Researchers are delving deeper into the links between smoking and cancer, teasing out the genes and molecules involved as well as other factors that affect cancer risk. They have found, for example, a specific protein that decreases with smoking cessation. Genetic factors are also being implicated in the lung cancers of people who have never smoked. New studies are revealing an association between smoking and ovarian cancer, as well as between second-hand smoke exposure and lung cancer survival. Understanding these diverse connections and how they work -- whether on the molecular, familial, or population level -- helps in understanding cancer risk and outcomes and in crafting programs to help people avoid or quit smoking, according to studies presented today at the 97th Annual Meeting of the American Association of Cancer Research.

The Association Between the Anti-Inflammatory Protein CC10 and Smoking Status Among Participants in a Chemoprevention Trial: Abstract No. 5738

People who have stopped smoking have higher blood levels of a protein called CC10 than those who are still smoking, a finding that may help to explain why former smokers have a lower risk of lung cancer than current smokers.

"We know that smoking cessation is good, that it reduces the risk of lung cancer compared to continuation of smoking, but we don't know the molecular basis for the lower risk," said Jiping Chen, M.D., Ph.D., a Cancer Prevention Fellow at the National Cancer Institute, Bethesda, Md. Chen is the lead author of the study, which was the first to demonstrate that CC10 levels, normally high in non-smokers and low in smokers, could be restored after long-term smoking cessation.

CC10 is a protein that is expressed in the lining of the bronchial system. Its biology is not completely understood but it is known to play a role in protecting the lining of the respiratory tract from oxidative damage and inflammation.

To determine whether smoking cessation affects CC10 levels, the researchers measured levels of the protein in 81 current and 23 former smokers. The former smokers had not smoked for about seven years on average. All of the participants had bronchial dysplasia, a precancerous lesion putting them at high risk for lung cancer. CC10 levels were measured in blood samples as well as samples from bronchoalveolar lavage - a procedure that uses a fiberoptic scope to inject sterile saline into the lung and remove the fluid.

After adjusting for age, CC10 levels in the blood of former smokers were 1.7 times higher than those of current smokers, a statistically significant difference. Protein levels in the bronchoalveolar lavage fluid levels were also higher in former smokers, although the difference was not statistically significant. The results were substantially the same after adjusting for sex and pack-years of smoking.

The researchers concluded that sustained smoking cessation is associated with increased blood levels of CC10. "This is good news for former smokers," said Chen. "It provides more evidence that quitting smoking can undo some of the damage to the lung resulting from tobacco exposure."

The researchers' next step may be to look at CC10 levels in a larger population of smokers and former smokers without bronchial dysplasia. Eventually, they would like to find out whether this marker could be useful in predicting cancer risk or the outcome of chemopreventive treatment, Chen said.

Aggregation of Cancer Among Relatives of Never Smoking Lung Cancer Patients: Abstract No. 436

First-degree relatives of lung cancer patients who have never smoked are at an increased risk of cancer and are also more likely to be diagnosed with lung cancer, especially at an early age, than first-degree relatives of healthy never-smokers, according to this large study.

"The findings suggest that genetic factors play an important role in lung cancer among never-smokers," said Olga Gorlova, Ph.D., assistant professor in the Department of Epidemiology at The M.D. Anderson Cancer Center in Houston and lead author of the study.

The researchers compared the number of cancers among first-degree relatives--parents, children, and siblings--of 316 never-smoking lung cancer patients and 318 never-smokers who were healthy. Patients and controls were matched for age, gender, and ethnicity. There were 2,465 first-degree relatives of the patients with lung cancer and 2,441 first-degree relatives of the control group. The median age of cases and controls was about 61 years; two thirds were women and about 80 percent were Caucasian.

The researchers found that the relatives of the lung cancer patients had a 25 percent increased risk of cancer compared to the controls. Offspring had a two-fold higher risk. Mothers of patients had more than double the risk of breast cancer compared to mothers of controls.

The risk of developing cancer at a young age was higher among relatives of never-smoking lung cancer patients. Compared to relatives of controls, their risk of developing lung cancer before age 50 was six times higher, and their risk of any sort of cancer before age 50 was 44 percent higher.

Among the non-smoking relatives of the lung cancer patients the average age of diagnosis of lung cancer was 60.6 years compared to 74.2 years for the non-smoking controls. Among smoking relatives of the patients, there was a nearly 70 percent (1.68) higher risk of lung cancer compared to control relatives.

Gorlova noted that the findings could be useful in counseling family members of people who never smoked and have lung cancer. "Relatives could be aggressively advised to stop smoking or, if lung cancer screening is recommended at some point in the future, this is a high-risk group that could be considered for regular screening," she said.

