WOMEN FROM FAMILIES WITH BRCA2+ WHO TEST NEGATIVE ARE STILL AT HIGHER RISK FOR BREAST CANCER

Women who are members of families withBRCA2 mutations but who test negative for the family-specific BRCA2 mutations are still at greater risk for developing breast cancer compared with women in the general population, according to a study by Evans et al published in Cancer Epidemiology, Biomarkers & Prevention.

Women with certain mutations in theirBRCA1 or BRCA2 genes are at increased risk for breast cancer. However, if a woman who comes from a BRCA family tests negative for her family-specific BRCAmutation, her risk for breast cancer is considered to be the same as someone in the general population, according to the National Cancer Institute. This study, however, suggests that it may not always be true.

Increased Risk Confined to BRCA2 Families

“We found that women who test negative for family-specific BRCA2mutations have more than four times the risk for developing breast cancer than the general population,” said Gareth R. Evans, MBBS, MD, MRCP, FRCP, Honorary Professor of Medical Genetics and Cancer Epidemiology at the Manchester Academic Health Science Center at the University of Manchester in the United Kingdom. “We also found that any increased risk for breast cancer is largely limited to BRCA2 families with strong family history and other genetic factors.

“It is likely that these women inherit genetic factors other than BRCA-related genes that increase their breast cancer risk,” he explained. “About 77 single nucleotide polymorphisms [SNPs] are linked to breast cancer risk. Identification of additional SNPs is necessary to understand why some of theBRCA-negative women from BRCA families are at higher risk.”

The authors note that specialists should use caution when stating that a woman’s breast cancer risk is the same as that of the general population following a negative test, because it may not be true for some women who come from BRCA2 families with a strong family history.

Study Details

Dr. Evans and colleagues used data from the M6-Inherited Cancer in England study, which has screened families of individuals with breast and/or ovarian cancer for mutations in BRCA1 and 2 since 1996. Details on affected individuals, and all tested and untested relatives, were entered into a Filemaker Pro-7 database. From 807 BRCA families, the researchers identified 49 women who tested negative for the family-specific BRCA mutation, but subsequently developed breast cancer. The researchers called these women “phenocopies.”

Of the 49 phenocopies identified, 22 were among 279 women who tested negative from BRCA1families, and 27 were among 251 women who tested negative from BRCA2 families. When the researchers stratified the phenocopies based on their age (30–39, 40–49, 50–59, and 69–80), they found that in each age range there were about twice as many cases of breast cancer as would have been expected from the general population.

Next, to conduct risk analyses, the researchers calculated the observed vs expected ratio, a ratio of observed risk for breast cancer in BRCA-negative women from BRCA families vs the risk expected for any woman in the general population.

They found the observed vs expected ratio for phenocopies from BRCA1 families was not substantially higher than that of the general population; however, the observed vs expected ratio for phenocopies from BRCA2 families was 4.57, leading them to conclude that the more than fourfold increased risk for breast cancer among BRCA-negative women is largely limited to BRCA-negative women from BRCA2 families.

When the researchers considered the date of predictive testing instead of the date of family ascertainment, the observed vs expected ratio dropped from 4.57 to 2.01, “because there is less follow-up in the predictive test group from time of testing and we may be unaware of breast cancers that have occurred in the near past,” explained Dr. Evans.

Dr. Evans is corresponding author of the article in Cancer Epidemiology, Biomarkers & Prevention.

This study was funded by the National Institute for Health Research. The study authors reported no potential conflicts of interest.