Variation in breast cancer risk in BRCA1 and BRCA2 mutation carriers
Breast Cancer Research volume 10, Article number: 108 (2008)
Genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations can provide important information for women who are concerned about their breast and ovarian cancer risks and need to make relevant prevention and medical management decisions. However, lifetime risks of breast cancer in individual BRCA1/2 mutation carriers have been confusing to apply in clinical decision-making. Published risk estimates vary significantly and are very dependent on the characteristics of the population under study. Recently, Begg and colleagues estimated cancer risks in a population-based study of BRCA1/2 mutation carriers. Here, we discuss the clinical decision-making implications of this research in the context of risk factors that may influence risk estimates in BRCA1/2 mutation carriers.
Variation in breast cancer risk in BRCA1 and BRCA2mutation carriers
In 1995, Easton and colleagues  provided an estimate of greater than 80% for the lifetime risk of breast cancer in BRCA1 carriers. This estimate, the highest reported, was based on families with at least four individuals with breast and/or ovarian cancer collected for linkage analysis to identify genes associated with familial breast cancer. In contrast, studies of unselected breast cancer patients have estimated risks in the 40% to 60% range, while studies examining risk estimates in families attending high-risk clinics have intermediate risk estimates of 60% to 80% [2–5]. These wide-ranging risk estimates, as well as studies that suggest wide interindividual variability in risk even within families with the same BRCA1/2 mutation, suggest that there is no 'correct' risk estimate that can be applied to all women, and there are risk modifiers in BRCA1/2 mutation carriers. These modifiers are likely to include reproductive and environmental exposures, genes at other loci, and the nature of an individual's family history.
Family history matters
In families with BRCA1/2 mutations, relatives of probands with ovarian cancer have a higher risk of ovarian cancer, and relatives of probands with breast cancer have a higher risk of breast cancer. For example, Lee and colleagues  examined the lifetime risk of cancer in first-degree relatives (FDRs) of BRCA1/2 mutation carriers with breast or ovarian cancers. The standardized incidence ratio for breast cancer was 10.6 (95% confidence interval 5.2 to 21.6) in FDRs of breast cancer probands and 3.3 (1.4 to 7.5) in FDRs of ovarian cancer probands (p = 0.02). Similarly, the standardized incidence ratio for ovarian cancer was 7.9 (1.2 to 5.3) for FDRs of breast cancer probands, and 11.3 (3.6 to 31.9) for FDRs of ovarian cancer probands, although this difference was not statistically significant (p = 0.37). Why should this be? Phenotype-genotype correlations of specific gene mutations exist that suggest that some mutations are more likely to confer risk of ovarian cancer versus breast cancer [7, 8]. However, it is not likely that such genotype-phenotype association is sufficient to explain the wide ranges of risks that have been observed. Thus, exposures or genes at other loci may also modify risk.
Factors including parity, age at menarche and first birth, duration of breast feeding, mammographic density, exogenous hormone exposures, and dietary factors, including alcohol intake, are known to impact breast cancer risk in the general population (reviewed in [9–13]). These factors may also cluster in families. The impact of reproductive factors on breast cancer risk in BRCA1/2 mutation carriers is largely unresolved, although recent large-scale studies have reported that exogenous hormone exposures (for example, oral contraceptives) and reproductive history may alter breast cancer risk [14–17]. Other environmental exposures have been investigated among BRCA1/2 mutation carriers, including cigarette smoking and caffeine intake, but results have been inconsistent [18–21].
Medical interventions, such as risk-reducing salpingo-oophorectomy (RRSO), have also been demonstrated to decrease breast and ovarian cancer risk, but are often not considered in studies estimating penetrance [22, 23]. Since it has been observed that use of RRSO varies by population , difference in risk estimates may also be affected by variable use of these preventive options.
Finally, variability in cancer risks have been reported by year of birth , suggesting that changes in reproductive history, exposures or other risk factors that vary by birth cohort may influence cancer risks . While it is not clear whether these effects are due to true cancer risk modification rather than selection biases, birth cohort effects could have influenced cancer risks and risks in different reports.
