Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer
2010; Elsevier BV; Volume: 85; Issue: 12 Linguagem: Inglês
10.4065/mcp.2010.0414
ISSN1942-5546
AutoresSandhya Pruthi, Bobbie S. Gostout, Noralane M. Lindor,
Tópico(s)Nutrition, Genetics, and Disease
ResumoWomen with a germline BRCA1 or BRCA2 mutation or a hereditary predisposition for breast and ovarian cancer have substantial risk of breast or ovarian cancer relative to the general US population. Health care professionals can be instrumental in identifying women at increased risk through obtaining a comprehensive family history and becoming familiar with family history characteristics associated with hereditary predisposition for breast and ovarian cancer. BRCA carriers and women at very high risk benefit from multidisciplinary, individualized medical evaluation and risk management. We conducted a search of MEDLINE from 1989 through 2010 for the terms BRCA1, BRCA2, breast cancer, ovarian cancer, risk assessment, and genetic testing. We reviewed abstracts and relevant randomized and prospective studies that included very high-risk patient groups and BRCA mutation carriers. Herein, we review the role of genetic consultation and BRCA testing and the comprehensive, multisystem recommendations for risk management. A multidisciplinary approach offers the ability to educate those at very high risk about cancer prevention, reduce cancer risk, maximize early detection of breast and ovarian cancer, and improve survival. Women with a germline BRCA1 or BRCA2 mutation or a hereditary predisposition for breast and ovarian cancer have substantial risk of breast or ovarian cancer relative to the general US population. Health care professionals can be instrumental in identifying women at increased risk through obtaining a comprehensive family history and becoming familiar with family history characteristics associated with hereditary predisposition for breast and ovarian cancer. BRCA carriers and women at very high risk benefit from multidisciplinary, individualized medical evaluation and risk management. We conducted a search of MEDLINE from 1989 through 2010 for the terms BRCA1, BRCA2, breast cancer, ovarian cancer, risk assessment, and genetic testing. We reviewed abstracts and relevant randomized and prospective studies that included very high-risk patient groups and BRCA mutation carriers. Herein, we review the role of genetic consultation and BRCA testing and the comprehensive, multisystem recommendations for risk management. A multidisciplinary approach offers the ability to educate those at very high risk about cancer prevention, reduce cancer risk, maximize early detection of breast and ovarian cancer, and improve survival. Since genetic testing was introduced, its use for risk assessment by health care professionals has been escalating. Hereditary BRCA1 and BRCA2 mutations account for about 60% of inherited breast cancer and are the only known causes of hereditary breast and ovarian cancer syndrome. Women with a germline mutation in BRCA1 or BRCA2 or a hereditary predisposition for breast cancer have markedly increased risk of early-onset breast cancer and ovarian cancer. Other, rarer hereditary gene mutations are associated with increased risk of breast cancer, such as Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer syndrome, but these syndromes are not discussed herein.1Lindor NM McMaster ML Lindor CJ Greene MH National Cancer Institute Division of Cancer Prevention Community Oncology and Prevention Trials Research Group Concise handbook of familial cancer susceptibility syndromes: second edition.J Natl Cancer Inst Monogr. 2008; 2008: 1-93Crossref Scopus (246) Google Scholar In the United States in 2009, there were approximately 192,370 new cases of breast cancer and 21,550 new cases of ovarian cancer.2Jemal A Siegel R Ward E Hao Y Xu J Thun MJ Cancer statistics, 2009.CA Cancer J Clin. 2009; 59: 225-249Crossref PubMed Scopus (9886) Google Scholar That year, breast cancer deaths were estimated at 40,170 and ovarian cancer deaths at 14,600. Approximately 80% of breast and 90% of ovarian cancer cases are thought to be sporadic with no associated family history. Multifactorial familial risk accounts for approximately 10% to 15% of breast cancer. In the future, testable panels of genetic variants likely will combine to subtly alter risk. Hereditary breast cancer—cancer attributable to a single hereditary gene mutation in either BRCA1 or BRCA2—accounts for approximately 5% of breast cancer cases, characteristically occurring before age 50 years. Approximately 4% to 11% of ovarian cancer is attributable to a germline mutation, with the greatest proportions in cancers diagnosed before age 50 years.3Risch HA McLaughlin JR Cole DE et al.Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.Am J Hum Genet. 