Purpose: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non–small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. Results: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). Conclusions: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. Clin Cancer Res; 17(11); 3812–21. ©2011 AACR.

To prospectively evaluate lung parenchyma on paired inspiration-expiration thin-section computed tomographic (CT) scans in patients recovering from severe acute respiratory syndrome (SARS). After the institutional review board approved the study and written consent was obtained from patients, 40 patients (25 female, 15 male; mean age, 42.8 years +/- 12.3 [standard deviation]) underwent thin-section CT at 51.8 days +/- 20.2 after onset of SARS symptoms. Twenty of the 40 patients underwent follow-up thin-section CT at 140.7 days +/- 26.7 after symptom onset. Lung findings were scored according to extent and then grouped in three categories (ground-glass opacity, interstitial opacity, and air trapping) for analysis. Mean CT scores for each finding in the various patient subgroups were compared by using the Mann-Whitney test. Clinical parameters and scores were evaluated for correlation by using Spearman rank correlation analysis. Mean scores for each finding were compared between the two serial examinations by using the Wilcoxon matched-pairs signed rank test. Air trapping, ground-glass opacity, and reticulation were found in 37 (92%), 36 (90%), and 28 (70%) of 40 patients, respectively, at initial thin-section CT examination and in 16 (80%), 14 (70%), and 10 (50%) of 20 patients, respectively, at follow-up examination. Scans from patients with adult respiratory distress syndrome (ARDS) had a significantly higher score for ground-glass opacity than did those from patients without ARDS (P = .009). A comparison of scores for the serial thin-section CT examinations indicated a significant reduction in the extent of ground-glass opacity (P < .001) and interstitial opacity (P < .001) but not in that of air trapping (P = .38) at follow-up examination. At initial thin-section CT, scores for ground-glass opacity, interstitial opacity, and air trapping correlated with age; those for ground-glass opacity and air trapping, with peak C-reactive protein level. At the second examination, scores for ground-glass opacity and interstitial opacity correlated with peak lactate dehydrogenase level; that for air trapping, with age and peak C-reactive protein level. Thin-section CT scores correlated with clinical and laboratory parameters in patients after SARS. Although ground-glass opacity and interstitial opacity resolve over time, air trapping persists.

Purpose: To explore predictive factors for time to treatment failure (TTF) in chemotherapy-naive non–small-cell lung cancer (NSCLC) patients receiving gefitinib treatment. Patients and Methods: We designed a phase II study to test gefitinib antitumor efficacy in advanced-stage, chemotherapy-naive NSCLC patients. Patients were treated with gefitinib 250 mg/d. Tumor assessments were performed every 2 months. Responding or stable patients were treated until progression or unacceptable toxicity. All scans were reviewed independently. EGFR exons 18-21 sequence, K-ras exon 2 sequence, and MET gene copy numbers were examined in available samples. Clinical or molecular predictors of TTF were examined by multivariate analysis. Results: One hundred six patients were enrolled. Ninety patients had tumor samples for biomarker tests. Overall response rate was 50.9% (95% CI, 41.4% to 60.4%). Median TTF was 5.5 months, and median overall survival (OS) was 22.4 months. The response rate and median TTF of the patients with exon 19 deletion (n = 20) were 95.0% and 8.9 months, for exon 21 L858R mutation (n = 23) were 73.9% and 9.1 month, and for other types of EGFR mutations (N = 12) were 16.7% and 2.3 months, respectively. In multivariate analysis, the presence of EGFR deletion exon 19 or L858R EGFR mutations in adenocarcinoma patients predicted longer TTF. High copy number of MET seemed to correlate with shorter TTF in patients with gefitinib-sensitive activating EGFR mutations. Conclusion: In this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.

Purpose: Whole-brain radiation therapy (WBRT) has been applied to inoperable brain metastases in lung adenocarcinoma. Recently, an in vitro study showed reduced clonogenic survival of mutant epidermal growth factor receptor (EGFR) lung cancer cell lines in response to ionizing radiation compared with that of the wild type. To elucidate the role of EGFR mutations in radiation treatment, we evaluated the clinical response to WBRT and survival of lung adenocarcinoma patients with brain metastases. Experimental Design: This was a retrospective analysis of 63 patients with brain metastases from lung adenocarcinoma who were treated with WBRT. Demographic data, EGFR mutation status, response to WBRT, and survival data were collected. Clinical response was assessed 1 month after the start of WBRT. Univariate and logistic regression models were used to test potential predictive factors associated with clinical response. Log-rank test and Cox regression were analyzed to identify factors that affected survival. Results: Clinical response to WBRT was observed in 29 patients (46%), with 34 nonresponder patients (54%). Patients with EGFR mutations had higher response rates to WBRT compared with those with the wild-type (54% versus 24%; P = 0.045). Both the administration of EGFR tyrosine kinase inhibitor (P = 0.034) and EGFR mutation (P = 0.029) were independently associated with response to WBRT. In Cox regression analysis, WBRT responder (P = 0.010) and absence of extracranial metastases (P = 0.002) were associated with better survival. Conclusions: Both the EGFR mutations and the administration of EGFR TKI during WBRT were independent predictors of response to WBRT in brain metastases of lung adenocarcinoma.