The role of estrogens in lung cancer remains elusive. Estrogens stimulate growth in both normal and tumoral lung epithelial cells. Aromatase is active in normal lung tissue and lung cancer cells. Both isoforms of estradiol receptor (ER), alpha (ERα) and beta (ERβ), have been detected in lung cancer tissue and normal lung cells. The results of literature concerning the presence of ERα in lung tumors and normal lung cells remain insufficiently documented, with divergent results. In a recently published study , the authors aimed to investigate whether serum estrogen levels and tumor ERα, ERβ and progesterone receptor (PR) gene expressions were associated with lung cancer survival in three independent cohorts. In addition, they examined the role of single-nucleotide polymorphisms (SNPs) of genes involved in the estrogen biosynthesis pathway in lung cancer survival. The three cohorts studied were the case–case cohort, the case–control cohort, and the case-only cohort. The National Cancer Institute-Maryland (NCI-MD) case–case cohort recruited 100 postmenopausal women and 205 men with non-small-cell lung cancer. In addition to usual demographic data, smoking habits and passive smoking were recorded by interview. Serum samples were available from 191 (63%) of the cases (126 males and 65 females). The NCI-MD case–control cohort recruited 227 patients with lung cancer and information was obtained by interviews. The Norwegian case-only cohort recruited 282 lung cancer cases at the time of surgery for non-small-cell lung cancer between 1986 and 2007 and also interviews were obtained. Blood samples were obtained at the time of interviews in the three cohorts.
The mean ages were identical between the three populations (65 years). Smoking status differed across the cohorts. Fifty-nine percent of the Norwegian cases were current smokers, whereas only 46% of the cases from the NCI-MD case–control cohort were current smokers. The main result was that higher levels of serum estrogen and poorer survival were very significantly correlated in the three studies. In addition, in the NCI-MD case–case cohort, lung cancers which were ERα mRNA-positive had worse survival than those which were tumor ERα mRNA-negative (hazard ratio (HR) 3.53, 95% confidence interval (CI) 1.17–10.62); however, this association was not significant in the Norwegian case-only cohort (HR 1.22, 95% CI 0.78–1.90). The association between estrogen levels and ER expression with poor prognosis was observed among both men and women. This association of tumor ERα expression with lung cancer survival was also more strongly observed among adenocarcinomas in the NCI-MD case–case cohort. Patients with ERβ-positive tumors had slightly shorter lung cancer survival than those that with ERβ-negative tumors in the NCI-MD case–case cohort ([i]p[/i] for log-rank 0.04), but this was not significant in the Norwegian case-only cohort ([i]p[/i] for log-rank 0.85). Several SNPs in the aromatase gene were associated with serum estrogen levels and with lung cancer survival in all three cohorts. The variant ESR1-07, a SNP in exon 8 of the ERα gene, was associated with tumor ERα mRNA expression levels and expression levels of tumor PR mRNA but not associated with serum estrogen levels; it was also significantly associated with poorer survival in all three cohorts. Higher levels of progesterone were associated with worse survival among men only in the NCI-MD case–case cohort but not in the other cohorts nor in women.
Unité de Gynécologie-Endocrinienne, APHP, Hôtel-Dieu Hospital and University Paris Descartes, France
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