Purpose: A role for estrogens in determining lung cancer risk and prognosis is suggested by reported sex differences in susceptibility and survival. Archival lung tissue was evaluated for the presence of nuclear estrogen receptor (ER)-a and ER-h and the relationship between ER status, subject characteristics, and survival. Experimental Design: Paraffin-embedded lung tumor samples were obtained from 214 women and 64 men from two population-based, case-control studies as were 10 normal lung autopsy samples from patients without cancer. Nuclear ER-a and ER-h expression was determined by immunohistochemistry. Logistic regression was used to identify factors associated with ER positivity and Cox proportional hazards models were used to measure survival differences by ER status. Results: Neither tumor (0 of 94) nor normal (0 of 10) lung tissue stained positive for ER-a. Nuclear ER-h positivity was present in 61% of tumor tissue samples (170 of 278; 70.3% in men and 58.3% in women) and 20% of normal tissue samples (2 of 10; P = 0.01). In multivariate analyses, females were 46% less likely to have ER-h^positive tumors than males (odds ratio, 0.54; 95% confidence interval, 0.27-1.08). This relationship was stronger and statistically significant in adenocarcinomas (odds ratio, 0.40; 95% confidence interval, 0.18-0.89). Women with ERh^positive tumors had a nonsignificant 73% (P = 0.1) increase in mortality, whereas men with ER-h^positive tumors had a significant 55% (P = 0.04) reduction in mortality compared with those with ER-h^negative tumors. Conclusions: This study suggests differential expression by sex and influence on survival in men of nuclear ER-h in lung cancer, particularly in adenocarcinomas.In the United States, lung cancer is the second most common cancer among both men and women and is the leading cause of cancer death in both sexes (1). A number of studies report that women are more susceptible, dose for dose, to the carcinogenic effects of cigarette smoke than men (2, 3). Women have been reported to have higher levels of polycyclic aromatic hydrocarbon-DNA adducts than men at any given level of smoking (4). Smoking females have significantly higher levels of expression of the gene encoding CYP1A1, a central enzyme in the metabolic activation of polycyclic aromatic hydrocarbons (4, 5). It has also been shown that G:C to T:A transversions in p53 are more common among females with lung cancer than males (6). One study also reported that the proportion of nonsmoking lung cancer cases in women was double that in men, suggesting that even nonsmoking women may be more susceptible to lung carcinogens than nonsmoking men (2).The reported sex difference in susceptibility suggests a role for hormones in determining lung cancer risk. Both exogenous estrogens [i.e., hormone replacement therapy (HRT) and oral contraceptives] and endogenous hormone levels (i.e., age at menopause) may contribute to the development of lung cancer (7 -10). Early age at menopause has been associated with decreased risk of adenocarci...

These findings suggest that postmenopausal hormone exposures are associated with reduced risk of ER-alpha- and ER-beta-expressing NSCLC. Understanding tumor characteristics may direct development of targeted treatment for this disease.

Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n = 238), EGFR expression (n = 158) and dual COX-2/EGFR expression (n = 157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01-2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64-48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72-2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32-0.98). COX-2-/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung.

7593 Background: ALK gene rearrangement is a recently identified molecular alteration in the tumors of a small proportion of NSCLC patients. Previous reports have shown that the rate of EGFR gene mutations may vary in NSCLC patients of different ethnic background. It is unclear if similar differences exist with regards to ALK positivity. We analyzed ALK expression in tumors of AA NSCLC patients and also assessed the epidemiologic features and outcomes of these patients, as well as the occurrence of known oncogene mutations. Methods: We identified 260 tumor tissues of AA NSCLC patients, enrolled on several epidemiologic studies conducted at our institution. Immunohistochemistry, using the anti-Alk D5F3 antibody (Cell Signaling Technology) was used to visualize ALK expression. Fifty-three of these tumors also underwent mutation analysis using the OncoCarta Panel V1 (Sequenom) to evaluate 238 mutations in 19 oncogenes. Results: Of the 260 tumors analyzed, 6 (2.3%, 95% CI- 0.5-4.1%) were ALK positive. All ALK positive patients had adenocarcinoma histology (6/157) while no patients with other NSCLC histologies were ALK positive, p=0.04. There was no difference in the rate of positivity based on sex, 1% (1/99) in males versus 3.1% (5/161) in females, p=0.27. Consistent with prior studies, patients with ALK positive tumors were slightly younger (median age 56 years vs 61 years, p = 0.27) and the positive rate was higher in never smokers 11% (2/18) than in ever smokers 1.6%, p=0.06. There was no correlation of ALK positivity with the stage of the disease at diagnosis. The survival of ALK positive and negative patients, adjusted for age, sex and stage, was similar (HR=0.77; 95% CI 0.19-3.13). Fifty-three tumors have been assessed for oncogene mutations in addition to ALK expression. Of these, 2 (3.8%) were ALK positive and neither of these tumors carried other tested mutations such as EGFR, Kras, PIK3 or AKT. Conclusions: The rate of ALK positive tumors among African-American NSCLC patients is similar to the general population and the demographic features of ALK positive AA patients is also similar to the general ALK positive NSCLC patient population.