Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women.
The role of tumor estrogen receptors (ERs) and serum estrogen in lung cancer is inconclusive. We investigated the hypothesis that ERs and functional single-nucleotide polymorphisms in the estrogen biosynthesis pathway are associated with poorer lung cancer survival. Lung cancer patients (n = 305) from a National Cancer Institute-Maryland (NCI-MD) case-case cohort in the Baltimore metropolitan area were used as a test cohort. To validate, 227 cases from the NCI-MD case-control cohort and 293 cases from a Norwegian lung cancer cohort were studied. Information on demographics, tobacco and reproductive histories was collected in an interviewer-administered questionnaire. Serum estrogen, progesterone, tumor messenger RNA expression of hormone receptors and germ line DNA polymorphisms were analyzed for associations with lung cancer survival. Patients in the highest tertile of serum estrogen had worse survival in all three cohorts (P combined < 0.001). Furthermore, the variant allele of estrogen receptor alpha (ER-α) polymorphism (rs2228480) was significantly associated with increased tumor ER-α levels and worse survival in all three cohorts [hazard ratio (HR) = 2.59, 95% confidence interval (CI): 1.20- 4.01; HR = 1.76, 95% CI: 1.08-2.87 and HR = 2.85, 95% CI: 1.31-4.36). Other polymorphisms associated with lower serum estrogen correlated with improved survival. Results were independent of gender and hormone replacement therapy. We report a significant association of increased serum estrogen with poorer survival among lung cancer male and female patients. Understanding the genetic control of estrogen biosynthesis and response in lung cancer could lead to improved prognosis and therapy.
Olivo-Marston
Susan E
SE
Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
Mechanic
Leah E
LE
Mollerup
Steen
S
Bowman
Elise D
ED
Remaley
Alan T
AT
Forman
Michele R
MR
Skaug
Vidar
V
Zheng
Yun-Ling
YL
Haugen
Aage
A
Harris
Curtis C
CC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics / Q000401:mortality*; D016022:Case-Control Studies; D015331:Cohort Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000032:analysis* / Q000235:genetics; D004967:Estrogens / Q000097:blood*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011374:Progesterone / Q000097:blood; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; D011374:Progesterone; D019363:Cytochrome P-450 CYP1A1