Molecular Pathology of Non–Small Cell Lung Cancer

This review offers an overview of the molecular pathology of lung cancer, with a focus on analyses that are most commonly part of the current clinical testing paradigm. Molecular testing of lung cancer has proved integral to the success of new targeted therapies, and their use is now commonplace in treatment selection. Traditional pathologic evaluation, however, plays a major role in these advances and serves an equally critical role to aid in determining optimal therapy.     

Characterization of the Effects of Cyclooxygenase-2 Inhibition in the Regulation of Apoptosis in Human Small and Non–Small Cell Lung Cancer Cell Lines

Background Cyclooxygenase-2 enzyme (COX-2) is overexpressed in human non–small cell lung cancer (NSCLC) but is not expressed in small cell lung cancer. Selective COX-2 inhibitors have been shown to induce apoptosis in NSCLC cells, an effect which is associated with the regulation of intracellular MAP kinase (MAPK) signal pathways. Our aims were to characterize the effects of COX-2 inhibition by rofecoxib on apoptosis in human NSCLC and small cell lung cancer cell lines. Methods The human NSCLC cell line NCI-H2126 and small cell lung cancer cell line DMS-79 were used. Constitutive COX-2 protein levels were first determined by Western blot test. Levels of apoptosis were evaluated by using propidium iodide staining on FACScan analysis after incubation of NCI-H2126 and DMS-79 with p38 MAPK inhibitor SB202190 (25 μM), NF-κB inhibitor SN50 (75 μg/mL), and rofecoxib at 100 and 250 μM. All statistical analysis was performed by analysis of variance. Results Western blot test confirmed the presence of COX-2 enzyme in NCI-H2126 and absence in DMS-79. Interestingly, rofecoxib treatment demonstrated a dose-dependent increase in apoptosis in both cell lines. Given this finding, the effect of rofecoxib on NF-κB and p38 MAPK pathways was also examined. Apoptosis in both cell lines was unaltered by SN50, either alone or in combination with rofecoxib. A similar phenomenon was observed in NCI-H2126 cells treated with SB202190, either alone or in combination with rofecoxib. In contrast, p38 MAPK inhibition greatly upregulated DMS-79 apoptosis in a manner that was unaltered by the addition of rofecoxib. Conclusions Rofecoxib led to a dose-dependent increase in apoptosis in both tumor cell lines. This effect occurred independently of COX-2, NF-κB, and p38 MAPK pathways in DMS-79 cells. As such, rofecoxib must act on alternative pathways to regulate apoptosis in human small cell lung cancer cells. Presented at the Society of Surgical Oncology (SSO) Annual Meeting, New York, 18th-21st March 2004.     

Overexpression of RhoE Has a Prognostic Value in Non–Small Cell Lung Cancer

Background Increasing evidence has suggested that RhoE plays an important role in carcinogenesis and progression. However, the correlation between RhoE expression and clinical outcome in lung cancer has not been investigated. Methods RhoE expression was detected by immunohistochemistry on tissue microarray containing samples from 115 patients with non–small cell lung cancer with a median follow-up of 54 months. Results RhoE was overexpressed in the cytoplasm of lung cancer cells compared with undetectable expression of RhoE in the adjacent nontumoral cells. Patients with RhoE-negative tumors had substantially longer cancer-related survival than did patients with RhoE-positive tumors. Multivariate analysis showed that RhoE overexpression was an independent marker for cancer-related survival in the entire population after adjusting for other prognostic factors. Conclusions RhoE expression may serve as an unfavorable prognostic factor in patients with non–small cell lung cancer.     

Induction Chemoradiotherapy Followed by Surgical Resection for Clinical T3 or T4 Locally Advanced Non–Small Cell Lung Cancer

Purpose

To examine the usefulness of trimodality therapy in patients with clinical T3 or T4 (cT3?C4) locally advanced non?Csmall cell lung cancer (LA-NSCLC).

Methods

Between 1997 and 2009, a total of 76 LA-NSCLC patients with cT3?C4 underwent surgery. Among them, 36 patients underwent induction chemoradiotherapy with docetaxel and cisplatin plus concurrent radiation followed by surgery (IC group). The other 40 patients initially underwent surgery (IS group). The outcomes of the IC and IS groups were then investigated. To minimize possible biases caused by confounding treatment indications, we performed a retrospective cohort analysis by applying a propensity score (PS). Patients were divided into three groups according to PS tertiles, and comparisons between the IC and IS groups were made by PS tertile-stratified Cox proportional hazard models.

Results

For the entire cohort, which had a median follow-up duration of 48?months, the 3- and 5-year overall survival rates were 83.8 and 78.9%, respectively, in the IC group, versus 66.8 and 56.5%, respectively, in the IS group (P?=?0.0092). After adjustments for potentially confounding variables, the IC group continued to have a significantly longer overall survival than the IS group (P?=?0.0045). In addition, when the analysis was limited to 52 patients with cT3?C4N0 or N1 disease, the IC group had a significantly longer overall survival than the IS group after adjustments for confounding variables (P?=?0.019).

Conclusions

Our study indicates that trimodality therapy is highly effective in patients with cT3?C4 LA-NSCLC.