2001; 68: 700-710Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar An estimated 1 in 300 to 1 in 800 US individuals are BRCA carriers (1 in 50 individuals with Ashkenazi Jewish heritage).4ACOG The American Congress of Obstetricians and Gynecologists Web site. Washington, DC: American Congress of Obstetricians and Gynecologists ACOG.http://www.acog.org/from_home/proxy/Google Scholar, 5Narod SA Foulkes WD BRCA1 and BRCA2: 1994 and beyond.Nat Rev Cancer. 2004; 4: 665-676Crossref PubMed Scopus (725) Google Scholar Hereditary breast and ovarian cancer attributed to a mutation in a particular gene (ie, BRCA1 or BRCA2) can be passed on to the next generation, transmitted in an autosomal dominant pattern. The gene mutation may originate from the maternal or the paternal side, and each offspring of a BRCA carrier has a 50% chance of inheriting the mutation.6Jatoi I Anderson WF Management of women who have a genetic predisposition for breast cancer.Surg Clin North Am. 2008; 88: 845-861Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Specific characteristics that indicate increased likelihood of a BRCA gene mutation are listed in Table 1.TABLE 1Family History Features Associated With Possible Hereditary Predisposition for Breast or Ovarian Cancer Multiple cases of early-onset breast cancer (age, <50 y)Ovarian cancerCombination of breast and ovarian cancer in the same womanBilateral breast cancer≥1 Family member 1 y and breast cancer riskProtective effectProtective effect7Andrieu N Goldgar DE Easton DF EMBRACE GENEPSO GEO-HEBON IBCCS Collaborators Group et al.Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS).J Natl Cancer Inst. 2006; 98: 535-544Crossref PubMed Scopus (169) Google Scholar, 13McLaughlin JR Risch HA Lubinski J Hereditary Ovarian Cancer Clinical Study Group et al.Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.Lancet Oncol. 2007; 8: 26-34Abstract Full Text Full Text PDF PubMed Scopus (211) Google ScholarBreastfeeding >1 y and ovarian cancer riskNo protectionNo protection14Modugno F Moslehi R Ness RB et al.Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers (United States).Cancer Causes Control. 2003; 14: 439-446Crossref PubMed Scopus (19) Google ScholarMammographically dense breast tissue and breast cancer riskNo increased riskNo increased risk15Passaperuma K Warner E Hill KA Gunasekara A Yaffe MJ Is mammographic breast density a breast cancer risk factor in women with BRCA mutations?.J Clin Oncol. 2010; 28: 3779-3783Crossref PubMed Scopus (26) Google ScholarDietary fat and breast and ovarian cancer riskInconclusiveInconclusive16Nkondjock A Ghadirian P Epidemiology of breast cancer among BRCA mutation carriers: an overview.Cancer Lett. 2004; 205: 1-8Abstract Full Text Full Text PDF PubMed Scopus (36) Google ScholarAlcohol consumption and breast and ovarian cancer riskInconclusiveInconclusive16Nkondjock A Ghadirian P Epidemiology of breast cancer among BRCA mutation carriers: an overview.Cancer Lett. 2004; 205: 1-8Abstract Full Text Full Text PDF PubMed Scopus (36) Google ScholarPhysical activity during teen yearsDelayed onset of breast cancerDelayed onset of breast cancer17King MC Marks JH Mandell JB New York Breast Cancer Study Group Breast and ovarian cancer risks due to inherited mutations in BRC1 and BRCA2.Science. 2003 Oct 24; 302: 643-646Crossref PubMed Scopus (1818) Google Scholar Open table in a new tab Epidemiological studies have shown that, in general, lifestyle modification decreases breast cancer in high-risk women. Risk modification options include regular exercise (30 minutes 3 times per week), avoidance of postmenopausal obesity, reduced alcohol intake (≤1 serving [eg, 12 oz of beer] per day), and avoidance of long-term hormone therapy. One study showed that physical activity during the teen years delayed onset of breast cancer in BRCA mutation carriers.17King MC Marks JH Mandell JB New York Breast Cancer Study Group Breast and ovarian cancer risks due to inherited mutations in BRC1 and BRCA2.Science. 2003 Oct 24; 302: 643-646Crossref PubMed Scopus (1818) Google Scholar Furthermore, normal weight at menarche (P=.02) and low weight at age 21 years (P=.02) also delayed breast cancer onset in carriers. Among BRCA carriers, data are limited on the role of lifestyle modification in reducing breast cancer risk.18Nkondjock A Robidoux A Paredes Y Narod SA Ghadirian P Diet, lifestyle and BRCA-related breast cancer risk among French-Canadians.Breast Cancer Res Treat. 2006; 98: 285-294Crossref PubMed Scopus (87) Google Scholar Among BRCA1 mutation carriers, the estimated lifetime risk of breast cancer is 40% to 85%, and lifetime risk of ovarian cancer is estimated at 25% to 65%. BRCA2 mutation carriers have about the same risk of breast cancer, with an ovarian cancer risk estimated to be 15% to 20%. The range of cancer risk estimates varies with the population in different studies and in accordance with the mode of ascertainment.19Chen S Parmigiani G Meta-analysis of BRCA1 and BRCA2 penetrance.J Clin Oncol. 