Are Carriers of BRCA Mutations Developing Cancer Earlier than Mothers/Aunts?

Jennifer Litton, MD

MD Anderson Cancer Center

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The identification of an association between mutations in BRCA 1/2 and hereditary breast and ovarian cancer has allowed many women to learn of their increased cancer risk at a young age and take measures to identify developing tumors early. According to Jennifer Litton, MD, assistant professor, Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, women positive for a deleterious eVmutation in one of the BRCA genes typically receive a breast cancer diagnosis 6 years earlier than did mothers or aunts with the mutation who had breast or ovarian cancer.

Dr Litton said the MD Anderson investigators first noticed this anecdotally in their practice and wondered whether the theory could be verified scientifically. They conducted a genetic screening study, which included 132 women with a BRCA mutation who developed breast cancer; these women were labeled “generation 2.” Of these patients, 107 had a family member in the preceding generation who suffered from BRCA-related breast or ovarian cancer, and these relatives were considered “generation 1.” Investigators recorded each patient’s age at diagnosis, location of mutation, and year of birth.

They calculated the median age at diagnosis for patients in each group, which was 42 years for generation 2 and 47 years for generation 1 (P <.001). In comparing members from both generations in the same family, the median difference between generation 1 and generation 2 at diagnosis was 6 years. Stratifying patients according to BRCA mutation, women in generation 2 who were BRCA1-positive were diagnosed at a median of 42 years of age compared with 43 years of age for generation 1. The difference was more pronounced in BRCA2-positive women, with those in the generation 2 group receiving a diagnosis at a median of age 44 years and those in the generation 1 group getting a diagnosis at a median of 50 years (P <.001).

Women with BRCA 1/2 mutations have nearly 5 times the risk of developing breast or ovarian cancer compared with women who lack a BRCA mutation. As a result, these women—particularly if they have a relative in the previous generation who had the mutation&mdash;are advised to start getting screened at age 25 years. Many women also choose to undergo prophylactic mastectomy or oophorectomy.

It is not clear whether improved screening schedules and techniques resulted in the earlier diagnosis for generation 2 or whether the cancers were occurring sooner in a patient’s lifetime. “These findings are certainly concerning and could have implications on the screening and genetic counseling of these women,” Dr Litton said. She questioned whether lifestyle and environmental factors might be contributing to earlier development of the BRCA 1/2-linked cancers.

The findings are limited by the small number of patients in the study and the possibility of recall bias on the part of the women in generation 2 who supplied the BRCA status of their generation 1 relative. Dr Litton said the research nevertheless supports the recommendation that women with a BRCA 1/2 mutation start getting screened for breast or ovarian cancer earlier than those without the mutation. Dr Litton suggested these women may need to get screened even earlier than the guidelines advised. She and her colleagues are conducting a follow-up study to determine whether biological factors account for the earlier age at diagnosis. Abstract No. 7.