The use of E+P was associated with an increased risk of incident lung cancer in this study. Although HRT use has declined38
and is not recommended except for short-term treatment of menopausal symptoms,39
our results indicate millions of women may remain at risk of developing lung cancer. We found that the association of HRT with lung cancer was duration dependent, with the highest risk for users of E+P ≥ 10 years. Use of E+P was also associated with an advanced stage at diagnosis in a duration-dependent manner. We do not have the power to estimate a safe length of HRT use.
There were not large differences in the associations between NSCLC and SCLC. Similarly, smoking status did not seem to modify the associations. A recent cohort study that also showed increased risks of lung cancer associated with HRT use did not see differences in the association with regard to histology and smoking status.11
Although obesity may modify the association between HRT and lung cancer,21
BMI was not an effect modifier in our study. The relatively small number of cases in each subcategory limits our ability to detect differences.
Previous studies of the association between HRT and lung cancer have been mixed.8–21
In the Cancer Prevention Study II, current use of any HRT was associated with a decreased risk of lung cancer (relative risk = 0.76; 95% CI, 0.62 to 0.92) that was not duration dependent and did not differ by formulation.9
A case-control study found a duration-dependent decreased risk for lung cancer with HRT use (odds ratio = 0.88; 95% CI, 0.78 to 1.00 for each duration quartile) and did not differ by formulation.20
Another case-control study reported protective associations with HRT use that did not differ between unopposed estrogen and E+P.18
Women in the Canadian National Breast Screening Study using HRT (formulation not specified) for 10 years or longer, however, had an elevated risk (HR = 1.51; 95% CI, 1.14 to 1.99).11
The Heart and Estrogen/Progestin Replacement Study (HERS) found a nonsignificantly increased risk of lung cancer for women randomly assigned to conjugated E+P (HR = 1.39; 95% CI, 0.84 to 2.28).25
Recent Women's Health Initiative analyses found that subjects randomly assigned to E+P had more lung cancer deaths than those taking placebo.26,27
A retrospective study also found decreased survival among HRT users with lung cancer.28
SEER collects mortality data, but we did not analyze lung cancer mortality because we do not have information on HRT use after diagnosis. However, to explore a possible explanation for the effect of HRT on lung cancer mortality, we analyzed the association of HRT use with stage at diagnosis and found an increased risk of advanced stages at diagnosis with E+P, consistent with the Women's Health Initiative results on lung cancer mortality.26,27
Although the mechanisms underlying this association are unknown, E+P may lead to more aggressive disease, may mask early symptoms, and/or users may be less likely to seek or receive medical care in a timely fashion.
The mechanisms that contribute to the association between exogenous hormone therapy and lung cancer risk are complex, with likely genetic and environment interactions.6,40
Estrogen and progesterone receptors are found in NSCLC tumors41,42
and the quantity of estrogen receptors is associated with decreased recurrence-free survival.42
Estradiol promotes growth in NSCLC cell lines that is blocked by antiestrogens.43
Similarly, a mouse model showed that estradiol increased the proliferative index of cells that had been initiated by expression of oncogenic Kras and concurrent deletion of Tp53.44
A combination of an estrogen antagonist and epidermal growth factor receptor tyrosine kinase inhibitor decreased tumor volume more than either drug alone in vivo in xenograft models41,45
and in vitro.46
Evidence for a protective association of HRT has been shown. Low levels of insulin-like growth factor 1 are associated with reduced risk of lung cancer,47
and HRT has been shown to decrease insulin-like growth factor 1 levels.14
Finally, a recent study found several associations between single nucleotide polymorphisms in genes involved with estrogen metabolic pathways and an increased risk of lung cancer.48
Our study has several strengths. We used a large, prospective, population-based cohort study design. We were able to analyze the duration of HRT use in a dose-response manner over a long period of time that is likely necessary for biologic plausibility. We controlled for the strong confounding effect of tobacco and examined multiple other variables that affect the risk of incident lung cancer. Finally, the SEER database is complete and accurate, so there is minimal risk of outcome misclassification.
Our results are similar to those observed in the randomized, placebo-controlled HERS trial,25
but there are potential limitations of our study. First, residual confounding may be a factor. We could not adjust for environmental tobacco or occupational exposures that increase lung cancer risk. However, we did adjust for several smoking variables and did not find evidence of confounding by indication from processes such as oophorectomy for which HRT is commonly taken. Second, the measurement of long-term use of HRT is based on subject recall and was not measured repeatedly. The VITAL questionnaire was validated for long-term use of supplements,49
suggesting our measure of HRT is reasonably accurate. We expect that exposure misclassification would have attenuated our results in this prospective study. Generalizability may be limited because only 24% of respondents returned the initial survey, but it is unlikely that selection bias could have affected our results because in a prospective design, women cannot participate jointly based on exposure and future (unknown) disease status.
Lung cancer is the second most common malignancy among women and causes more deaths than breast cancer.1
Our results indicate that the use of E+P is associated with an increased risk of incident lung cancer and advanced stages at diagnosis in a duration-response manner. These findings represent an important contribution to current evidence against HRT use, which may be useful for counseling women about their risk of developing lung cancer, as well as prompting further study about the biologic mechanisms underlying this association.