There is increasing evidence that genetic modifiers of BRCA1/2 risk exist. The most clear-cut is modification of BRCA2-associated breast cancer risk by RAD51 , but other genes, including FGFR2, TNRC9, AURKA, and MAP3K1 [26–28], have been suggested as risk modifiers. Although their effects are quite modest, interactions of genotypes with exposures, birth cohort effects, reproductive factors, and interventions such as RRSO may provide significant information about risk.
The Begg study
Begg and colleagues  examined cancer risks using 2,098 women diagnosed with breast cancer between 1985 and 2000 (1,394 with unilateral breast cancer, 704 with bilateral breast cancer) who participated in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) study. A total of 109 BRCA1 and 72 BRCA2 mutation carriers were identified. Cancer risks were estimated for FDRs of these women. The study found risk estimates significantly lower than in studies of high-risk families , with a cumulative risk of breast cancer to age 70 of 36% to 48% for BRCA1 carriers, and 47% to 59% for BRCA2 carriers. Increased risk was associated with a younger age of the proband, and a trend toward increased risk was seen for relatives of probands with bilateral versus unilateral breast cancer.
Despite the useful information provided by this research, there are several considerations to be made in interpreting this study. Despite the large population based sample, only 181 mutation carriers were identified (with 598 FDRs, of whom 50% were estimated to be mutation carriers), thus limiting the power to estimate cumulative risks. A very large number of BRCA1/2 mutation carriers, 58%, had no FDR affected with breast cancer; however, several reasons based on the design of the study may account for this. First, only FDRs were examined and thus breast cancer in the paternal linage was not considered. Information is not given on the percentage of probands with no sisters or daughters, a fact particularly relevant in those with a mutation inherited from the paternal lineage. It is not known if probands or their FDRs were aware of their mutation status and, if so, what pro-phylactic measures might have been taken, such as mastectomy or oophorectomy. Both of these interventions would significantly alter cancer risk. Ovarian cancer was not considered as an endpoint. The study population was uniquely selected as patients were eligible only if they had node negative breast cancer diagnosed under the age of 55 between 1985 and 2000, and then were recruited between 2000 and 2004. Therefore, survival and other biases may exist. Finally, the authors did not consider potential birth cohort effects, which have been identified in multiple studies and may have influenced some results.
The major limitation in making clinical inferences from this study, however, is that the sample studied by Begg and colleagues may not represent the women who currently undergo genetic testing. Individuals without a significant family history are not recommended to have genetic testing  and this population will not have routine insurance coverage for genetic testing. Thus, the clinical implications of Begg and colleagues (and other studies of this type) are limited by sampling/design issues.
What do we need to know before changing clinical recommendations?
Individualized risk assessment is the holy grail of the human genome – not only for BRCA1/2 mutation carriers but for the general population. Such assessment may be possible: proband cancer type matters, evidence for genotype-phenotype correlations exist; there is evidence for modifier genes. However, the most important question is whether decision-making will change when this information is available. Will we ever feel comfortable telling a mutation carrier that she does not need RRSO, particularly if we continue to have no effective ovarian cancer screening strategy? Will physicians ever insist on prophylactic mastectomy? Will women make different decisions based on a 40% lifetime risk of breast cancer versus a 60% lifetime risk? These and many other unanswered questions remain even as we strive for improved risk estimation and stratification.
Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995, 56: 265-271.
Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, Brower ST, Eng CM: Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet. 1998, 63: 45-51. 10.1086/301903.
Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR, Easton DF, Venter DJ: Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999, 8: 741-747.
Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002, 94: 1365-1372.
King MC, Marks JH, Mandell JB: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003, 302: 643-646. 10.1126/science.1088759.
Lee JS, John EM, McGuire V, Felberg A, Ostrow KL, DiCioccio RA, Li FP, Miron A, West DW, Whittemore AS: Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations. Cancer Epidemiol Biomarkers Prev. 2006, 15: 359-363. 10.1158/1055-9965.EPI-05-0687.
Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997, 15: 103-105. 10.1038/ng0197-103.
Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M, Seal S, Hamoudi R, van Rensburg EJ, Dunning AM, Love R, Evans G, Easton D, Clayton D, Stratton MR, Ponder BA: Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet. 1995, 11: 428-433. 10.1038/ng1295-428.
