BRCA1 and BRCA2: Cancer Risk and Genetic Testing Key Points What are BRCA1 and BRCA2 How do BRCA1 and BRCA2

Transcription

1 BRCA1 and BRCA2: Cancer Risk and Genetic Testing Key Pints BRCA1 and BRCA2 are human genes that belng t a class f genes knwn as tumr suppressrs. Mutatin f these genes has been linked t hereditary breast and varian cancer. A wman's risk f develping breast and/r varian cancer is greatly increased if she inherits a deleterius (harmful) BRCA1 r BRCA2 mutatin. Men with these mutatins als have an increased risk f breast cancer. Bth men and wmen wh have harmful BRCA1 r BRCA2 mutatins may be at increased risk f ther cancers. Genetic tests are available t check fr BRCA1 and BRCA2 mutatins. A bld sample is required fr these tests, and genetic cunseling is recmmended befre and after the tests. If a harmful BRCA1 r BRCA2 mutatin is fund, several ptins are available t help a persn manage their cancer risk. Federal and state laws help ensure the privacy f a persn s genetic infrmatin and prvide prtectin against discriminatin in health insurance and emplyment practices. Many research studies are being cnducted t find newer and better ways f detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutatin carriers. Additinal studies are fcused n imprving genetic cunseling methds and utcmes. Our knwledge in these areas is evlving rapidly. 1. What are BRCA1 and BRCA2? BRCA1 and BRCA2 are human genes that belng t a class f genes knwn as tumr suppressrs. In nrmal cells, BRCA1 and BRCA2 help ensure the stability f the cell s genetic material (DNA) and help prevent uncntrlled cell grwth. Mutatin f these genes has been linked t the develpment f hereditary breast and varian cancer. The names BRCA1 and BRCA2 stand fr breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2, respectively. 2. Hw d BRCA1 and BRCA2 gene mutatins affect a persn's risk f cancer? Nt all gene changes, r mutatins, are deleterius (harmful). Sme mutatins may be beneficial, whereas thers may have n bvius effect (neutral). Harmful mutatins can increase a persn s risk f develping a disease, such as cancer. A wman s lifetime risk f develping breast and/r varian cancer is greatly increased if she inherits a harmful mutatin in BRCA1 r BRCA2. Such a wman has an increased risk f develping breast and/r varian cancer at an early age (befre menpause) and ften has multiple, clse family members wh have been diagnsed with these diseases. Harmful BRCA1 mutatins may als increase a wman s risk f develping cervical, uterine, pancreatic, and cln cancer (1, 2). Harmful BRCA2 mutatins may additinally increase the risk f pancreatic cancer, stmach cancer, gallbladder and bile duct cancer, and melanma (3). Men with harmful BRCA1 mutatins als have an increased risk f breast cancer and, pssibly, f pancreatic cancer, testicular cancer, and early-nset prstate cancer. Hwever, male breast cancer, pancreatic cancer, and prstate cancer appear t be mre strngly assciated with BRCA2 gene mutatins (2 4).