2007; 25: 1329-1333Crossref PubMed Scopus (1353) Google Scholar Lifetime risk is increased dramatically compared with the general population, in which the risk of breast cancer is approximately 13% and the risk of ovarian cancer is 1.5%.20National Cancer Institute Surveillance Research Web site. Where can I find statistics related to the Lifetime Risk of Developing or Dying of Cancer? Updated January 22, 2010.http://surveillance.cancer.gov/statistics/types/lifetime_risk.htmlGoogle Scholar Yet, given these increased risks relative to the general population, approximately 20% to 30% of BRCA carriers never have breast cancer, and 35% to 85% do not have ovarian cancer.19Chen S Parmigiani G Meta-analysis of BRCA1 and BRCA2 penetrance.J Clin Oncol. 2007; 25: 1329-1333Crossref PubMed Scopus (1353) Google Scholar Several unique features differentiate BRCA1 carriers from BRCA2 carriers and may influence surveillance and management options subsequently. In general, risks and age at onset of breast cancer are similar, but molecular and biological features are different. Regarding ovarian cancer, the risk is considerably greater in BRCA1 mutation carriers and age at diagnosis is younger on average than in BRCA2 mutation carriers (Table 3).TABLE 3Features Unique to BRCA1 Carriers vs BRCA2 CarriersaER = estrogen receptor; HER2/neu = human epidermal growth factor receptor 2; PR = progesterone receptor; RR = relative risk.MutationOnset of breast cancerOnset of ovarian cancerTumor featuresOther associated malignancies (RR)bData from references 1, 8, 21, and 22.BRCA1Risk begins to increase considerably by age 40 yRisk begins to increase by age 36–39 y, with a 2%–3% risk by age 40 yHigh grade, ER negative, PR negative, HER2/neu negative, basal phenotypePancreatic (2.3), prostate (1.8), fallopian tubes (120)BRCA2Risk begins to increase considerably by age 45 yRisk begins to increase by age 44–46 y, with a 2%–3% risk by age 50 yHigh grade, ER positive, PR positive, HER2/neu negative, luminal phenotypePancreatic (3.5), prostate (4.6), fallopian tubes (120), male breast cancer (cumulative probability to age 70 y, 6%)a ER = estrogen receptor; HER2/neu = human epidermal growth factor receptor 2; PR = progesterone receptor; RR = relative risk.b Data from references 1Lindor NM McMaster ML Lindor CJ Greene MH National Cancer Institute Division of Cancer Prevention Community Oncology and Prevention Trials Research Group Concise handbook of familial cancer susceptibility syndromes: second edition.J Natl Cancer Inst Monogr. 2008; 2008: 1-93Crossref Scopus (246) Google Scholar, 8Antoniou A Pharoah PD Narod S et al.Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies [published correction appears in Am J Hum Genet. 2003;73(3):709].Am J Hum Genet. 2003; 72: 1117-1130Abstract Full Text Full Text PDF PubMed Scopus (2790) Google Scholar, 21Robson M Offit K Clinical practice: management of an inherited predisposition to breast cancer.N Engl J Med. 2007; 357: 154-162Crossref PubMed Scopus (201) Google Scholar, 22Thompson D Easton DF Breast Cancer Linkage Consortium Cancer incidence in BRCA1 mutation carriers.J Natl Cancer Inst. 2002; 94: 1358-1365Crossref PubMed Scopus (915) Google Scholar Open table in a new tab Breast cancer risk assessment is complicated and can be challenging. Furthermore, no consistent and well-defined definition or threshold for “high-risk” has been established. The Gail model, a computerized method validated in large populations (available at http://www.cancer.gov/bcrisktool), is not ideal for predicting individual risk. This model incorporates age, reproductive history, breast biopsy history, and breast cancer occurrence in first-degree relatives. The model is valid only for women aged 35 years or older and does not include breast cancer occurrence in second-degree relatives, paternal history, or age at breast cancer diagnosis in affected relatives. It is not appropriate for use in individuals with multiple young affected relatives across several generations or for determining whether to order genetic testing. In general, a 5-year predicted risk of breast cancer that exceeds 1.66% as calculated by the Gail model is considered high risk. This model has been used in determining eligibility for chemoprevention with tamoxifen or raloxifene.23Gail MH Brinton LA Byar DP et al.Projecting individualized probabilities of developing breast cancer for white females who are being examined annually.J Natl Cancer Inst. 1989; 81: 1879-1886Crossref PubMed Scopus (2609) Google Scholar, 24Euhus DM Leitch AM Huth JF Peters GN Limitations of the Gail model in the specialized breast cancer risk assessment clinic.Breast J. 2002; 8: 23-27Crossref PubMed Scopus (50) Google Scholar The Claus model is a statistical model that calculates cumulative (lifetime) breast cancer risk specifically on the basis of family history and includes maternal and paternal second-degree relatives and the ages at diagnosis of breast cancer. It does not incorporate ovarian cancer or nonhereditary or reproductive risk factors. Risk estimates are derived from the family history of 5000 breast cancer cases (age, 20-54 years) and age-matched controls in the United States. Both published tables and computerized versions of this model are useful in clinical practice.25Claus EB Risch N Thompson WD The calculation of breast cancer risk for women with a first degree family history of ovarian cancer.Breast Cancer Res Treat. 