On this page, we highlight recent publications that utilize data collected by the Breast Cancer Family Registry. For a full listing of all BCFR publications, please see the Publications page.
10-year performance of four models of breast cancer risk: a validation study.
Terry MB, Liao Y, Whittemore AS, Leoce N, Buchsbaum R, Zeinomar N, Dite GS, Chung WK, Knight JA, Southey MC, Milne RL, Goldgar D, Giles GG, McLachlan SA, Friedlander ML, Weideman PC, Glendon G, Nesci S, Andrulis IL, John EM, Phillips KA, Daly MB, Buys SS, Hopper JL, and MacInnis RJ.
Lancet Oncol. 2019 Feb 21 [Epub ahead of print].
Independent validation is essential to justify use of models of breast cancer risk prediction and inform decisions about prevention options and screening. In this validation study, we used the Breast Cancer Prospective Family Study Cohort (ProF-SC), which includes 18 856 women from Australia, Canada, and the USA who did not have breast cancer at recruitment, between March 17, 1992, and June 29, 2011. We used this cohort to calculate 10-year risk scores and compare four models of breast cancer risk prediction: the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model (BOADICEA), BRCAPRO, the Breast Cancer Risk Assessment Tool (BCRAT), and the International Breast Cancer Intervention Study model (IBIS).
We found that BOADICEA and IBIS were well calibrated in the overall validation cohort, whereas BRCAPRO and BCRAT underpredicted risk. For BRCA-negative participants, BOADICEA, BCRAT and IBIS were well calibrated, but BRCAPRO underpredicted risk. For BRCA-positive participants, BOADICEA and IBIS were well calibrated, but BRCAPRO underpredicted risk. We noted similar patterns of calibration for women younger than 50 years at recruitment. BOADICEA and IBIS predictive scores were not appreciably affected by limiting input data to family history for first-degree and second-degree relatives.
Our results suggest that models that include multigenerational family history, such as BOADICEA and IBIS, have better ability to predict breast cancer risk, even for women at average or below-average risk of breast cancer. Although BOADICEA and IBIS performed similarly, further improvements in the accuracy of predictions could be possible with hybrid models that incorporate the polygenic risk component of BOADICEA and the non-family-history risk factors included in IBIS.
Risk-reducing oophorectomy and breast cancer risk across the spectrum of familial risk.
Terry MB, Daly MB, Phillips KA, Ma X, Zeinomar N, Leoce N, Dite GS, MacInnis RJ, Chung WK, Knight JA, Southey MC, Milne RL, Goldgar D, Giles GG, Weideman PC, Glendon G, Buchsbaum R, Andrulis IL, John EM, Buys SS, and Hopper JL.
J Natl Cancer Inst. 2019 March 1; 11(3): 331-334
There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. Using the Breast Cancer Prospective Family Study Cohort (ProF-SC), we examined the association between RRSO and breast cancer risk using a prospective cohort of 17,917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall or by tertiles of predicted absolute risk based on family history or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk.
Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) Study.
John EM, Hines LM, Phipps AI, Koo J, Longacre TA, Ingles SA, Baumgartner KB, Slattery ML, Wu AH.
Int J Cancer. 2018 Jun 1; 142(11): 2273-2285.
Few risk factors have been identified for triple negative breast cancer (estrogen receptor negative, progesterone receptor negative, HER2 negative), a subtype that is more aggressive, does not respond to hormonal therapy such as tamoxifen or aromatase inhibitors, and has a worse prognosis than other subtypes. About 10-20% or breast cancers are triple negative, but they are more common among young women and among African American and Hispanic women.
This project combined questionnaire data from 3 studies conducted in California, including the Northern California site of the Breast Cancer Family Registry, to investigate risk factors for triple negative breast cancer (TNBC). The study included 558 women with TNBC from all racial/ethnic groups, and is therefore one of the largest and most diverse TNBC studies done to date. This report shows that breast-feeding lowers the risk of TNBC, but only among younger women under age 50 years. Women who breast-fed for 24 months or longer over their lifetime had an almost 50% lower risk than women who never breast-fed or did so for less than 12 months. Women with 3 or more full-term pregnancies had a two-fold increased risk of TNBC, but only if they never breast-fed or did so for less than 12 months. No increased risk was seen in women with 3 or more full-term pregnancies who breast-fed for 12 months or longer. No associations with breast-feeding and reproductive history were found among women age 50 years or older. Breast-feeding is one of the few factors that has been associated with TNBC risk in younger women. Given that breast-feeding is a modifiable lifestyle behavior, our findings are of public health importance. There are notable differences in initiation and duration of breast-feeding between racial/ethnic groups, pointing to opportunities to increase breast-feeding.