2 The likelihd that a breast and/r varian cancer is assciated with a harmful mutatin in BRCA1 r BRCA2 is highest in families with a histry f multiple cases f breast cancer, cases f bth breast and varian cancer, ne r mre family members with tw primary cancers (riginal tumrs that develp at different sites in the bdy), r an Ashkenazi (Central and Eastern Eurpean) Jewish backgrund (see Questin 6). Hwever, nt every wman in such families carries a harmful BRCA1 r BRCA2 mutatin, and nt every cancer in such families is linked t a harmful mutatin in ne f these genes. Furthermre, nt every wman wh has a harmful BRCA1 r BRCA2 mutatin will develp breast and/r varian cancer. Accrding t estimates f lifetime risk, abut 12.0 percent f wmen (120 ut f 1,000) in the general ppulatin will develp breast cancer smetime during their lives cmpared with abut 60 percent f wmen (600 ut f 1,000) wh have inherited a harmful mutatin in BRCA1 r BRCA2 (4, 5). In ther wrds, a wman wh has inherited a harmful mutatin in BRCA1 r BRCA2 is abut five times mre likely t develp breast cancer than a wman wh des nt have such a mutatin. Lifetime risk estimates fr varian cancer amng wmen in the general ppulatin indicate that 1.4 percent (14 ut f 1,000) will be diagnsed with varian cancer cmpared with 15 t 40 percent f wmen ( ut f 1,000) wh have a harmful BRCA1 r BRCA2 mutatin (4, 5). It is imprtant t nte, hwever, that mst research related t BRCA1 and BRCA2 has been dne n large families with many individuals affected by cancer. Estimates f breast and varian cancer risk assciated with BRCA1 and BRCA2 mutatins have been calculated frm studies f these families. Because family members share a prprtin f their genes and, ften, their envirnment, it is pssible that the large number f cancer cases seen in these families may be due in part t ther genetic r envirnmental factrs. Therefre, risk estimates that are based n families with many affected members may nt accurately reflect the levels f risk fr BRCA1 and BRCA2 mutatin carriers in the general ppulatin. In additin, n data are available frm lng-term studies f the general ppulatin cmparing cancer risk in wmen wh have harmful BRCA1 r BRCA2 mutatins with wmen wh d nt have such mutatins. Therefre, the percentages given abve are estimates that may change as mre data becme available. 3. D inherited mutatins in ther genes increase the risk f breast and/r varian tumrs? Yes. Mutatins in several ther genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been assciated with hereditary breast and/r varian tumrs (4, 6, 7). Hwever, the majrity f hereditary breast cancers can be accunted fr by inherited mutatins in BRCA1 and BRCA2 (8). Overall, it has been estimated that inherited BRCA1 and BRCA2 mutatins accunt fr 5 t 10 percent f breast cancers and 10 t 15 percent f varian cancers amng white wmen in the United States (6). 4. Are specific mutatins in BRCA1 and BRCA2 mre cmmn in certain ppulatins? Yes. Fr example, three specific mutatins, tw in the BRCA1 gene and ne in the BRCA2 gene, are the mst cmmn mutatins fund in these genes in the Ashkenazi Jewish ppulatin. In ne study, 2.3 percent f participants (120 ut f 5,318) carried ne f these three mutatins (9). This frequency is abut five times higher than that fund in the general ppulatin (10). It is nt knwn whether the increased frequency f these

3 mutatins is respnsible fr the increased risk f breast cancer in Jewish ppulatins cmpared with nn-jewish ppulatins. Other ethnic and gegraphic ppulatins arund the wrld, such as the Nrwegian, Dutch, and Icelandic peples, als have higher frequencies f specific BRCA1 and BRCA2 mutatins. In additin, limited data indicate that the frequencies f specific BRCA1 and BRCA2 mutatins may vary amng individual racial and ethnic grups in the United States, including African Americans, Hispanics, Asian Americans, and nn-hispanic whites (11 13). This infrmatin abut genetic differences between racial and ethnic grups may help health care prviders in selecting the mst apprpriate genetic test(s) (see Questin 5). 5. Are genetic tests available t detect BRCA1 and BRCA2 mutatins, and hw are they perfrmed? Yes. Several methds are available t test fr BRCA1 and BRCA2 mutatins (14). Mst f these methds lk fr changes in BRCA1 and BRCA2 DNA. At least ne methd lks fr changes in the prteins prduced by these genes. Frequently, a cmbinatin f methds is used. A bld sample is needed fr these tests. The bld is drawn in a labratry, dctr's ffice, hspital, r clinic and then sent t a labratry that specializes in the tests. It usually takes several weeks r lnger t get the test results. Individuals wh decide t get tested shuld check with their health care prvider t find ut when their test results might be available. Genetic cunseling is generally recmmended befre and after a genetic test. This cunseling shuld be perfrmed by a health care prfessinal wh is experienced in cancer genetics (see Questin 17). Genetic cunseling usually invlves a risk assessment based n the individual s persnal and family medical histry and discussins abut the apprpriateness f genetic testing, the specific test(s) that might be used and the technical accuracy f the test(s), the medical implicatins f a psitive r a negative test result, the pssibility that a test result might nt be infrmative (an ambiguus result) (see belw), the psychlgical risks and benefits f genetic test results, and the risk f passing a mutatin t children. 6. Hw d peple knw if they shuld cnsider genetic testing fr BRCA1 and BRCA2 mutatins? Currently, there are n standard criteria fr recmmending r referring smene fr BRCA1 r BRCA2 mutatin testing. In a family with a histry f breast and/r varian cancer, it may be mst infrmative t first test a family member wh has breast r varian cancer. If that persn is fund t have a harmful BRCA1 r BRCA2 mutatin, then ther family members can be tested t see if they als have the mutatin. Regardless, wmen wh have a relative with a harmful BRCA1 r BRCA2 mutatin and wmen wh appear t be at increased risk f breast and/r varian cancer because f their family histry shuld cnsider genetic cunseling t learn mre abut their ptential risks and abut BRCA1 and BRCA2 genetic tests. The likelihd f a harmful mutatin in BRCA1 r BRCA2 is increased with certain familial patterns f cancer. These patterns include the fllwing (15):