The researchers are planning to follow up on this study by investigating genetic factors that appear to underlie the increased cancer incidence in these families.

Cigarette Smoking and Risk of Ovarian Cancer in Scandinavian Women: Abstract No. 4557

Women who smoke or have smoked in the past are at an increased risk of ovarian cancer, according to a large study that has followed more than 100,000 women for over a decade. Up to now, most studies have not shown an association between smoking and ovarian cancer.

"Our study shows consistent results for the association between both current and former smoking and the risk of invasive or borderline ovarian cancer, including different histological subtypes of ovarian cancer," said Inger T. Gram, M.D., Ph.D., a professor in the Department of Preventive Medicine at the University of Tromsø in Norway and lead author of the study.

The researchers followed more than 100,000 women, who were between 30 and 50 years of age in 1991 and 1992 when they enrolled in the Norwegian-Swedish Cohort Study. A mailed questionnaire completed at the beginning of the study collected data on age at smoking initiation, duration, and number of cigarettes smoked daily. National cancer registries were used to identify members of the cohort who developed ovarian cancer.

By the end of 2003, a total of 312 women had developed either invasive or borderline ovarian cancer. The researchers found that current smokers had a 60 percent (1.60) greater risk of ovarian cancer compared to those who had never smoked at the time of entry into the study. Former smokers had a 50 percent (1.48) higher risk than those who had never smoked. This was after taking into account other possible risk factors, such as age, number of children, menopausal status, oral contraceptive use, and hormone therapy use.

Gram noted that 28 percent of the women were current smokers at study entry. Those who had been smoking for more than 25 years and still were smoking had twice (2.0) the risk of ovarian cancer compared with never smokers.

Plans to follow up on these findings include a study in 300,000 Norwegian women that will look at the associations between smoking and various kinds of cancer, including ovarian cancer.

Given the rising number of women who are beginning to smoke in many countries and the high mortality for ovarian cancers, the findings give teenage girls and adult women yet another reason to avoid smoking or to quit, said Gram.

Second-Hand Smoke Exposure and Survival in Early-Stage, Non-Small Cell Lung Cancer Patients: Abstract No. LB-345

Lung cancer patients who have been exposed to high levels of second-hand smoke do not live as long, on the average, as those with low levels of exposure.

"We know that second-hand smoking increases the risk of lung cancer and studies have suggested that it is associated with lung cancer mortality," said lead author Wei Zhou, M.D, Ph.D., a Research Scientist at the Harvard School of Public Health in Boston. "But this is the first study to show that second-hand smoking also is associated with lung cancer survival."

The study included 393 patients with early-stage, non-small cell lung cancer (stages IA - IIB) at the Massachusetts General Hospital. All had their tumors removed surgically, and most had not had any additional therapy. Their median age was 69.

The researchers, led by David C. Christiani, M.D., a professor at Harvard School of Public Health and Harvard Medical School, collected information on the patients' exposure to second-hand smoke at three different places - work, home, and leisure-time locations, such as restaurants. The questionnaire, administered by an interviewer, collected data on the length of exposure at each location over each patient's lifetime, before the diagnosis of lung cancer.

Total exposure times were then divided into four quartiles. Patients in the highest quartile had more than 48 years of exposure (the average among the three locations). Those in the lowest quartile had fewer than 28 years' exposure on average.

After a median of 66 months follow-up from the time of their diagnosis, patients with the least second-hand smoke exposure had the highest survival rates. Moreover, the overall five-year survival rate decreased with increasing exposure: 71 percent of patients with the lowest exposures were alive after five years compared to 61 percent in the next highest quartile, and 49 percent in the third highest. In the highest quartile - those with the highest exposure to second-hand smoke - just 47 percent survived five years.

The association with survival was strong even after accounting for age, gender, stage of cancer, and the patients' own cigarette smoking over their lifetimes.

Workplace exposure appeared to be the most important factor. Total exposure in the workplace was greater than 42 years for those in the highest exposure group and less than 7 years in the lowest exposure group. The association with both overall survival and relapse-free survival was statistically significant for workplace exposure. The study also showed an association between home and leisure second-hand smoke exposure, but it was not statistically significant.

"The reason for the strong association with workplace exposure may be due both to the length of time people spend at work and the higher levels of smoke they could be exposed to there," said Zhou.

The researchers now plan to look at survival differences among lung cancer patients who are exposed to second-hand smoke after their diagnosis and at the genetic factors associated with second-hand smoking, smoking, and survival, Zhou said.

###

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 60 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts over 16,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

Warren R. Froelich
froelichaacr
American Association for Cancer Research