N° 125
June 1998 

Smoking Cuts Breast Cancer Risk In Small Fraction of Women with Mutated Gene.
Scientists Do Not Advocate Smoking, as Risks Outweigh Advantages.

Smoking cuts the risk of developing breast cancer by 50 percent in a tiny fraction of women who carry a genetic pre-disposition for the disease, says a new study published in the Journal of the National Cancer Institute (JNCI).

Only one out of every 250 women has one of the inherited mutated genes, BRCA1 or BRCA2, whose normal function is not yet fully understood. However, 80 percent of women with one of the mutated genes will get breast cancer before the age of 70.

"The protection associated with smoking increased with the amount smoked (among women with the mutated gene)," says the JNCI article, co-authored by all scientists participating in the study. "The risk reduction associated with up to four pack-years (one pack-year equals one pack per day for one year) of smoking was 35 percent, and for greater than four pack-years of smoking was 54 percent."

"This study should not cause women to take up smoking or continue the smoking habit, because the adverse health effects of tobacco are overwhelming," says Paul Kleihues, MD, Director of the International Agency for Research on Cancer (IARC), part of the World Health Organization, which participated in the study. "In the United States and in some European countries, as many women die from smoking-induced lung cancer as from breast cancer."

Scientists believe that smoking influences the metabolism of estrogen, a female sex hormone assumed to be involved in the development of breast cancer. The reduction in breast cancer risk by smokers with the mutated gene may be associated with reduced levels of circulating estrogens.

" We believe our data provide evidence of a protective effect of smoking against breast cancer in BRCA1 and BRCA2 carriers, " the article says. " The magnitude of the risk reduction was large and the possibility that this finding was due to chance is remote."

"Our research may lead to the development of medication that reduces breast cancer risk, without any of the many drawbacks of smoking, first for women with the genetic disposition, and perhaps later for all women," says Steven Narod, MD, Chair of Breast Cancer Research at the Centre for Research in Women's Health, Women's College Hospital, Toronto, who coordinated the study.

Breast cancer is the most frequent cancer striking women worldwide. In Western countries, one woman in nine is likely to suffer from the disease. The mutated gene leads to just two percent of all breast cancer cases, however. A variety of risk factors has been identified as influencing the development of breast cancer, including dietary habits, reproductive lifestyle and radiation.

"The findings have to be confirmed in other investigations, " says Dr Kleihues. "The study, however, can lead to a better understanding of how some cancers are formed, and how they can be prevented.

Previous studies have found that smokers are also at a decreased risk of endometrial cancer, another hormone-dependent cancer. But other studies show that women who smoke run a much higher risk for lung cancer.

In the study, entitled "The Effect of Smoking on Breast Cancer in BRCA1 and BRCA2 Carriers", scientists compared 186 women in the United States and Canada who carried one of the mutated genes and who had developed breast cancer with 186 women of the same age who also had the mutated gene, but who had not developed breast cancer -- which is called a "matched case-control study."

Researchers compiled information about the lifetime smoking history of each of the 186 cases in the study from a questionnaire, which was then compared with their 186 age matched healthy controls.

To determine lifetime cigarette exposure, researchers multiplied the duration of smoking by the average daily cigarette consumption reported for the period, using a standardized measure called pack-years. One pack-year equals one package of cigarettes smoked per day for one year.

The average age of diagnosis of breast cancer in the cases participating in the study was 39.6 years. The mean current age for the cases was 49.7 years at the time they took part in the study. The controls had the same mean current age of 49.7.

"Smoking has not been found to be a risk factor for breast cancer in women in the general population, " says Gilbert Lenoir, DVM, of the IARC. Dr Lenoir coordinated one of the centers performing the direct sequencing of DNA of participants, which confirmed the mutation detection initially performed by a range of techniques to discover women with the mutated genes.

The study was supported by the U. S. National Institutes of Health, the Canadian Breast Cancer Research Initiative, the U. S. Department of the Army, the Canadian Genetics Diseases Network, the Canadian Breast Cancer Foundation (Ontario Chapter), the Fonds de la Recherche en Santé du Québec, and the Women's Cancer Program of the Dana Farber Cancer Institute. The article was published in the May issue of the Journal of the National Cancer Institute.

Because it is possible that the observed effect of smoking could be attributed to the effect of other factors, a "multivariate matched analysis " was performed. Cases and controls were matched to be born within one year of each other. Researchers determined the odds ratio for developing breast cancer for smokers versus non-smokers, using "conditional logistic regression" for matched sets, after adjustment for other known risk factors. Conditional logistic regression is a statistical method of adjusting for other potential factors such as age, reproductive factors, geography. When the adjustment was made, researchers still got the same answer -- the risk of breast cancer in smokers remained roughly one-half of that of non-smokers. No other variable was as important as smoking in predicting breast cancer risk.

Hereditary breast cancer is primarily a disease of pre-menopausal women, and interactions between genes, hormonal and environmental risk factors may be particularly important to these people. The age-specific incidence of breast cancer in BRCA1 carriers peaks at about age 45, in contrast to non-carriers, for whom the risk continues to rise after menopause. It is possible that this pattern of onset is explained by an interaction between ovarian hormones and genetic predisposition.

Released from Washington, D.C. (USA) - For further information, please contact:
Marshall Hoffman at +1 (703) 820-2244 (bus.) - +1 (703) 533-8482 (home)
Paul Kleihues, M.D., Director of the International Agency for Research on Cancer, and
Dr Gilbert Lenoir, will be available for phone interviews. Please call +1 (703) 820-2244.

World Health Organization
International Agency for Research on Cancer

Organisation mondiale de la Santé
Centre international de Recherche sur le Cancer

150, cours Albert-Thomas 69372 Lyon Cedex 08 (France)
Telephone: 33 472 738 485     Facsimile: 33 472 738 311