4 Fr wmen wh are nt f Ashkenazi Jewish descent: tw first-degree relatives (mther, daughter, r sister) diagnsed with breast cancer, ne f whm was diagnsed at age 50 r yunger; three r mre first-degree r secnd-degree (grandmther r aunt) relatives diagnsed with breast cancer regardless f their age at diagnsis; a cmbinatin f first- and secnd-degree relatives diagnsed with breast cancer and varian cancer (ne cancer type per persn); a first-degree relative with cancer diagnsed in bth breasts (bilateral breast cancer); a cmbinatin f tw r mre first- r secnd-degree relatives diagnsed with varian cancer regardless f age at diagnsis; a first- r secnd-degree relative diagnsed with bth breast and varian cancer regardless f age at diagnsis; and breast cancer diagnsed in a male relative. Fr wmen f Ashkenazi Jewish descent: any first-degree relative diagnsed with breast r varian cancer; and tw secnd-degree relatives n the same side f the family diagnsed with breast r varian cancer. These family histry patterns apply t abut 2 percent f adult wmen in the general ppulatin. Wmen wh have nne f these family histry patterns have a lw prbability f having a harmful BRCA1 r BRCA2 mutatin. 7. Hw much des BRCA1 and BRCA2 mutatin testing cst? The cst fr BRCA1 and BRCA2 mutatin testing usually ranges frm several hundred t several thusand dllars. Insurance plicies vary with regard t whether r nt the cst f testing is cvered. Peple wh are cnsidering BRCA1 and BRCA2 mutatin testing may want t find ut abut their insurance cmpany s plicies regarding genetic tests. 8. What des a psitive BRCA1 r BRCA2 test result mean? A psitive test result generally indicates that a persn has inherited a knwn harmful mutatin in BRCA1 r BRCA2 and, therefre, has an increased risk f develping certain cancers, as described abve. Hwever, a psitive test result prvides infrmatin nly abut a persn s risk f develping cancer. It cannt tell whether an individual will actually develp cancer r when. Nt all wmen wh inherit a harmful BRCA1 r BRCA2 mutatin will develp breast r varian cancer. A psitive genetic test result may have imprtant health and scial implicatins fr family members, including future generatins. Unlike mst ther medical tests, genetic tests can reveal infrmatin nt nly abut the persn being tested but als abut that persn s relatives. Bth men and wmen wh inherit harmful BRCA1 r BRCA2 mutatins, whether they develp cancer themselves r nt, may pass the mutatins n t their sns and daughters. Hwever, nt all children f peple wh have a harmful mutatin will inherit the mutatin. 9. What des a negative BRCA1 r BRCA2 test result mean? Hw a negative test result will be interpreted depends n whether r nt smene in the tested persn s family is knwn t carry a harmful BRCA1 r BRCA2 mutatin. If smene in the family has a knwn mutatin, testing ther family members fr the same

