Study: Is breast cancer risk increased in women who test negative for the BRCA mutation in their family?

IN DEPTH REVIEW OF RESEARCH

Study background:

Researchers have noted the development of breast cancer in women who do not carry their family’s BRCA mutation. Researchers studied whether these women may have increased risk for breast cancer, even though they do not share their family’s BRCA abnormality.

In December 2013, Gareth Evans and his colleagues from the University of Manchester and other institutions published an article that examined whether women who tested negative for a familial BRCA mutation were at increased risk for breast cancer. Published over two years ago, the study raised a still controversial question regarding appropriate care for women who test negative for a BRCA mutation but are from a BRCA-positive family, as this is still an area of uncertainty.

Researchers of this study wanted to know:

Whether a woman with a negative BRCA test result may have increased risk of breast cancer if she is from a family that carries a BRCA mutation.

Population(s) looked at in the study:

This study included only first-degree relatives (parent or sibling) of BRCA mutation carriers in 809 families (428 BRCA1 families and 381 BRCA2 families).

Study findings: 

1. Women who tested negative for their familial BRCA2 mutation developed breast cancer about 4.5 times more than expected for women of their age. Within this population, 14 breast cancers developed at the follow-up time, rather than the 3 that were expected.
   • This result was statistically significant, meaning that the result did not occur by chance, and was more likely to be a real finding.
2. Women who tested negative for their familial BRCA1 mutation developed breast cancer about 1.8 times more than expected for women of their age. Within this population, 7 breast cancers developed at the follow-up time, rather than the 4 that were expected.
   • This result was not statistically significant, meaning that it may have occurred by chance, and may not be a real finding. 

Limitations:

Women in this study who tested negative for BRCA may have been screened much more than women in the general population. Increased MRI or mammography could have resulted in more cancers being caught. Additionally, we have not identified and cannot always test for every gene that can affect cancer risk within families—abnormalities in other genes may influence risk in families with BRCA mutations. This study only looked at whether the women carried BRCA mutations; it did not consider whether they might have carried other genetic mutations that raise cancer risk. This is important, because if the BRCA-negative women who developed breast cancer carried mutations in other genes, their cancers could be attributed to those other mutations. Finally, this study was conducted through a cancer genetics clinic, a type of clinic that often sees families with very high cancer rates, which may have biased the results.

Conclusions:

The study authors wrote: “In the context of a family BRCA2 mutation, especially when there are multiple close relatives affected with early-onset breast cancer, specialists should advise that breast cancer risks may still be increased compared with the general population.” However, this is the result of only one study. Other work involving this issue has resulted in the exact opposite conclusion: that a woman with a BRCA-negative test result for her family mutation is not at higher risk for breast cancer. Currently, the NCCN has no clear guidelines regarding care for women in this population, and more work is needed to understand the cancer risk for women who do not carry their familial BRCA mutation. This underscores the importance of genetic counseling by a genetics expert to determine what screening is appropriate for each individual woman.