Breast Cancer Gene May Carry Less Risk Than Thought

By Merritt McKinney

NEW YORK Aug 20, 2002 (Reuters Health) - For women who carry genetic mutations that have been linked to an increased risk of breast cancer, the risk may not be as high as first thought, a new report suggests.

While this may sound like good news to women who carry the BRCA1 or BRCA2 mutations, which have been linked to a 71% to 85% lifetime risk of breast cancer, determining an individual woman"s risk remains difficult, according to Dr. Colin B. Begg of Memorial Sloan-Kettering Cancer Center in New York.

BRCA1 and BRCA2 mutations, which occur in about 1 out of every 40 women of Ashkenazi Jewish descent, have been linked to an increased lifetime risk of both breast and ovarian cancers.

The connection between these mutations and cancer risk is not in doubt. But, according to Begg, studies that have tried to predict women"s lifetime risk of cancer have often failed to take into account the effects of other risk factors besides the BRCA1 and BRCA2 mutations.

"The notion that the presence of a...BRCA1 or BRCA2 mutation in a woman completely defines her risk for breast cancer is probably far from the truth, and, in fact, numerous unknown genetic risk modifiers are likely to exist," Begg writes in a report in the August 21st issue of the Journal of the National Cancer Institute.

Begg points out that the first studies to estimate breast cancer risk among BRCA1 and BRCA2 carriers focused on families in which multiple cases of breast cancer had occurred. These studies led to very high lifetime risks of breast cancer. In later studies, rather than starting with families with multiple cases of cancer, researchers identified women with breast cancer and then examined the frequency of breast cancer among their relatives. This approach led to lower, but still high, lifetime risks of breast cancer.

A problem with these approaches, Begg asserts, is that they fail to take into account the influence of other risk factors on the lifetime risk of breast cancer. Among women with BRCA mutations, those who develop cancer are likely to have more unidentified risk factors than those who do not develop the disease, according to the researcher.

Studies that compare women with BRCA mutations with a "control" group of women from the general population may be more accurate at estimating breast cancer risk, Begg suggests. He notes that other approaches "are a pragmatic strategy," but improvements need to be made to correct some of their statistical problems.

In comments to Reuters Health, Dr. Wylie Burke, of the University of Washington in Seattle, said that Begg raises an important point about the need to consider other risk factors.

"Even when a particular genetic change is a major contributor to a health problem, it is rarely the whole story," according to Burke, who co-authored an editorial accompanying the report.

Increasingly, researchers are identifying other factors that influence whether disease actually occurs, Burke said. "As we do so, we are likely to develop insights into new ways to prevent disease."

"For women with BRCA1 and BRCA2 mutations, Dr. Begg"s article indicates that the average risk associated with these mutations is likely to be lower than previously thought," Burke said.

"In other words," he added, "cancer is not inevitable."

But even though the cancer risk for these women may be lower than once believed, Burke noted that it is still much higher than in women who do not carry one of the mutations. "It is still prudent to consider carefully the preventive options available," he said.

Prophylactic mastectomy, in which both breasts are removed before cancer has a chance to develop, is one strategy that has been shown to cut the cancer risk of women with BRCA1 or BRCA2 mutations. The drug tamoxifen is a less invasive option, although the medication can cause side effects, such as an increased risk of potentially fatal blood clots, strokes and a certain type of uterine cancer.

SOURCE:

• Journal of the National Cancer Institute 2002;94:1185-1187, 1221-1226.