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R. T. Chlebowski, A. Schwartz, H. Wakelee, G. L. Anderson, M. L. Stefanick, J. E. Manson, J. W.Chien, C. Chen, J. Wactawski-Wende, M. Gass, for the Women's Health Initiative Investigators

Background: Sex differences in lung cancer outcome suggest a potential hormonal influence; however, observational studies provide mixed findings regarding menopausal hormone therapy (HT) and lung cancer.

Methods: Secondary analyses of the WHI randomized, placebo-controlled trial of daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) in 16,608 multi-ethnic postmenopausal women, aged 50-79 were conducted on lung cancer incidence and mortality. Lung cancers were confirmed by medical record review.

Results: Groups were balanced for age, race/ethnicity, and prior HT. Smoking status was also comparable (never 50%, past 40%, current 10% in both groups). Cumulative risk for lung cancer was highest in current (0.51%), compared to past (0.14%) and never (0.04%) smokers. After 5.6 years on trial intervention and 2.4 years additional follow-up (median), small cell lung cancer incidence was comparable between randomization groups (total n=26), as was subsequent small cell lung cancer mortality. Although a trend for more non-small cell lung cancer (NSCLC) diagnoses in the active hormone group was not significant (p=0.12), an apparent divergence emerged after five years, with more diagnoses in the CEE + MPA group. In addition, mortality after NSCLC diagnosis was significantly higher for the CEE + MPA group (46.3% vs 27.0%, respectively, hazard ratio (HR) 1.59, 95% CI 1.03-2.46, p=0.04). As a result, CEE + MPA group women were more likely to die from NSCLC than those on placebo (p=0.02).

Conclusions: Use of CEE + MPA for over 5 years increases a woman's risk for NSCLC mortality, the leading cause of cancer death in women. These data, together with recent results indicating higher breast cancer risk (Cancer Res 2009;69(2):78s), suggest cancer impact should influence risk-to-benefit consideration for combined HT use.