Heterogeneity of epidermal growth factor receptor mutations within a mixed adenocarcinoma lung nodule.

It has been proposed that stepwise progression occurs from atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive lung adenocarcinoma. However, the underlying molecular mechanisms have not been identified. We report a patient with a mixed adenocarcinoma of the lung that had different EGFR mutations in the papillary subtype, the acinar subtype, and the surrounding AAH and BAC areas. EGFR mutations may accumulate during tumor progression and lead to heterogeneity of EGFR mutations within the tumor.

Stepwise progression from ground-glass opacity towards invasive adenocarcinoma: long-term follow-up of radiological findings.

The natural history of lung adenocarcinoma with ground-glass opacity (GGO) remains undetermined. We describe a lung adenocarcinoma in which GGO transformed through a scar-like lesion over the long term into a solid nodule of poorly differentiated adenocarcinoma. Whether poorly differentiated lung adenocarcinoma can evolve from GGO-type adenocarcinoma is an important issue that requires clarification.

Phase I study of vinorelbine and irinotecan in previously untreated patients with advanced non-small cell lung cancer.

INTRODUCTION: Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). METHODS: Previously untreated patients (or=4 days or febrile neutropenia, grade 4 thrombocytopenia, >or=grade 3 non-hematological toxicities, or the need to cancel drug administration on both days 8 and 15. RESULTS: A total of 23 patients were enrolled. DLT was observed in 1 of 6 patients at level 3 (20 mg/m(2) vinorelbine, 50 mg/m(2 )irinotecan), in 2 of 3 at level 4 (25 mg/m(2), 50 mg/m(2)), and in 2 of 5 at modified level 4 (20, 60 mg/m(2)). Level 4 and modified level 4 were considered to be the MTD; dose level 3 was therefore recommended. DLTs included liver dysfunction, pneumonitis, colitis, and arrhythmia. Injection site reactions were mild. Hematological and non-hematological toxicities were mild and easily controlled. CONCLUSION: Use of 20 mg/m(2) vinorelbine on days 1 and 8 followed by 50 mg/m(2 )irinotecan on days 1, 8, and 15 every 4 weeks warrants a phase II study.

Analysis of intratumor heterogeneity of EGFR mutations in mixed type lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor mutations are predictive of the success of EGFR tyrosine kinase inhibitor treatment in patients with advanced non--small-cell lung cancer. As with other solid tumors, lung cancer is thought to be the result of an accumulation of genetic alterations after exposure to carcinogens. The aim of the present study was to clarify the relationship between multistep carcinogenesis and the accumulation of EGFR mutations. PATIENTS AND METHODS: The intratumor heterogeneity of EGFR mutations was analyzed in 38 patients with resected mixed-type lung adenocarcinoma according to histological patterns, and the clinical features of the patients harboring intratumor heterogeneity of EGFR mutations were evaluated. RESULTS: Intratumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors. EGFR mutations were more common in the bronchioloalveolar (lepidic) carcinoma pattern than in the papillary and acinar patterns, although this difference was not significant. However, there was a significant correlation between intratumor heterogeneity of EGFR mutations and smoking history (P < .043). CONCLUSION: Intratumor heterogeneity of EGFR mutations correlates with the distribution of histological subtype in mixed type adenocarcinoma and is associated with smoking history.

Direct comparison of 3 PCR methods in detecting EGFR mutations in patients with advanced non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are predictive of response to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Several methods have been used to detect EGFR mutations; however, it is not clear which is the most suitable for use in the clinic. In this study, we directly compare the clinical sensitivity and specificity of 3 PCR methods. PATIENTS AND METHODS: We compared the 3 PCR methods (mutant-enriched PCR, PNA-LNA PCR, and PCR clamp) in patients with advanced NSCLC. A patient who showed sensitive mutations by at least 1 PCR method was treated with gefitinib. A patient who showed no sensitive mutations was treated with chemotherapy with cytotoxic agents. RESULTS: Fifty patients with advanced NSCLC previously untreated with EGFR-TKIs were enrolled in this trial. Seventeen patients were harboring EGFR mutations, 5 of whom showed discrepancies between the results of different PCR methods. All 5 patients responded to gefitinib. All patients harboring EGFR mutations received gefitinib treatment and 21 of 33 EGFR-mutation-negative patients received chemotherapy with cytotoxic agents. Median progression-free survival of the gefitinib group and the chemotherapy group were 8.2 and 5.9 months, respectively. CONCLUSION: We considered that all the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reason for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each PCR method, a large prospective clinical trial is warranted.

Serum levels of surfactant protein D predict the anti-tumor activity of gefitinib in patients with advanced non-small cell lung cancer.

PURPOSE: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment. METHODS: We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status ≤3, age ≤80 years, and stage IIIB-IV disease. In addition, EGFR mutations were analyzed in 24 patients. RESULTS: Multivariate analysis showed that favorable progression-free survival (PFS) after gefitinib treatment was associated with adenocarcinoma and high serum SP-D levels before treatment. EGFR mutation analysis of 24 patients showed that 16 patients had exon 19 deletion and/or exon 21 point mutations. EGFR mutations were significantly correlated with response to gefitinib and serum SP-D levels before treatment was significantly high in patients with the EGFR mutations. Serum SP-A levels were not associated with PFS. CONCLUSIONS: The present study showed that measurement of serum SP-D levels before treatment in patients with NSCLC may be a new surrogate marker for predicting the response to gefitinib.