Tjønneland A, Christensen J, Olsen A, Stripp C, Thomsen BL, Overvad K, Peeters PH, van Gils CH, Buenode-Mesquita HB, Ocké MC, Thiebaut A, Fournier A, Clavel-Chapelon F, Berrino F, Palli D, Tumino R, Panico S, Vineis P, Agudo A, Ardanaz E, Martinez-Garcia C, Amiano P, Navarro C, Quirós JR, Key TJ, Reeves G, Khaw KT, Bingham S, Trichopoulou A, Trichopoulos D, et al: Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control. 2007, 18: 361-373. 10.1007/s10552-006-0112-9.
Vachon CM, van Gils CH, Sellers TA, Ghosh K, Pruthi S, Brandt KR, Pankratz VS: Mammographic density, breast cancer risk and risk prediction. Breast Cancer Res. 2007, 9: 217-
Kiley J, Hammond C: Combined oral contraceptives: a comprehensive review. Clin Obstet Gynecol. 2007, 50: 868-877.
Troisi R, Potischman N, Hoover RN: Exploring the underlying hormonal mechanisms of prenatal risk factors for breast cancer: a review and commentary. Cancer Epidemiol Biomarkers Prev. 2007, 16: 1700-1712. 10.1158/1055-9965.EPI-07-0073.
Michels KB, Mohllajee AP, Roset-Bahmanyar E, Beehler GP, Moysich KB: Diet and breast cancer: a review of the prospective observational studies. Cancer. 2007, 109: 2712-2749. 10.1002/cncr.22654.
Brohet RM, Goldgar DE, Easton DF, Antoniou AC, Andrieu N, Chang-Claude J, Peock S, Eeles RA, Cook M, Chu C, Noguès C, Lasset C, Berthet P, Meijers-Heijboer H, Gerdes AM, Olsson H, Caldes T, van Leeuwen FE, Rookus MA: Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS collaborating group. J Clin Oncol. 2007, 25: 3831-3836. 10.1200/JCO.2007.11.1179.
Chang-Claude J, Andrieu N, Rookus M, Brohet R, Antoniou AC, Peock S, Davidson R, Izatt L, Cole T, Nogues C, Luporsi E, Huiart L, Hoogerbrugge N, Van Leeuwen FE, Osorio A, Eyfjord J, Radice P, Goldgar DE, Easton DF, Epidemiological Study of Familial Breast Cancer (EMBRACE); Gene Etude Prospective Sein Ovaire (GENEPSO); Genen Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland (GEO-HEBON); International BRCA1/2 Carrier Cohort Study (IBCCS) collaborators group: Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev. 2007, 16: 740-746. 10.1158/1055-9965.EPI-06-0829.
Andrieu N, Goldgar DE, Easton DF, Rookus M, Brohet R, Antoniou AC, Peock S, Evans G, Eccles D, Douglas F, Noguès C, Gauthier-Villars M, Chompret A, Van Leeuwen FE, Kluijt I, Benitez J, Arver B, Olah E, Chang-Claude J, EMBRACE; GENEPSO; GEO-HEBON; IBCCS Collaborators Group: Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst. 2006, 98: 535-544.
Antoniou AC, Shenton A, Maher ER, Watson E, Woodward E, Lalloo F, Easton DF, Evans DG: Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2006, 8: R72-10.1186/bcr1630.
Colilla S, Kantoff PW, Neuhausen SL, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Brown M, Weber BL, Rebbeck TR: The joint effect of smoking and AIB1 on breast cancer risk in BRCA1 mutation carriers. Carcinogenesis. 2006, 27: 599-605. 10.1093/carcin/bgi246.
Ghadirian P, Lubinski J, Lynch H, Neuhausen SL, Weber B, Isaacs C, Baruch RG, Randall S, Ainsworth P, Friedman E, Horsman D, Tonin P, Foulkes WD, Tung N, Sun P, Narod SA: Smoking and the risk of breast cancer among carriers of BRCA mutations. Int J Cancer. 2004, 110: 413-416. 10.1002/ijc.20106.
Brunet JS, Ghadirian P, Rebbeck TR, Lerman C, Garber JE, Tonin PN, Abrahamson J, Foulkes WD, Daly M, Wagner-Costalas J, Godwin A, Olopade OI, Moslehi R, Liede A, Futreal PA, Weber BL, Lenoir GM, Lynch HT, Narod SA: Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst. 1998, 90: 761-766. 10.1093/jnci/90.10.761.
