August of 2012. After 3 months, computed tomography -scan showed a partial response (Fig. 1). The clinical response was maintained under gefitinib treatment with 22 months of follow up. The second patient was a Caucasian, 58-year-old female smoker, referred in February of 2013. A stage IV lung adenocarcinoma, in the lower right lobe, with mediastinal lymph nodes as well as cerebral and right adrenal gland metastases was diagnosed. Two-point mutations in exon 18, p.E709K and p.G719A, were detected. Erlotinib treatment and whole brain radiotherapy began. After 2 months, the patient's performance status improved and computed tomography scan demonstrated a partial response on brain metastases and primary tumor. Then she presented with a progression of extracerebral metastases. Erlotinib was stopped. A chemotherapy combining cisplatin and pemetrexed was administered. In September of 2013, due to disease progression, carboplatin and paclitaxel were proposed. The patient presented a stable disease for 4 months and then progressed. She died 11 months after diagnosis of metastatic disease. The clinical significance of EGFR complex mutations differs whether complex mutations include the most frequent mutations or not. Hata et al5Hata A Yoshioka H Fujita S et al.Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer.J Thorac Oncol. 2010; 5: 1524-1528Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar showed that tumours with complex mutations, including deletion of exon 19 or L858R point mutation, had the same response rate to EGFR-TKI than those with the same mutations alone. Wu et al2Wu JY Yu CJ Chang YC Yang CH Shih JY Yang PC Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer.Clin Cancer Res. 2011; 17: 3812-3821Crossref PubMed Scopus (381) Google Scholar showed that patients with rare and complex mutations, compared with patients with classic or rare mutation alone or classic mutation with rare mutations, had a worse response rate to EGFR-TKI (25% versus 74.8, 68.8, and 80%, respectively) and a poorer progression-free survival (1.4 versus 11.9, 8.1, and 8.0 months). Beau-Faller et al6Beau-Faller M Prim N Ruppert AM et al.Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.Ann Oncol. 2014; 25: 126-131Crossref PubMed Scopus (241) Google Scholar showed that EGFR-TKI efficacy was similar or slightly poorer in patients with complex mutations including p.G719X. Keam et al3Keam B Kim DW Park JH et al.Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer.Int J Clin Oncol. 2014; 19: 594-600Crossref PubMed Scopus (90) Google Scholar reported only two double mutations in exon 18, including the G719A + I706T, in a series of 306 patients. The overall survival of this patient, treated with erlotinib, was 53 months.3Keam B Kim DW Park JH et al.Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer.Int J Clin Oncol. 2014; 19: 594-600Crossref PubMed Scopus (90) Google Scholar This is the first description of the p.E709K + p.G719A mutation. To date, the behavior of these NSCLCs with complex mutations are not completely understood. The report of these rare and complex mutations and their response to EGFR-TKI should be very useful for the constitution of well-annotated databases and to improve the knowledge of their specific response to EGFR-TKI. We thank Mrs. L Françoise, C Bocquet, and C Dupont for their excellent technical assistance." @default.
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• W2040923265 title "Two Cases of Non–Small-Cell Lung Cancer with Rare Complex Mutation of EGFR Exon 18 But Different Response to Targeted Therapy" @default.
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