A population-based analysis of more than 3,000 families including women with breast cancer, published online October 31, 2011, in the Journal of Clinical Oncology, a tri-monthly peer-reviewed journal of the American Society of Clinical Oncology (ASCO), found that close relatives of women who carry mutations in a BRCA gene ? but who themselves do not have such genetic mutations – do not have an increased risk of developing breast cancer compared to relatives of women with breast cancer who do not have such mutations.

While these results support most previous evidence regarding risks for non-carriers of BRCA mutations, they run counter to a 2007 study that indicated first-degree relatives (mothers, sisters and daughters) of women with BRCA gene mutations are several times more likely than the general population to develop breast cancer ? despite not having the mutation themselves. The new findings suggest that women who test negative for the mutation may not need extra cancer screening and other increased preventive measures.

Incidence in non-carriers of family-specific mutations
?This new study gives reassurance to non-carriers that they do not have an increased risk due to the familial mutation, and should be regarded the same as other non-carriers with first-degree relatives who have had breast cancer,? said study first author Allison Kurian, MD, assistant professor of medicine and health research and policy at Stanford University School of Medicine. ?One strength of the current study is the control women it used as a yardstick for comparing the breast cancer incidence in non-carriers of family-specific mutations. The control women were also relatives of breast cancer patients, but of patients without mutations. This is a more appropriate yardstick than average risk in the general population, since close relatives of all breast cancer patients have somewhat higher than average risks.?

Considerably lower risk for breast cancer
.Women who inherit a mutation in the BRCA1 or BRCA2 gene carry a 5- to 20-fold higher risk of developing breast or ovarian cancers. First-degree relatives who have not inherited the same familial BRCA mutation have been considered to have a considerably lower risk for breast cancer.

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In 2007, a study of women who tested negative for a specific familial BRCA mutation showed they had a 2- to 5-fold increased risk of developing breast cancer; which could be considered comparable to the risk of having a BRCA mutation. According to Kurian, the results raised concerns that non-carriers might require similar screening and preventive measures as their mutation-carrying relatives, such as annual breast MRI and prophylactic surgery, and cast some doubt on the meaning of a negative BRCA test.

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Close relatives of breast cancer patients
Kurian said that the studies had looked at women who were in cancer family clinics and compared their breast cancer risk to that of women in the general population. Women from cancer family clinics were more likely to have intensive screening, and breast cancer risks tend to be higher among close relatives of breast cancer patients than those in the general population.

The investigators took a different approach in this research by studying women with breast cancer in 3,047 families in three population-based cancer registries in Northern California (1,214), Australia (799) and Canada (1,034) through a consortium called the Breast Cancer Family Registry. They found 292 families in which a woman had a BRCA mutation. This is the largest analysis to date of breast cancer risk of non-carriers of family-specific BRCA mutations.

No elevated risk
They compared the risk of breast cancer among first-degree relatives of breast cancer patients who did and did not carry a BRCA mutation and found no significant difference. This means that non-carriers of a familial BRCA mutation did not have a markedly elevated risk of developing breast cancer.

Different genetic variants
The investigators also found that a small percentage of women ? 3.4 percent of women in the general populations of Australia, Canada and the U.S. ? who are at highest risk for unexplained reasons (reasons other than a BRCA mutation) account for approximately 32% of all breast cancer cases, reflecting the wide range of factors that could play a role in breast cancer development. Recent research suggests that many different genetic variants affect breast cancer risk, and that the women at highest risk have inherited many of these variants.

?Earlier reports of higher risk among non-carriers of family-specific BRCA mutations compared to risks in the general population may reflect a comparison of women with and without a family history of breast cancer,? noted senior author Alice Whittemore, PhD, professor of epidemiology and biostatistics at Stanford University School of Medicine. ?The control group we used ? relatives of breast cancer patients in families without a BRCA mutation ? was important. The results suggest that women who test negative for their family?s BRCA mutation have no greater breast cancer risk than a woman who also has relatives with breast cancer but no family-specific mutation.?

American Society of Clinical Oncology
Commenting on the analysis, Andrew Seidman, MD, American Society of Clinical Oncology and breast cancer specialist noted that “Many patients and their physicians incorrectly apply the same standard for screening and risk-reducing intervention for mutation-negative, first degree relatives as for mutation positive individuals. This work underscores that the risk for developing breast cancer is considerably lower in women who do not carry a BRCA mutation. Raising awareness of these findings could serve the public well in dissuading some women from unwarranted and excessive screening and/or risk-reducing interventions.”

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