Association analysis identifies 65 new breast cancer risk loci.
Michailidou K, Lindström S, Dennis J et al.
Nature, 2017 Nov 2; 551(7678):92-94.
The discovery of breast cancer susceptibility genes has played a major role in our understanding of the molecular basis of breast cancers in general and has been beneficial for the screening and development of novel treatments for this disease. In addition to the high and intermediate risk variants in the major breast cancer susceptibility genes, there are also common variants in many genes associated with modest increased risks of breast cancer. Large numbers of participants are required for these studies; therefore investigators from many countries collaborate on these large-scale international efforts. The BCFR has contributed to these studies that have identified over 180 common variants and resulted in high-impact publications. In this study published in the journal Nature, 65 new potentially important breast cancer risk loci were identified. To date, these new variants together with the other common susceptibility variants explain 18% of the familial relative risk of breast cancer. Furthermore, using bioinformatics approaches combining genetic data and pathway analysis, the study also showed that these genes are often the same as those that are altered in breast tumors. This study enhances our knowledge of the potential role of the variants in breast cancer development in addition to improving the usefulness of risk prediction that may be of benefit for early detection and prevention.
Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores.
LeCarpentier J, Silvestri V, Kuchenbaecker KB, et al.
J Clin Oncol, 2017 Jul 10; 35(20): 2240-2250.
Mutations in BRCA1 or BRCA2 increase the risk for breast and ovarian cancer in women, with the absolute risk for cancer being influenced by environmental factors such as reproductive history, smoking history, and body size, as well as by other genetic factors besides BRCA genes. This study, published in the Journal of Clinical Oncology, evaluated the effect of other genetic factors on the risk of breast and prostate cancer in men with mutations in BRCA genes.
Over 1800 men, all of whom had mutations in BRCA1 or BRCA2 (including men enrolled in the Breast Cancer Family Registry), were studied by a group of investigators called the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Men with breast cancer or prostate cancer were compared to men without breast or prostate cancer to determine the influence of common genetic variations in non-BRCA genes on the risk for breast and prostate cancer. The investigators found that non-BRCA genes that have previously been shown to influence the risk for breast cancer in women, and the risk of prostate cancer in men, also affect the risk for breast and prostate cancer in men with BRCA gene mutations. For example, men with BRCA2 mutations who are in the top 5% of risk based on variants in multiple non-BRCA genes, have up to a 61% risk for prostate cancer by age 80, and a 14% risk for breast cancer, whereas for men in the lowest 5% of risk, these risks are 5% and 19%, respectively. These data may be used to make personalized recommendations for prevention and screening for breast and prostate cancer in men with BRCA gene mutations.
Characterizing genetic susceptibility to breast cancer in women of African Ancestry.
Feng Y, Rhie SK, Juo D, et al.
Cancer Epidemiol Biomarkers Prev, 2017 Jul; 26(7): 1016-1026.
Genetic sequencing studies have identified several genetic variants that are thought to confer an increased risk for breast cancer. The identification of these variants will help to predict future risk of breast cancer in women who are not yet affected by the disease. The majority of these studies have been performed in Caucasian women of European descent. There is very little data on the proportion of women of African descent who carry these variants. In order to better understand the role of the relationship of these variants to breast cancer in women of African descent, genetic data from 6,522 breast cancer cases and 7,643 controls, all of African descent, were analyzed for the presence of 74 breast cancer related variants. 68 of these variants were associated with breast cancer risk in a pattern similar to the findings in Caucasian women. Six of the variants appeared to be more consistently associated with breast cancer risk in women of African descent that seen in Caucasian women. These potential differences in risk variants could be useful in creating personalized risk estimates for women of different ancestries.
Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
Kuchenbaecker KB, Hopper JL, Barnes DR, et al.
JAMA, 2017 Jun 20; 317(23):2402-16.
The Breast Cancer Family Registry and similar studies have combined forces to track almost 10,000 women with mutations in the genes BRCA1 or BRCA2 for up to 20 years and in doing so have provided the clearest picture yet of the long-term breast and ovarian cancer risks for women who have inherited an abnormality in these cancer-risk genes.
This prospective study followed women who initially were unaffected forward in time to see who develops breast cancer. Published in The Journal of the American Medical Association, the study is substantially larger and more powerful than previous studies of these issues, and because the study has been prospective, the findings are considered more reliable than results of retrospective studies.
The study found that women with BRCA1 gene mutations have on average a 72% risk of developing breast cancer by 80 years of age. For BRCA2 mutations, the risk of breast cancer is 69% while for ovarian cancer the average lifetime risk is 44% for BRCA1 and 17% for BRCA2.
