Menopausal Hormone Therapy Does Not Influence Lung Cancer Risk: Results from the California Teachers Study

Cigarette smoking, the leading cause of lung cancer, is responsible for 80% to 90% of lung malignancies (1). Nevertheless, lung cancers develop among lifetime never smokers highlighting the need to investigate other factors that may modify lung cancer risk (2). Lung cancer pathology, risk factors, and prognosis differ by sex, prompting researchers to investigate hormonal and reproductive factors (3). The association between hormone therapy (HT) and lung cancer has been investigated; however, the results have differed across studies (4, 5). We examined HT use in relation to lung cancer risk among women in the California Teacher Study (CTS) capitalizing on detailed information on HT use (including formulation, duration, and timing), smoking history, and type of menopause.

The CTS cohort, established in 1995–1996, consists of 133,479 active and retired female teachers and administrators (6). CTS participants residing in California are followed annually for cancer diagnosis and death. The questionnaire participants completed at baseline covered a wide range of issues related to cancer risk and women's health including recent and past HT use, menopausal status, and cigarette smoking. For estrogen (E), questions were asked about Premarin and other estrogens and information was collected on mode of administration, dose if Premarin was used, ages at first and last use, and duration of use. For progestins (P), participants were asked to report the type of progestin used, ages at first and last use, years of use, days per month of use, and dose. A 5-category smoking variable was created on the basis of baseline smoking status and median pack-years (never, former light, former heavy, current light, and current heavy).

Women were sequentially excluded from the analytic cohort if not a California resident at baseline (n = 8,867), the medical history portion of the questionnaire was incomplete (n = 662), participant reported a prior diagnosis of lung cancer at baseline (n = 215), or participant limited her participation to breast cancer research (n = 18). In addition, we excluded premenopausal women (n = 47,976), women with indeterminate menopausal status (n = 4,957), women with missing information on smoking (n = 2,924), and women with incomplete HT histories (n = 7,268). Of 60,592 eligible postmenopausal women, 727 had a diagnosis of lung cancer a month or more after joining the cohort and before December 31, 2007.

Relative risks (RR) and 95% CIs for lung cancer associated with HT use were estimated using multivariable Cox proportional hazards regression with age (days) used as the timescale. Models were age stratified (years) and adjusted for race/ethnicity, smoking status/pack-years, type of menopause, and body mass index (BMI; kg/m²). Follow-up time began on the date the baseline questionnaire was completed and ended on the date of lung cancer diagnosis, death, move out of California, or December 31, 2007, whichever occurred first.

A majority (74.5%) of eligible postmenopausal women had used HT; 16.0% were former and 58.5% were current users of either E-alone therapy or E + P therapy at baseline (Table 1). In the multivariable model, the use of any HT was not associated with lung cancer risk (RR, 0.95, 95% CI, 0.80–1.13; Table 2). Neither former HT use nor recent HT use (i.e., current use at baseline) was associated with risk (RR, 0.98, 95% CI, 0.79–1.21; RR, 0.94, 95% CI, 0.78–1.13; respectively). No association was observed for duration of use (P_trend = 0.71) or years since quitting HT use (≤5 years: RR, 1.11, 95% CI, 0.80–1.55; >5 years: RR, 0.92, 95% CI, 0.71–1.18). Furthermore, we observed no variations in risk by smoking status (never, ever, former, current; Table 2), type of HT (E-alone, E + P use), type of menopause, or lung cancer histology (data not shown).

We observed no associations between HT use and lung cancer risk in this large study of postmenopausal women with up to 11 years of follow-up. One explanation for the lack of effect may be the overwhelming magnitude of the association between smoking and lung cancer, masking smaller associations with other exposures such as HT. However, if this were true, we would expect to observe significant HT use lung cancer associations among never smokers and we did not.

A recent meta-analysis of 11 studies did not support an association between HT use and lung cancer risk (5). In contrast, Greiser and colleagues reported a significant increased risk of lung cancer among never smokers (4). However, in that study, significant associations were found only when smokers and nonsmokers, various hormone regimens, or histologic subtypes were pooled (4). Furthermore, combined risk estimates from meta-analyses are difficult to interpret, in part, due to study heterogeneity and should be interpreted with considerable caution.

One limitation of our study is that residual confounding from smoking may exist. However, a major strength was our use of a 5-category smoking variable that combined smoking status and median pack-years to control for both smoking status and smoking intensity.

Overall, our findings do not support an association between HT and lung cancer.

The ideas and opinions expressed herein are those of the authors. Endorsement by the State of California, Department of Health Services, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended, nor should be inferred.

The work reported here was supported by National Cancer Institutes grants R01 CA77398, K05 CA136967, R25T CA57730, R25 056452, and R25 DA026120. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the Public Health Institute.