Nkondjock A, Ghadirian P, Kotsopoulos J, Lubinski J, Lynch H, Kim-Sing C, Horsman D, Rosen B, Isaacs C, Weber B, Foulkes W, Ainsworth P, Tung N, Eisen A, Friedman E, Eng C, Sun P, Narod SA: Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Int J Cancer. 2006, 118: 103-107. 10.1002/ijc.21296.
Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E, Olopade OI, Weber BL, Prevention and Observation of Surgical End Points Study Group: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. [see comment]. New Eng J Med. 2002, 346: 1616-1622. 10.1056/NEJMoa012158.
Kramer JL, Velazquez IA, Chen BE, Rosenberg PS, Struewing JP, Greene MH: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol. 2005, 23: 8629-8635. 10.1200/JCO.2005.02.9199.
Friebel TM, Domchek SM, Neuhausen SL, Wagner T, Evans DG, Isaacs C, Garber JE, Daly MB, Eeles R, Matloff E, Tomlinson G, Lynch HT, Tung N, Blum JL, Weitzel J, Rubinstein WS, Ganz PA, Couch F, Rebbeck TR: Bilateral prophylactic oophorectomy and bilateral prophylactic mastectomy in a prospective cohort of unaffected BRCA1 and BRCA2 mutation carriers. Clin Breast Cancer. 2007, 7: 875-882.
Antoniou AC, Sinilnikova OM, Simard J, Leone M, Dumont M, Neuhausen SL, Struewing JP, Stoppa-Lyonnet D, Barjhoux L, Hughes DJ, Coupier I, Belotti M, Lasset C, Bonadona V, Bignon YJ, Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO), Rebbeck TR, Wagner T, Lynch HT, Domchek SM, Nathanson KL, Garber JE, Weitzel J, Narod SA, Tomlinson G, Olopade OI, Godwin A, Isaacs C, Jakubowska A, Lubinski J: RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet. 2007, 81: 1186-1200. 10.1086/522611.
Rebbeck TR, Wang Y, Kantoff PW, Krithivas K, Neuhausen SL, Godwin AK, Daly MB, Narod SA, Brunet JS, Vesprini D, Garber JE, Lynch HT, Weber BL, Brown M: Modification of BRCA1 – and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Research. 2001, 61: 5420-5424.
Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kämpjärvi K, Nevanlinna H, Simard J, Beesley J, Chen X, Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopade OI: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008, 82: 937-948. 10.1016/j.ajhg.2008.02.008.
Couch FJ, Sinilnikova O, Vierkant RA, Pankratz VS, Fredericksen ZS, Stoppa-Lyonnet D, Coupier I, Hughes D, Hardouin A, Berthet P, Peock S, Cook M, Baynes C, Hodgson S, Morrison PJ, Porteous ME, Jakubowska A, Lubinski J, Gronwald J, Spurdle AB, kConFab, Schmutzler R, Versmold B, Engel C, Meindl A, Sutter C, Horst J, Schaefer D, Offit K: AURKA F31I Polymorphism and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A Consortium of Investigators of Modifiers of BRCA1/2 Study. Cancer Epidemiol Biomarkers Prev. 2007, 16: 1416-1421. 10.1158/1055-9965.EPI-06-0783.
Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, Langholz B, Bernstein L, Olsen JH, Lynch CF, Anton-Culver H, Capanu M, Liang X, Hummer AJ, Sima C, Bernstein JL: Variation of breast cancer risk among BRCA1/2 carriers. JAMA. 2008, 299: 194-201. 10.1001/jama.2007.55-a.
US Preventive Services Task Force: Genetic risk assessment and BRCA mutation testing: recommendation statement. Ann Intern Med. 2005, 143: 355-361.
The authors declare that they have no competing interests.
Rights and permissions
About this article
Cite this article
Rebbeck, T.R., Domchek, S.M. Variation in breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 10, 108 (2008). https://doi.org/10.1186/bcr2115
- Breast Cancer
- Ovarian Cancer
- Breast Cancer Risk
- Mutation Carrier
- Mammographic Density