1993; 28: 115-120Crossref PubMed Scopus (154) Google Scholar The IBIS model (IBIS Breast Cancer Risk Evaluation Tool, RiskFileCalc version 1.0, copyright 2004, available by contacting [email protected]), also known as the Tyrer-Cuzick model, is another risk prediction algorithm for assessing breast cancer risk and the probability of having a BRCA mutation found. It incorporates a more extensive family history and includes reproductive risk factors and benign breast disease history.26Tyrer J Duffy SW Cuzick J A breast cancer prediction model incorporating familial and personal risk factors [published correction appears in Stat Med. 2005;24(1):156].Stat Med. 2004; 23: 1111-1130Crossref PubMed Scopus (873) Google Scholar, 27Cuzick J IBIS Breast Cancer Risk Evaluation Tool Web site. Description of breast cancer risk program. Updated January 31, 2008.http://ems-trials.org/riskevaluator/Google Scholar The BRCAPRO model, version 4.3 (available at http://www.4.utsouthwestern.edu/breasthealth/cagene/default.asp), includes information on affected (both breast and ovarian cancer) and unaffected relatives and, using a Bayesian approach to risk assessment, estimates the likelihood of finding BRCA1 or BRCA2 mutations in a family. This model incorporates family history, age at diagnosis of cancers in the family, presence of bilateral breast cancer, male breast cancer, and Ashkenazi Jewish heritage.4ACOG The American Congress of Obstetricians and Gynecologists Web site. Washington, DC: American Congress of Obstetricians and Gynecologists ACOG.http://www.acog.org/from_home/proxy/Google Scholar, 5Narod SA Foulkes WD BRCA1 and BRCA2: 1994 and beyond.Nat Rev Cancer. 2004; 4: 665-676Crossref PubMed Scopus (725) Google Scholar, 28Berry DA Parmigiani G Sanchez J Schildkraut J Winer E Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history.J Natl Cancer Inst. 1997; 89: 227-238Crossref PubMed Scopus (315) Google Scholar, 29UT Southwestern Medical Center Requesting CancerGene. The University of Texas Southwestern Medical Center at Dallas, Dallas, TX2010http://www8.utsouthwestern.edu/utsw/cda/dept47834/files/68221.htmlGoogle Scholar Numerous other models are designed specifically to estimate the likelihood of a genetic alteration or deleterious mutation. Their results should be interpreted cautiously because they do not predict true breast cancer risk and may give significantly different results for the same patient because of differences in data input and assumptions in output. Genetic counselors use these likelihood models to estimate the probability of carrying a BRCA mutation in order to help inform subsequent discussion regarding the role of genetic testing. No specific risk level has been defined as the right level at which to offer BRCA testing. Health care professionals who use breast cancer risk calculation models need to be familiar with the limitations, strengths, and weaknesses of each model. Risk assessment is not a static number and patient risk changes over time; therefore, risk needs to be reassessed periodically.30US Preventive Services Task Force Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement [published correction appears in Ann Intern Med. 2005;143(7):547].Ann Intern Med. 2005; 143: 355-361Crossref PubMed Scopus (355) Google Scholar Compared with breast cancer risk modeling, tools for predicting ovarian cancer risk are substantially more limited. The algorithm for evaluating risk of ovarian cancer combines an individual's age and trends in CA-125 levels to assess the likelihood that she has ovarian cancer at the point of testing, but it does not predict future risk or the likelihood of being a carrier of a BRCA mutation.31Menon U Gentry-Maharaj A Ryan A et al.Recruitment to multicentre trials–lessons from UKCTOCS: descriptive study [published correction appears in BMJ. 2008;337:a2976].BMJ. 2008; 337: a2079Crossref PubMed Scopus (110) Google Scholar Other models, including ultrasonographic scoring systems and tumor marker panels, are designed to assess malignancy risk in a woman with a pelvic mass. Beyond population statistics that describe the occurrence of ovarian cancer in BRCA mutation carriers, no prospective modeling based on biomarkers is available currently to provide individualized assessment of short- or long-term