Elsevier

The Lancet

Volume 374, Issue 9697, 10–16 October 2009, Pages 1243-1251
The Lancet

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Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial

https://doi.org/10.1016/S0140-6736(09)61526-9Get rights and content

Summary

Background

In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period.

Methods

The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50–79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0·625 mg conjugated equine oestrogen plus 2·5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611.

Findings

After a mean of 5·6 years (SD 1·3) of treatment and 2·4 years (0·4) of additional follow-up, 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%; hazard ratio [HR] 1·23, 95% CI 0·92–1·63, p=0·16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0·14% vs 0·11%; HR 1·28, 0·94–1·73, p=0·12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0·11% vs 0·06%; HR 1·71, 1·16–2·52, p=0·01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0·09% vs 0·05%; HR 1·87, 1·22–2·88, p=0·004). Incidence and mortality rates of small-cell lung cancer were similar between groups.

Interpretation

Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk–benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer.

Funding

National Heart, Lung and Blood Institute, National Institutes of Health.

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.

Section snippets

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

References (46)

  • GL Anderson et al.

    Implementation of the Women's Health Initiative study design

    Ann Epidemiol

    (2003)
  • HA Wakelee et al.

    Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group trial 1594

    J Thorac Oncol

    (2006)
  • JE Rossouw et al.

    Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial

    JAMA

    (2002)
  • RT Chlebowski et al.

    Estrogen plus progestin influence on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial

    JAMA

    (2003)
  • JA Cauley et al.

    Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial

    JAMA

    (2003)
  • JE Manson et al.

    Estrogen plus progestin and the risk of coronary heart disease

    N Engl J Med

    (2003)
  • S Wassertheil-Smoller et al.

    Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial

    JAMA

    (2003)
  • M Cushman et al.

    Estrogen plus progestin and risk of venous thrombosis

    JAMA

    (2004)
  • RT Chlebowski et al.

    Estrogen plus progestin and colorectal cancer in postmenopausal women

    N Engl J Med

    (2004)
  • RT Chlebowski et al.

    Breast cancer after estrogen plus progestin use in postmenopausal women

    N Engl J Med

    (2009)
  • G Heiss et al.

    Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin

    JAMA

    (2008)
  • LP Stabile et al.

    Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects

    Cancer Res

    (2005)
  • DC Marquez-Garban et al.

    Targeting aromatase and estrogen signaling in human non-small cell lung cancer

    Ann N Y Acad Sci

    (2009)
  • PT Cagle et al.

    Estrogen and progesterone receptors in bronchogenic carcinoma

    Cancer Res

    (1990)
  • LP Stabile et al.

    Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen

    Cancer Res

    (2002)
  • AG Schwartz et al.

    Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women

    J Clin Oncol

    (2007)
  • Z Hammoud et al.

    Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma

    Endocr Relat Cancer

    (2008)
  • Albain KS, Unger J, Gotay CC, et al. Toxicity and survival by sex in patients with advanced non-small cell lung cancer...
  • Ross H, Oldham FB, Bandstra B, et al. Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive...
  • Design of the Women's Health Initiative clinical trial and observational study

    Control Clin Trials

    (1998)
  • Surveillance Epidemiology and End Results

  • JE Rossouw et al.

    Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause

    JAMA

    (2007)
  • DR Cox

    Regression analysis and life tables

    J R Stat Soc

    (1972)
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