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Micro abstractIntra-tumor heterogeneity of epidermal growth factor receptor (EGFR) mutations in patients with mixed-type lung adenocarcinoma was analyzed according to histological patterns. Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and there was a significant correlation between heterogeneity of EGFR mutations and smoking history (P<0.043).
Clinical Practice Points• EGFR mutations are factors predictive of response to EGFR-TKI treatment. However, lung cancer is thought to be the result of the accumulation of genetic alterations over a long course of exposure to a carcinogen, and the existence of intra-tumor heterogeneity of EGFR mutations remains unclear. Thus, the existence of intra-tumor heterogeneity was analyzed in patients with mixed-type lung adenocarcinoma according to histological patterns.• Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and a significant correlation between heterogeneity of EGFR 3 mutations and smoking history was found.• Response to EGFR-TKIs might be partial and insufficient in tumors having intra-tumor heterogeneity of EGFR mutations. New treatment strategies for patients with lung adenocarcinoma harboring heterogeneous EGFR mutations are needed.
Micro abstractWe compared three PCR methods (mutant-enriched PCR, PNA-LNA PCR and PCR clamp) to detect EGFR mutations in 50 patients with advanced NSCLC. Seventeen were harboring EGFR mutations, five of whom showed discrepancies between the results of different PCR methods. All five responded to gefitinib, which we consider to suggest that the discrepancies were false negatives.
Clinical Practice Points• Several methods have been used to detect EGFR mutations in non-small-cell lung cancer (NSCLC): however, it is not clear which is the most suitable for use in the clinic.• We compared three PCR methods (mutant-enriched PCR, PNA-LNA PCR and PCR clamp) in 50 patients with advanced NSCLC. Seventeen of the patients were harboring EGFR mutations, five of whom showed discrepancies between the results of different PCR methods. All five patients responded to gefitinib.• We considered that all of the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reasons for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each method, a large prospective clinical trial is warranted.
AbstractBackground: Epidermal growth factor receptor (EGFR) mutations are predictive of
7569 Background: We conducted a phase I/II study of combination chemotherapy with nedaplatin (CDGP) and amrubicin (Amr) for patients with untreated, advanced non small-cell lung cancer (NSCLC). Methods: Eligible patients were having adequate organ function and PS of 0-1. CDGP was given on day 1 and amrubicin on days 1, 2 and 3. The treatment was repeated every 3 weeks. We fixed the dose of CDGP as 100 mg/m2, and escalated the dose of amrubicin from a starting dose of 25 mg/m2 by 5mg/m2 per each levels until the maximum tolerated dose (MTD). The MTD was defined as the dose level at which at least two of three or two of six patients experienced a dose-limiting toxicity (DLT). Results: Between June 2009 and May 2011, 36 patients were enrolled. In the phase I study, two DLTs occurred in six patients at level 2; dose level 1 was therefore recommended (25 mg/m2 Amr, 100mg/m2 CDGP). DLTs included cerebral infarction and grade 4 thrombocytopenia. In the phase II study, including phase I study, a total of 36 patients were enrolled and 132 cycles of chemotherapy were conducted. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 75%, 16.6% and 19.4% in all cycles, respectively. Febrile neutropenia occurred in 4cycles (3%) but all of them were controllable. Eighteen patients achieved a partial response and the overall response rate was 51.4%. Conclusions: Combination of CDGP and Amr was highly effective and well tolerable in patients with untreated, advanced NSCLC.
Background: The epidermal growth factor receptor thyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, every patient eventually relapse even if the treatment of EGFR-TKIs was effective remarkably. It have been reported a secondary T790M mutation, MET amplification and some mechanisms attribute to the drug resistance. Intratumor EGFR genetic heterogeneity has also been considered as a potential cause of the acquired resistance. We previously reported a patient with mixed adenocarcinoma of the lung that had different EGFR mutations in papillary, acinar and BAC subtypes. In this study, we analyzed EGFR mutations in each histological subtypes of mixed adenocarcinoma after surgery and pre EGFR-TKIs treatment.
Material and Methods: We recruited twelve mixed adenocarcinoma patients who were treated surgical therapy. Tumor cells in different histological subtypes were microdissected from paraffin-embedded surgical specimens with AS LMD system. Genomic DNA was extracted from each sampled area. EGFR mutations, limited to exon19 deletions and L858R mutations, were examined using the simple polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) methods.
Results: Acinar, BAC and papillary sanmples were microdissected from six, ten and eleven tumor tissues. Exon19 deletions and L858R mutation were detected in five and one tissues. From acinar, BAC and papillary samples, one exon19 deletion, two exon19 deletions and three exon19 delitions and one L858R were detected. Out of the six mixed adenocarcinoma, five tissues consisted both mutated and non-mutated cells. Conclusions: Our results indicates that 41% of lung adenocarcinoma with mixed subtypes have intratoumor genetic heterogeneity. EGFR mutations were detected most frequently in papillary samples. There may be some relations between histological subtype and EGFR mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2124.
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