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Researchers define cancer risk in BRCA1/BRCA2 carriers

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June 20, 2017

Women with BRCA1 mutations were more likely to develop breast cancer, ovarian cancer and contralateral breast cancer, and at earlier ages, than with women with BRCA2 mutations, according to a large investigative analysis published in JAMA.

Additional risk variables included family history of breast cancer and mutation location, researchers reported.

Mary B. Daly
Antonis C. Antoniou

“This is a large prospective study whose main goal was to estimate age-specific risks for breast, ovarian and contralateral breast cancers among BRCA1 and BRCA2 mutation carriers,” Mary B. Daly, MD, PhD, department of clinical genetics at Fox Chase Cancer Center and member of the BRCA1 and BRCA2 Cohort Consortium that conducted the study, told HemOnc Today. “It has the advantage of a large sample size and long follow-up.”

Researchers analyzed data from 6,036 women with BRCA1 mutations and 3,820 women with BRCA2 mutations from 1997 through 2011 recruited from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON) and France (GENEPSO). At baseline, 4,810 women had breast and/or ovarian cancer and 5,046 did not.

Annualized incidence and cumulative risks for breast, ovarian and contralateral breast cancer served as the main outcomes.

“Most studies to date that estimated cancer risks for BRCA1 and BRCA2 mutation carriers have been retrospective, and estimates from such studies are prone to biases,” Antonis C. Antoniou, PhD, reader in cancer risk prevention at Center for Genetic Cancer Epidemiology at University of Cambridge, told HemOnc Today. “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.”

Median follow-up was 5 years.

Among 3,886 women eligible for breast cancer analysis (median age, 38 years), 426 (11%) received a breast cancer diagnosis during follow-up. Of 5,066 women eligible for ovarian cancer analysis (median age, 38 years), 109 (2%) were diagnosed with ovarian cancer. Lastly, of 2,213 women eligible for contralateral breast cancer analysis (median age, 47 years), 245 (12%) were diagnosed with contralateral breast cancer.

Breast cancer

Previous retrospective studies reported breast cancer incidence estimates of 40% to 87% in BRCA1 carriers and 27% to 84% in BRCA2 carriers.

In the current study, cumulative risk estimates for breast cancer by age 80 years were 72% (95% CI, 65-79) for BRCA1 carriers and 69% (95% CI, 61-77) for BRCA2 carriers. Although risk to age 80 years appeared similar, researchers noted the cumulative risks to age 50 years were higher for BRCA1 carriers (P = .03).

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Breast cancer incidence increased rapidly in early adulthood in BRCA1 carriers until ages 30 to 40 years (age 21-30 years, 5.9 incidences per 1,000 women; age 31-40 years, 23.5; age 41-50 years, 28.3; age 51-60 years, 25.7) and in BRCA2 carriers through age 40 to 50 years (21-30 years, 4.8; 21-40 years, 10.8; 41-50 years, 27.5; 51-60 years, 30.6). After those ages, incidence remained a similar, steady rate — 20 to 30 cases per 1,000 person-years — until age 80 years.

“A novel finding in this study is that breast cancer risk for women with faults in BRCA1 and BRCA2 increases rapidly at a young age, then remains at a constant high level for the rest of their lives,” Antoniou said. “It peaks in women in their 40s for BRCA1 mutation carriers and in women in their 50s for BRCA2 carriers, but carriers of mutations in both genes are at about the same high risk in later life. This is important information to inform clinical management.”

Regarding contralateral breast cancer, researchers estimated the cumulative risk 20 years after original breast cancer diagnosis at 40% (95% CI, 35-45) for BRCA1 carriers and 26% (95% CI, 20-33) for BRCA2 carriers (HR for BRCA2 vs. BRCA1 = 0.62; 95% CI, 0.47-0.82).

Women had less of a chance of contralateral breast cancer when initial diagnosis occurred at age 40 to 50 years (BRCA1, HR = 0.81; 95% CI, 0.58-1.12; BRCA2, HR = 0.73; 95% CI, 0.41-1.26) or at age 50 and older (BRCA1, HR = 0.71; 95% CI, 0.45-1.11; BRCA2, HR = 0.76; 95% CI, 0.43-1.26) compared with women diagnosed before age 40 years.

Ovarian cancer

Previous studies estimated ovarian cancer risk at 16% to 68% for BRCA1 carriers and 11% to 30% in BRCA2 carriers. In the current analysis, the cumulative risk to age 80 was 44% (95% CI, 36-53) in BRCA1 carriers compared with 17% (95% CI, 11-25) in BRCA2 carriers.

An increase in ovarian cancer incidence occurred with age up to age 61 to 70 years.

Women with BRCA1 mutations had greater rates of ovarian cancer between 51 to 60 years (13.8 per 1,000) and 61-70 years (29.4 per 1,000) compared with BRCA2 carriers (51-60 years, 6.5 per 1,000; 61-70 years, 10.3 per 1,000; HR for BRCA1 vs. BRCA2 = 3.6; 95% CI, 2.2-5.9).

Family history

Breast cancer risk estimates for both BRCA1 and BRCA2 carriers increased with the number of first- and second-degree relatives previously diagnosed with breast cancer. Researchers estimated that compared with women with no family history of breast cancer, women with two or more first- or second-degree relatives diagnosed with breast cancer had had an increased risk for breast cancer in BRCA1 carriers (HR = 1.99; 95% CI, 1.41-2.82) carriers and BRCA2 carriers (HR = 1.91; 95% CI, 1.08-3.37).

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There was no significant difference in ovarian cancer risk for BRCA1 and BRCA2 carriers with a family history of ovarian cancer.

“Although women with mutations are on average at high risk for developing breast and ovarian cancer, these risks are not necessarily applicable to all women found to carry faults in BRCA1 and BRCA2,” Antoniou said. “Using a robust epidemiological study design, we have shown that there are likely to be other factors that modify cancer risks for these women.”

Mutation location

Researchers reported mutations located outside the region bounded by positions c.2282 to c.4071 in BRCA1 (HR = 1.46; 95% CI, 1.11-1.93) and c.2831 to c.6401 in BRCA2 (HR = 1.7; 95% CI, 1.18-2.46) were associated with a significantly higher risk for breast cancer compared with mutations within the regions.

Mutation location had no significant association with ovarian cancer risk.

“Information on both family history of cancer and mutation position should be considered when performing cancer risk assessment,” Antoniou said. “The results may have practical implications on clinical management decisions taken by women with BRCA1 and BRCA2 mutations. For example, decisions on risk-reducing surgery tend to be taken around childbearing age, but some women with lower risks may choose to delay surgery until they complete their families.”

The findings are similar to those reported in other smaller studies, Daly noted, adding that the information gathered from the study is useful in the clinical setting when counseling women about the options and timing of prophylactic surgery options.

“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 both on the position of the specific fault within the gene and the extent of the woman’ family history of cancer,” Antoniou said. – by Chuck Gormley

For more information:

Antonis C. Antoniou, PhD, can be reached at Strangeways Research Laboratory, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Univeristy of Cambridge, Worts Causeway, Cambridge CB1 8RN, England; email: aca20@medschl.cam.ac.uk.

Mary B. Daly, MD, PhD, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111.

Disclosure: Cancer Research-UK funded this study. Daly reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.