For both cancers, however, a woman’s family history influenced the risk – in other words, a carrier who had one or more relatives with breast cancer is at higher risk than a carrier of the same mutation with no family history. The researchers also found that the specific location of the abnormality within the gene also influences cancer risks.
This study provides much more precise information about cancer risks for carriers, and will help personalize decision-making about the use and timing of prevention strategies such as medication, surgery and changing lifestyle factors.
Other important findings which should change the way prevention strategies are offered to women with BRCA gene mutations include:
• Breast cancer risk was found to increase rapidly at a young age then remain at a constant high level for the rest of a woman’s life. It peaks in the 30s for BRCA1 mutation carriers and in the 40s for BRCA2 mutation carriers, but both types of carriers are at about the same high risk in later life.
• There was no tail-off in risk as the women aged, overturning previous thinking that if a BRCA1 or BRCA2 mutation carrier turned 60 without a diagnosis then she is less likely to develop cancer subsequently.
Further analysis of data from this study will examine whether modifiable and lifestyle-related factors – such as timing of pregnancies, contraceptive use, use of hormone replacement medication, or alcohol and smoking – can influence a woman’s risk.
This study is showing that breast and ovarian cancers are not caused solely by a woman’s genes, or by her environment, but by a combination of both. Understanding the modifiable risk factors that influence whether women with high-risk gene mutations go on to develop cancer will allow us to further improve advice and tailor effective cancer prevention strategies.
Dietary isoflavone intake and all-cause mortality in breast cancer survivors: the Breast Cancer Family Registry.
Zhang FF, Haslam DE, Terry MB, Knight JA, Andrulis IL, Daly M, Buys SS, John EM.
Cancer, 2017 Jun; 123(11):2070-79.
It remains controversial whether women diagnosed with breast cancer should be advised to avoid or decrease their consumption of dietary isoflavones through soy foods or supplements. Some studies in Chinese women suggest that dietary isoflavone may reduce the risk of breast cancer risk or progression, but there is concern that soy foods may possess estrogen-like properties and have adverse effects on breast cancer.
This study examined survival of 6,235 women with breast cancer enrolled in the Breast Cancer Family Registry. At enrollment, study participants completed a food frequency questionnaire that assessed usual dietary intake around the time of diagnosis. We found that women with a high intake of isoflavones from foods had a 21% lower risk of mortality compared to women with a low intake. Larger reductions in mortality risk were seen for two subgroups of women: a 51% mortality reduction for women diagnosed with estrogen receptor (ER) and progesterone receptor (PR) negative breast cancer, and a 32% mortality reduction for women who did not receive hormone therapy as part of their treatment for breast cancer. These results suggest that isoflavone intake from soy foods is unlikely to have a negative impact on survival of women with breast cancer. Although the consumption of isoflavones in North America is much lower than in Asian countries, we did see a benefit from higher levels of isoflavone intake among women from North America.
Dependence of cancer risk from environmental exposures on underlying genetic susceptibility: an illustration with polycyclic aromatic hydrocarbons and breast cancer.
Shen J, Liao Y, Hopper JL, Goldberg M, Santella RM, Terry MB.
Br J Cancer. 2017 Apr 25;116(9):1229-33.
Polycyclic aromatic hydrocarbons (PAH) are a group of environmental pollutants comprised of hundreds of different chemicals. They occur naturally in petroleum and coal products such as crude oil, gasoline and coal and are released in the atmosphere when coal, oil, gas, wood, garbage, or tobacco are burned. As a class, PAH represent the most prevalent of environmental pollutants. People are exposed to PAH through motor vehicle exhaust, cigarette smoke, wood smoke, fumes from asphalt roads, or by eating grilled or charred meats or foods contaminated by PAH during the food manufacturing process. Previous studies have found that high exposure to PAH is associated with increased risk of breast cancer. It is not clear if women with a high risk of breast cancer due to their family history also experience an increase in breast cancer risk if exposed to PAH.
In this study, we measured markers of PAH exposure in the blood of 80 women that were later diagnosed with breast cancer and 156 women that have not been diagnosed with breast cancer, all of whom are enrolled in the Metropolitan New York Registry. We estimated the 10-year risk of breast cancer for the women based on family history and genes where relevant using the BOADICEA risk model. High breast cancer risk in clinical terms is usually defined as a 10-year risk of 3.4% or more. PAH exposure above the mean was associated with a twofold increase in breast cancer risk in all women. Very high PAH exposure was associated with a 3-7 fold increased risk of breast cancer for women with a 10-year breast cancer risk above 4%.
This is the first study to prospectively examine whether exposure to PAH, as measured through blood biomarkers, increases risk in women at high risk of breast cancer and demonstrates that environmental exposures may modify breast cancer risk even in those at highest risk of breast cancer.