Fast track — ArticlesOestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial
Introduction
The Women's Health Initiative (WHI) trial of oestrogen plus progestin in postmenopausal women was stopped early when health risks were found to exceed benefits.1 At a mean follow-up of 5·6 years (SD 1·3), participants assigned to combined hormone therapy had higher risks of cardiovascular disease, coronary heart disease, stroke, venous thromboembolism, and breast cancer, and lower risks of fractures and colorectal cancers than did women assigned to placebo.2, 3, 4, 5, 6, 7, 8 All-cause mortality did not differ between study groups.1 During the post-intervention period, which comprised an additional mean follow-up of 2·4 years (0·4), there was an apparent excess in mortality and a higher risk of cancer in the combined hormone therapy group compared with the placebo group, with the latter difference reaching significance. The excess mortality was not accounted for by deaths associated with the protocol-specified cancer outcomes (ie, breast, colorectal, endometrial, or ovarian cancers); however, there was a higher number of deaths from lung cancer in the intervention group than in the placebo group (33 vs 15 deaths, respectively).9
Substantial preclinical evidence suggests that there is an effect of oestrogen on lung cancer.10, 11 Among other factors, oestrogen receptors can be expressed in normal lung,12 non-small-cell lung cancer cell lines, and in lung cancers.12, 13, 14 Oestradiol modulates gene expression associated with proliferation and growth of non-small-cell lung cancer cell lines.13, 15 Although clinical evidence is limited, higher oestradiol concentrations have been associated with higher mortality in both men and women with advanced non-small-cell lung cancer.16, 17
Our findings in the WHI trial—and the evidence suggesting oestrogen could be associated with lung cancer—led to the question of whether combined hormone therapy increases mortality from lung cancer. To address this issue, we undertook analyses of lung cancers diagnosed in the WHI trial over the entire follow-up period.
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Participants
The study design of the WHI trial has been reported elsewhere.1, 18 Briefly, predominantly healthy postmenopausal women aged 50–79 years with an intact uterus were enrolled at 40 clinical centres in the USA from 1993 to 1998. Women with previous breast cancer, anticipated survival of less than 3 years, or other previous cancer within the past 10 years apart from non-melanoma skin cancer were excluded. Women who were taking menopausal hormone therapy at initial screening could be enrolled after
Results
The flow of participants in this trial throughout the study period has been described in detail elsewhere.9 Table 1 shows the baseline characteristics of all 16 608 randomised participants. At a mean follow-up of 7·9 years (SD 1·6), 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0·16% vs 0·13%; HR 1·23, 95% CI 0·92–1·63, p=0·16; table 2, figure 1). Although the incidence of non-small-cell lung cancer
Discussion
This post-hoc analysis of the WHI randomised, placebo-controlled trial showed that in postmenopausal women, conjugated equine oestrogen plus medroxyprogesterone acetate did not increase incidence of lung cancer, but increased mortality from lung cancer, the leading cause of cancer-related death in women.23
In the initial report from the trial, combined hormone therapy had no effect on incidence of lung cancer during the treatment phase (intervention, n=50; placebo, n=54; HR 1·04, 0·71–1·53).1
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