Cancer Risk High For Relatives of Women with BRCA Mutations

November 6, 2006

MANCHESTER, England -- If they don't have a BRCA breast-cancer susceptibility gene mutation themselves, female relatives of women who do have one have been considered at low risk. But now this conventional wisdom is being doubted.

MANCHESTER, England, Nov. 6 -- If they don't have a BRCA breast-cancer susceptibility gene mutation themselves, female relatives of women who do have one have been considered at low risk.

But now this conventional wisdom is being doubted, according to Gareth Evans, M.D., of St. Mary's Hospital here.

In fact, such women appear to face a substantially higher risk of breast or ovarian cancer than the general population and should get continued surveillance, rather than simply being re-assured, Dr. Evans and colleagues reported in the online issue of the Journal of Medical Genetics.

So-called "phenocopies" -- people who are affected by a mutation-caused disease, although they do not have the mutation -- "pose an important clinical problem for the optimum management of families with familial breast cancer," Dr. Evans and colleagues said.

In particular, such women should get increased screening for breast cancer from the age of about 35 or 40, they said.

The researchers retrospectively examined a database of women tested since 1996 in the north of England and identified 165 families with the pathogenic BRCA1 mutation and 112 with the BRCA2 mutation.

Of the index cases, 190 had breast cancer, 48 had ovarian cancer, 33 had both, and six were unaffected, although they had a mutated BRCA1 or BRCA2 gene.

Among the 531 living female relatives who were tested, 258 (or 49%) did not have the family mutation, although 28 had breast cancer and four had ovarian cancer. Conversely, when living affected female relatives were tested, 28 of 118 (or 24%) were negative for a mutation.

Compared with the expected number of cases in the general population, women in these families who tested negative for the family mutation still faced an elevated risk of cancer, Dr. Evans and colleagues found. Specifically:

  • For all relatives who tested negative, breast cancer was seen in 28 of 258, while the expected number of cases was 5.3, for a relative risk of 5.3 (with a 95% confidence interval from 3.5 to 7.7).
  • When the analysis was confined to first-degree relatives, the risk was 5 (with a 95% confidence interval from 2.9 to 7.8).
  • Similar risk elevations were seen for ovarian cancer.

First-degree relatives of a known BRCA1 or BRCA2 carrier who tested negative for the family mutation, the researchers found, had a cumulative risk of breast cancer of 6.5% by the age of 50.

The comparable figure for the general population is 2%, Dr. Evans and colleagues reported so that the relative risk for the first-degree relatives was 3.2.

"If confirmed, these findings have serious implications for the management of these people," the researchers said, adding a prospective study is needed to "inform decisions about ongoing surveillance."

One other implication, they said, is that if a woman has either breast or ovarian cancer and a family history of the diseases, but no BRCA1 or BRCA2 mutation, physicians should suspect she is a phenocopy.

Further information on the family should be sought, the researchers said, including mutation testing on other members.