In an effort to understand lung cancer risk factors and develop prevention strategies for the disease, Christina S. Baik, MD, MPH, thoracic oncologist and staff scientist at the Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, has examined epidemiologic trends in lung cancer, including the role that hormones may play in making women more vulnerable to the disease. She is particularly interested in lung cancer development among women who have never smoked.
Three years ago, with support from the Lung Cancer Research Foundation, Dr. Baik studied the associations among reproductive factors, the use of hormone replacement therapy, and lung cancer incidence in women participating in the Nurses’ Health Study. Dr. Baik assessed a number of factors, including age at menopause, age at menarche, age at first birth, postmenopausal use of hormone replacement therapy, and past oral contraceptive use, as well as smoking history. The results from her study demonstrated that female hormones may influence lung carcinogenesis.1 Although the effect appeared to be small, the results correspond to the findings of other studies showing a potential link between hormones and lung cancer in women.
The ASCO Post spoke with Dr. Baik about her work in identifying the risk factors for lung cancer in women and the need to continue research in this area.
Basis for Research
What compelled you to study the role hormones may play in the development of lung cancer?
For many years, researchers have suspected that the causes of lung cancer in women may be different from the causes of lung cancer in men. And that suspicion is based on epidemiologic data showing that the proportion of lung cancer in women in the United States who have never smoked is between 15% and 20%, compared to 10% in men who have never smoked. Some reports even suggest that as much as 50% of lung cancers in women globally, especially in East Asia, could be coming from never-smokers. These are rough estimates, but we certainly see a lot of Asian women coming into our clinic with lung cancer who have never smoked.
Based on these observations, many researchers began to ask the question, is there a relationship between the female hormones estrogen and progesterone and lung cancer? That’s when I started to become interested in studying the possible connection as well.
Is there a theory about why estrogen and progesterone potentially raise a woman’s risk for lung cancer?
Researchers have looked into estrogen and progesterone receptors in lung cancer in both lung cancer–derived human cell lines and in actual tumor specimens from patients and found estrogen receptor expression in the lung cancers. In mouse studies where ovariectomized mice were treated with estradiol, the mice also developed lung cancer, and when they were given antiestrogens it reversed the process. Based on the data from the mouse studies and early laboratory studies, it looks like estrogen does affect lung cancer, so there is some biologic explanation.
We know that female hormones and some reproductive factors are associated with breast cancer. I was curious to find out whether there was a similar association in lung cancer in women. who were followed for nearly 22 years as part of the Nurses’ Health Study, we found that among never-smokers, the more children a woman had, the less risk she had for developing lung cancer. That finding is actually similar to what we see in breast cancer incidence, but we don’t know whether the mechanism is the same.
Hormone Replacement Therapy
Did you find an increase in risk for lung cancer among women taking hormone replacement therapy as well?
We were interested in looking into the effect of hormone replacement therapy on lung cancer within the Nurses’ Health Study cohort, and we found that there is likely an increased risk of developing the disease—especially the adenocarcinoma subtype—but the findings were not statistically significant. Data from the Women’s Health Initiative (WHI), which looked at the role of hormone replacememt therapy in older postmenopausal women, also showed some increase in lung cancer incidence, although, similar to our study, it was not statistically significant. The WHI study did find, however, that hormone replacement use increased lung cancer mortality.
So, it looks like estrogen alone or estrogen and progesterone together have some effect in lung cancer development and progression, but there is a lot more we need to understand about the role of female hormones in lung cancer. One interesting finding from the WHI study was that there was no increase in lung cancer rates—or in breast cancer rates—in the estrogen-only arm.
Role of Progesterone
Is progesterone, then, the potential culprit in the development of these cancers?
It is a possibility. Progesterone has been shown to promote angiogenesis in cancers, and maybe that is what makes cancers more aggressive, or there may be a synergistic effect with estrogen. We still have to sort all this out.
Something about lung cancer makes it behave like a hormone-driven cancer. Of course, smoking is the main cause of lung cancer, but it appears that there are other factors that play a big part in its development as well.
Much to Clarify
According to the American Cancer Society, lung cancer affects slightly more men than women [115,060 vs 106,070 new cases annually], but research may be showing that women are at greater risk for developing the disease. Does that add more credence to the theory that lung cancer is hormone-driven?
Possibly. Some studies show that women may be more sensitive to tobacco, but other studies dispute that, so it is unclear whether women are at higher risk from cigarettes or from other factors in addition to cigarettes. Also, whether women actually have a higher risk of developing lung cancer than men is not clear. I think the important thing is to recognize that there are risk factors that are specific in women and in men and develop specific preventative strategies that address those risk factors. ■
Disclosure: Dr. Baik reported no potential conflicts of interest.
1. Baik CS, Strauss GM, Speizer FE, et al: Reproductive factors, hormone use, and risk for lung cancer in postmenopausal women, the Nurses’ Health Study. Cancer Epidemiol Biomarkers Prev 19:2525-2533, 2010.