Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Looking for a reason to quit, ladies? Look no further.

As women have become more like men in their smoking habits and a greater proportion of men abandon the habit, lung cancer has become the leading cause of cancer deaths among women in the U.S., resulting in more deaths annually than breast, uterine, and ovarian cancer combined.

While the rise in female lung cancer has been attributed to the increase in smoking among women, 20 percent of women who develop the diseases in the U.S. have never smoked. Fifteen to 20 percent of lung cancers occur in individuals who have never smoked, but 70 percent to 80 percent of people who “never smoked” are women.

According to the NCI, combined trends in lung cancer incidence and mortality rates have closely mirrored historical patterns of smoking prevalence, after accounting for an appropriate latency period. Because of historical differences in smoking prevalence between men and women, lung cancer rates in men have been consistently declining since 1990. The incidence rate in men declined from a high of 102.1 cases per 100,000 men in 1984 to 82.7 cases per 100,000 men in 2009, but consistent declines in women have not yet been observed.

In 2013, the National Cancer Institute estimates that 72,220 deaths will occur among U.S. women due to lung cancer, compared with 39,620 deaths due to breast cancer alone.

As the NCI notes, the reason for the increase in deaths among women can’t be attributed solely to increased smoking among women. Patricia Thistlethwaite, M.D., Ph.D., a cardiothoracic surgeon at the University of California at San Diego explained women are younger at the time of diagnosis of lung cancer than men, the proportion of adenocarcinoma and bronchoalveolar carcinoma is higher in women than in men, and women are less likely to have a smoking history. The cause for the “huge increase” in these two types of cancers among women is not known and is under investigation.

And scientists are looking for molecular differences characterizing lung cancers that may be responsible for increased susceptibility in women. Women exhibit decreased DNA repair capability and increased mutations in specific cancer genes such as p53, epidermal growth factor receptor (EGFR), and K-ras. Mutations in these genes are found at a much higher frequency in adenocarcinomas, particularly in women.

Estrogen and Smoking

One obvious factor that may make a difference between men and women is estrogen. Estrogen receptors ERα and ERβ have been detected on lung cancer cells, and estrogens have been shown to stimulate growth of lung cancer cells in tissue culture. On the other hand, clinical studies suggest that estrogen-progesterone supplementation probably promotes lung cancer rather than just estrogen alone.

Some have proposed that anti-estrogen treatments might be effective in treating lung cancer, because of the presence of estrogen receptors and because interruption of estrogen receptor (ER)-α function has proven an effect effective therapeutic strategy in breast cancer. However, the function of these receptors in lung cancer remains poorly understood.

In 2009 investigators working at the University of Pittsburgh Cancer Institute reported results of a study examining how estrogen receptors might modulate the growth of non-small cell lung cancer (NSCLC) cells.

They showed that NSCLC cells expressed ERβ, but not ERα receptors. They also reported that ERβ-specific ligands, but not ERα-specific ligands, promoted the growth of lung cancer cells, and that knockdown of ERβ by short hairpin RNA constructs resulted in loss of estrogen-dependent lung cancer cell growth. Nonetheless, the authors said, estrogen caused rapid activation of cAMP- and MAPK-signaling pathways in lung cancer cells, suggesting that the proliferative effects of estrogen in lung cancer cells is mediated primarily, if not exclusively, by the nongenomic action of ER. In summary, their data indicated that ERβ is not a nuclear protein in lung cancer cells, providing a unique model system to study the extranuclear functions of the estrogen receptor.

Genetic Mutations

In 2012, investigators led by pathologist Mark Ladanyi, M.D., at Memorial Sloan Kettering Cancer Center studied genotyped 3,026 lung adenocarcinomas for the major EGFR mutations (exon 19 deletions and L858R) and KRAS (G12, G13) examining correlations with demographic, clinical, and smoking history data.

The researchers focused on KRAS, which is frequently mutated in lung adenocarcinomas, and found that smokers and people who never smoked (“never smokers”) had different KRAS mutations in their tumors. Smokers usually had a mutation called KRAS G12C, while never smokers typically had a mutation called KRAS G12D. Women were more likely than men to have the KRAS G12C mutation, and they developed the disease at a younger age and with a shorter history of smoking.

Dr. Ladanyi said the data support the theory that women are more vulnerable than men to carcinogenic effects of tobacco smoke. He commented that researchers have speculated for decades that women who smoke are at greater risk for lung cancer than men, but various analyses have produced conflicting data.

And back in 2003, Shinichi Toyooka, M.D., and colleagues at Kagawa Prefectural Central Hospital, Takamatsu, Japan, presented findings of an analysis of 1,775 lung cancer cases for mutations of the TP53 suppressor gene. The investigators looked for mutations characterized by an excess of G:C to T:A transversions thought to be characteristic of smoking-related cancers.

The transversions were present in 26% of male smokers who developed any type of lung cancer, compared with 37% of female smokers who developed lung cancer. Also, such transversions were found in 31% of males who developed lung cancer despite a history of never smoking, compared with 12% of such females, the study showed.

Dr. Toyooka said the study shows for the first time that cancers in female smokers have significantly more tobacco-related mutations, helping to explain the greater susceptibility of women to tobacco carcinogens.

The Million Women Study

And from an epidemiologic perspective, The Million Women Study, a collaborative project between Cancer Research U.K. and the National Health Service, aimed to “answer many outstanding questions about the factors affecting women’s health in this age group.”

The study enrolled 1.3 million women recruited between 1996 and 2001, aged 50 to 65 years. Rachel Huxley, Ph.D., associate professor at the School of Public Health, University of Minnesota, and an author of the study commented, “That we had to wait until the 21st century to observe the full consequences in women of a habit that was already widespread in the mid-20th century… when tobacco smoking pervaded much of the developed world, might seem paradoxical. But this is because, in most of Europe and the U.S.A., the popularity of smoking among young women reached its peak in the 1960s, decades later than for men. Hence, previous studies have underestimated the full eventual impact of smoking on mortality in women, simply because of the lengthy time lag between smoking uptake by young women and disease onset in middle and old age.”

Taken together, as molecular studies and epidemiologic data accumulate, smoking looks like a particularly hazardous habit for women, and quitting early or not starting at all is the best way not to die from it.

Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is technical editor at Genetic Engineering & Biotechnology News.

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