"We don't know all the causes of breast cancer, and this study provides some insights into another pathway that could lead to the discovery of additional genes that might help explain the causes of hereditary breast cancer," says study co-author Ann S. Hamilton, Ph.D., assistant professor of preventive medicine at the Keck School and USC/Norris Comprehensive Cancer Center.
Hamilton and co-author Thomas M. Mack, M.D., M.P.H., professor of preventive medicine at the Keck School, conducted the study among 1,811 pairs of female twins, one or both of whom had breast cancer. Mack recruited both identical and fraternal twins for the study between 1980 and 1991.
Mack asked the twins a variety of questions about their history: age at first menstrual period, age when each twin had her first child, how many children they had, age at the beginning of menopause, and similar factors thought to be linked to breast cancer risk.
Among identical twins who both were diagnosed with breast cancer, one factor stood out: The twin who began menstruating earlier was more than five times as likely as the other twin to get breast cancer first. Women who started menstruating before age 12 were especially susceptible to getting breast cancer first within the pair.
"We think these concordant twins are the most likely to have heritable disease," Mack says.
In contrast, later first pregnancy, lower number of childbirths and later age at menopause were associated with breast cancer only among pairs of identical and fraternal twins in which one twin had breast cancer, but not among those in which both twins had the disease.
Epidemiologic studies show that reproductive factors such as later age at menopause are linked to a greater risk of breast cancer. Experts have suspected that risk increases the more a woman is exposed to estrogens during her life.
"But we think these results should lead scientists to consider another pathway that might lead to breast cancer, related to women with a genetic susceptibility," Hamilton says. "All breast cancer might not be due to hormone exposure over a lifetime."
In the view of Mack and Hamilton, a girl's changes during adolescence may do more than just alter her silhouette and usher in her fertility. In some genetically susceptible women, ovarian hormones that surge through the body at puberty might tweak breast cells when they are still immature and vulnerable. This damage may not manifest itself as cancer until four or five decades later.
The researchers suspect that genes responsible for fixing damaged DNA might not work as well in these women as they should. Perhaps a genetic error makes cells more sensitive to hormones. "There are some candidate genes," Mack says, "but we really have no idea yet which ones are the right ones."
Hamilton and Mack say the study provides a starting point for trying to identify the genes at fault. The researchers plan to study genetic factors in these twin pairs.
Unfortunately, Mack says, the typical age for first menstruation for an American girl has been dropping, "and if it hasn't stabilized, there will be people with a genetic susceptibility who will be more likely to get breast cancer. But if we can identify the mechanism at play, then perhaps we can intervene."
Ann S. Hamilton and Thomas M. Mack, "Puberty and Genetic Susceptibility to Breast Cancer: A Case-Control Study in Twins," New England Journal of Medicine. Vol. 348, No. 23, pp. 2313-2322.
Journal
New England Journal of Medicine