risk of ovarian cancer in high-risk women. The output of the BRCAPRO model provides ovarian cancer risk estimates, subject to all the limitations of computerized modeling. Genetic consultation and testing are currently mainstream components of a multidisciplinary, individualized medical evaluation aimed at identification of individuals at risk for hereditary breast cancer syndromes. The US Preventive Services Task Force guideline on genetic risk assessment and BRCA mutation testing strongly recommends referral of high-risk individuals for genetic counseling. Programs that provide expertise in clinical genetics are important because BRCA testing has major medical, psychological, ethical, legal, and social implications,32Amir E Evans DG Shenton A et al.Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme.J Med Genet. 2003; 40: 807-814Crossref PubMed Scopus (243) Google Scholar in addition to the consideration of its relevance to potentially numerous family members. Genetic counselors are trained in the collection of family history and the use of models that quantify an individual's risk of a BRCA mutation. They provide pretesting education about possible outcomes of testing, the implications of both positive and negative test results for the person's health care and for her relatives, and the risks and limitations of testing. Genetic counselors can determine whether a person is predisposed to other hereditary gene syndromes and provide counseling on appropriate genetic testing associated with specific syndromes. They aid women with the insurance approval process, if necessary, and arrange for collection and submission of the blood sample to Myriad Genetics, Salt Lake City, UT (the only laboratory that provides clinical BRCA testing in the United States at this time). Complete testing (sequencing plus testing for large gene rearrangements in BRCA1 and BRCA2) currently costs around $4000. A list of specialized genetic counselors is available through the National Society of Genetic Counselors (http://www.nsgc.org/resourcelink.cfm).33National Society of Genetic Counselors. (nsgc) Web site. National Society of Genetic Counselors, Inc, 1995-2009http://www.nsgc.org/Google Scholar Referral to a genetic counselor is recommended for individuals in whom breast cancer developed before age 40 years and those with a strong family history of breast or ovarian cancer30US Preventive Services Task Force Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement [published correction appears in Ann Intern Med. 2005;143(7):547].Ann Intern Med. 2005; 143: 355-361Crossref PubMed Scopus (355) Google Scholar (Table 1). Genetic counselors can helpidentify the individual in a family for whom genetic testing is most likely to be informative for family members. Generally, this person is the youngest living, affected, and willing family member. It is paramount that women are counseled that a BRCA test is a predictive test and, although it provides information regarding the likelihood of breast or ovarian cancer, it is not a diagnostic test and does not confirm that a woman will have breast or ovarian cancer. Similarly, a negative result does not guarantee that an individual will not have breast cancer, either due to sporadic causes or other, as yet undefined, genetic factors. Beyond the associated health care fees, the risks of genetic counseling are minimal. In contrast, genetic testing has known risks, as well as benefits. Genetic testing offers the following benefits: identification of high-risk individuals who will benefit from the initiation of recommended cancer risk management; identification of noncarriers in families with a known mutation, who do not need to have rigorous cancer screening and would be considered at “general population risk”; education in early detection and prevention strategies; and perhaps relief of anxiety through increasing the understanding of medical options. However, it also has its risks and limitations, including its inability to detect all mutations, the continued risk of sporadic cancer, the unproven efficacy of some interventions, and the possibility of psychosocial or economic harm. In 2008, the Genetic Information Nondiscrimination Act was signed into law by President George W. Bush.34Genetic Information Nondiscrimination Act of 2008. Pub L 110-233, 122 Stat. 881 (May 21, 2008).Google Scholar Genetic counselors can inform patients about this law, which provides protection against discrimination in health insurance underwriting decisions based on genetic information. This protection includes group and individual health insurance and employment practices but does not cover life, disability, or long-term–care insurance and other forms of insurance. The act appears to exclude individuals with health care coverage through the US military, Veterans Affairs, and I
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