According to popular wisdom, the lifetime risk of developing breast cancer among women with a BRCA gene mutation is as high as 70%. This is compared to a lifetime risk of around 8% in the general population.

When researchers study breast cancer risk associated with BRCA gene mutations, they often study families in which multiple women developed breast cancer. Another method is to identify women with breast cancer and then study their relatives to determine how many have a BRCA mutation and how many developed breast cancer. But these methods may tend to exaggerate the risk of breast cancer among women with BRCA gene mutations for two reasons. First, BRCA mutation carriers who develop breast cancer generally have other risk factors in addition to their gene mutation. Second, women in families with high breast cancer incidence may have other family-related factors that increase their risk of breast cancer, such as shared environmental exposures common to all family members or hereditary factors other than BRCA mutation.

Research published in the August 21, 2002 issue of the Journal of the National Cancer Institute suggests that current research designs mistakenly attribute all breast cancer risk in a carrier to the gene mutation. Such a flaw in study design may inflate estimates of a BRCA mutation carrier’s risk of breast cancer.

About the study

Colin Begg, PhD, a researcher at Memorial Sloan-Kettering Cancer Center in New York, reviewed eight studies of breast cancer risk associated with BRCA gene mutation. All of these studies were designed to estimate the penetrance of breast cancer among BRCA mutation carriers. Penetrance is the lifetime risk of developing a disease among carriers of a given genetic mutation.

Dr. Begg looked at whether the studies included only BRCA mutation carriers who developed breast cancer (called case probands) or if they also included BRCA mutation carriers who did not develop breast cancer (called control probands). A proband is a person who brings a family under study, either because he or she has developed a disease or because he or she has a genetic predisposition for a disease. Dr. Begg compared the penetrance estimates of studies that used only case probands with the penetrance estimates of studies that used control probands as well.

The findings

Only two of eight studies included control probands. One yielded a lower estimate of penetrance than the studies that used only case probands. The other, which actually yielded a higher estimate of penetrance, included women at higher risk of breast cancer irrespective of their BRCA mutation status.

These findings seem to support the hypothesis of Dr. Begg and others that including BRCA mutation carriers who don’t develop breast cancer lowers penetrance estimates and provides more accurate estimates of risk.

In addition, the penetrance estimates from all but one study suggest that BRCA2 mutation has a lower penetrance than BRCA1 mutation.

Although these results suggest that many current estimates of breast cancer penetrance among BRCA mutation carriers may be inflated, this study has its limitations. The researcher reviewed and analyzed data from many studies in an attempt to test his hypothesis that exclusion of control probands drives up penetrance estimates. Because studies are designed differently, this method of comparing the findings of several studies lacks precision, though it is useful for drawing general conclusions and identifying a need for new research methods.

How does this affect you?

These findings suggest that women with a BRCA mutation may not be as likely to develop breast cancer as was once believed. Many studies used to estimate the likelihood of BRCA mutation carriers developing breast cancer did not account for other breast cancer risk factors that may be common to members of a given family. More research involving BRCA mutation carriers who did not develop breast cancer is needed to more accurately assess the penetrance of breast cancer among BRCA mutation carriers. Results of this research ought to provide BRCA mutation carriers and their families with better information on which to base their decisions regarding prevention of breast cancer.