For Women With BRCA Mutations, Who Is Most at Risk of Breast and Ovarian Cancer?


A recent study has shown that the cancer risks for women with BRCA1 and BRCA2 mutations depend on the extent of the woman’s family history of cancer and the position of the specific fault within the gene.

Antonis Antoniou, PhD

Antonis Antoniou, PhD

Antonis Antoniou, PhD

The extent to which having a BRCA1 or BRCA2 mutation increases a woman's lifetime risk of developing breast and ovarian cancer has been lacking in the research, but a recent study published in the Journal of the American Medical Association is shedding more light on the subject by estimating the age at which these women are most at risk.

Researchers from Europe, Australia, and the United States analyzed 6036 BRCA1 and 3820 BRCA2 carriers. Of those, 5046 women did not have cancer, whereas 4810 women had breast, ovarian cancer, or both. Women were recruited from 1997 through 2011 from the United Kingdom, the Netherlands, and France and followed through December 2013.

“This large prospective cohort of women with BRCA1 and BRCA2 mutations has enabled us to obtain the most precise estimates of age-specific breast and ovarian cancer risks to date,” study author Antonis Antoniou, PhD, explained in an interview. “These should provide more confidence in the counselling and clinical management of women with faults in the BRCA1 and BRCA2 genes.” Antoniou is a research fellow with the Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, at the University of Cambridge.

During a median follow-up of 5 years, 426 women were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer. Researchers found that the cumulative breast cancer risk to age 80 for BRCA1 was 72% (95% CI, 65%-79%) and 69% for BRCA2 (95% CI, 61%-77%). In addition, researchers reported a rapid increase in breast cancer cases among women with BRCA1 in early adulthood up to the age of 30 to 40 years and until age 40 to 50 years for women harboring the BRCA2 mutation. For women with either mutation, the incidence of breast cancer then remained steady at 20 to 30 cases per 1000 years until age 80.

The number of relatives diagnosed with the disease affected breast cancer risk for women with either mutation. The hazard ratio [HR] for ≥2 first- or second-degree relatives versus no affected relatives was 1.99 (95% CI, 1.41-2.82; P <.001 for trend) in women with the BRCA1 mutation and for those with BRCA2, (HR, 1.91; 95% CI, 1.08-3.37; P = .02 for trend). Breast cancer risk also varied by whether the mutation was located outside versus within specific positions in the BRCA1 and BRCA2 genes.

For ovarian cancer, researchers discovered that women with BRCA1 had a 44% cumulative risk to age 80 years (95% CI, 36%-53%) and 17% for those with BRCA2 (95% CI, 11%-25%).

The cumulative risk of contralateral breast cancer 20 years after a breast cancer diagnosis was 40% for BRCA1 carriers (95% CI, 35%-45%) and 26% for BRCA2 (95% CI, 20%-33%).

“The results show clearly, and for the first time in a prospective study, that the cancer risks for women with BRCA1 and BRCA2 mutations depend on the extent of the woman’s family history of cancer and the position of the specific fault within the gene,” Antoniou said. “Therefore, the mutation location can now be confidently incorporated in the risk assessment of women with BRCA1 and BRCA2 mutations.”

Although genetic testing for such mutations seems like the logical next step for women who are unsure if they carry the genes, the debate continues over who needs to be tested.

“There are ongoing studies that are aiming to assess the benefits and harms of such population-based screening approaches,” said Antoniou. “The cancer risk estimates from our study will provide critical information for these studies. For example, our results show that women without family history of cancer are likely to be at lower breast cancer risk than women with strong cancer family history. These differences would need to be factored in when considering offering BRCA1 and BRCA2 mutation screening to all women.”

To further investigate the BRCA-related cancer risk, Antoniou and his colleagues will be examining how other factors play a role, such as use of oral contraceptive pills, hormone replacement therapy, pregnancy, and lifestyle factors like alcohol consumption.

“We will then be able to combine all the findings to provide more personalized information on the age-specific cancer risks, and help women decide on the timing and on the options to use to reduce their risk of cancer,” he said.

Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416. doi: 10.1001/jama.2017.7112

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