November 26. 2008 — Women with a significant family history of breast cancer, even if they are negative for the BRCA1 and BRAC2 mutations, remain at increased risk of developing the disease. Having 2 or more cases of breast cancer among close relatives younger than 50 years or 3 cases among close relatives of any age is associated with a risk for breast cancer that is 4 times greater than that seen in the general population.

The data, which were presented at the Seventh Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research, held in Washington, DC, show that women with a strong family history who lack BRCA1 and BRCA2 mutations are still much more at risk than average women.

"All women are at risk for breast cancer and about 10% will eventually develop the disease," said lead author Steven Narod, MD, who holds the Canada Research Chair in breast cancer at the University of Toronto and Women's College Research Institute, in Ontario. "We need to look at screening those who are at the highest risk. When the BRCA mutation was identified, it led to a genetic test."

Relatively few women carry mutations for BRCA1/2, but it increases the risk for breast cancer to 80%, Dr. Narod pointed out. "These women tend to have a family history or young onset, so they go and get tested . . . . About 1 in 5 of these women will be told that they carry a mutation. but what about the thousands who have a negative test and yet have a strong family history of breast cancer?"

To answer that question, Dr. Narod and colleagues conducted a prospective study in which they estimated risk for women with a family history of breast cancer who had tested negative for a BRCA1 or BRCA2 mutation. They identified 1492 women from 365 families who met the criteria of either having 2 or more breast cancers in members younger than 50 years or having 3 breast cancer in members of any age.

The researchers collected follow-up information on cancer status in all first-degree relatives of breast cancer cases. They calculated the standardized incidence ratios (SIRs) for breast cancer by dividing the observed number of breast cancers by the expected number, based on available rates in provincial cancer registries.

Risk of Disease is 4-Fold

The 1492 first-degree relatives of breast cancer cases contributed 9109 person-years of follow-up. Compared with control rates, the number of cancer cases was much higher among women with a strong family history. A total of 65 women developed breast cancer, although the expected number was 15.2 (SIR, 4.3). The highest relative risk was for women younger than 40 years, where the increased risk was nearly 15 times higher than the average risk (SIR, 14.9). The SIR decreased with advancing age, but the absolute risk was higher for women between 50 and 70 years (1% per year) than for those between the ages of 30 and 50 years (0.4% per year).

No elevated risk for ovarian or any other type of cancer was observed in this cohort.

The women with strong family histories had a 40% risk for breast cancer, and the findings suggest that other genetic mutations could play a role in the disease. Although these findings do not call for prophylactic surgery, Dr. Narod suggests that this population consider undergoing magnetic resonance imaging (MRI) screening. "The American Cancer Society recommends MRI for women with a 20% to 25% risk," he said. "It is much more sensitive than mammography."

Dr. Narod also points out that women with strong family histories might be candidates for tamoxifen chemoprevention. "We do need to confirm this in other studies, and we need to pinpoint what is putting these women at high risk."

These studies help us to identify patients at risk for cancer, commented Steven M. Dubinett, MD, director of the Lung Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center, in Los Angeles, California, and moderator of a press briefing in which these data were presented. "The utilization of genetic studies helps us move forward with defining risk in these populations."

American Association for Cancer Research's Seventh Annual International Conference on Frontiers in Cancer Prevention Research: Abstract B7. Presented November 17, 2008.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.