5 mutatin can prvide infrmatin abut their cancer risk. If a persn tests negative fr a knwn mutatin in his r her family, it is unlikely that they have an inherited susceptibility t cancer assciated with BRCA1 r BRCA2. Such a test result is called a true negative. Having a true negative test result des nt mean that a persn will nt develp cancer; it means that the persn s risk f cancer is prbably the same as that f peple in the general ppulatin. In cases in which a family has a histry f breast and/r varian cancer and n knwn mutatin in BRCA1 r BRCA2 has been previusly identified, a negative test result is nt infrmative. It is nt pssible t tell whether an individual has a harmful BRCA1 r BRCA2 mutatin that was nt detected by testing (a false negative ) r whether the result is a true negative. In additin, it is pssible fr peple t have a mutatin in a gene ther than BRCA1 r BRCA2 that increases their cancer risk but is nt detectable by the test(s) used. 10. What des an ambiguus BRCA1 r BRCA2 test result mean? If genetic testing shws a change in BRCA1 r BRCA2 that has nt been previusly assciated with cancer in ther peple, the persn s test result may be interpreted as ambiguus (uncertain). One study fund that 10 percent f wmen wh underwent BRCA1 and BRCA2 mutatin testing had this type f ambiguus result (16). Because everyne has genetic differences that are nt assciated with an increased risk f disease, it is smetimes nt knwn whether a specific DNA change affects a persn s risk f develping cancer. As mre research is cnducted and mre peple are tested fr BRCA1 r BRCA2 changes, scientists will learn mre abut these changes and cancer risk. 11. What are the ptins fr a persn wh has a psitive test result? Several ptins are available fr managing cancer risk in individuals wh have a harmful BRCA1 r BRCA2 mutatin. Hwever, high-quality data n the effectiveness f these ptins are limited. Surveillance Surveillance means cancer screening, r a way f detecting the disease early. Screening des nt, hwever, change the risk f develping cancer. The gal is t find cancer early, when it may be mst treatable. Surveillance methds fr breast cancer may include mammgraphy and clinical breast exams. Studies are currently under way t test the effectiveness f ther breast cancer screening methds, such as magnetic resnance imaging (MRI), in wmen with BRCA1 r BRCA2 mutatins. With careful surveillance, many breast cancers will be diagnsed early enugh t be successfully treated. Fr varian cancer, surveillance methds may include transvaginal ultrasund, bld tests fr CA 125 antigen, and clinical exams. Surveillance can smetimes find varian cancer at an early stage, but it is uncertain whether these methds can help reduce a wman's chance f dying frm this disease. Prphylactic Surgery This type f surgery invlves remving as much f the "at-risk" tissue as pssible in rder t reduce the chance f develping cancer. Bilateral prphylactic mastectmy (remval f healthy breasts) and prphylactic salping-phrectmy (remval f healthy fallpian tubes and varies) d nt, hwever, ffer a guarantee against develping cancer. Because nt all at-risk tissue can be remved by these prcedures, sme wmen have develped breast

6 cancer, varian cancer, r primary peritneal carcinmatsis (a type f cancer similar t varian cancer) even after prphylactic surgery. In additin, sme evidence suggests that the amunt f prtectin salping-phrectmy prvides against the develpment f breast and varian cancer may differ between carriers f BRCA1 and BRCA2 mutatins (17). Risk Avidance Certain behavirs have been assciated with breast and varian cancer risk in the general ppulatin (see Questin 16). Research results n the benefits f mdifying individual behavirs t reduce the risk f develping cancer amng BRCA1 r BRCA2 mutatin carriers are limited. Chempreventin This apprach invlves the use f natural r synthetic substances t reduce the risk f develping cancer r t reduce the chance that cancer will cme back. Fr example, the drug tamxifen has been shwn in numerus clinical studies t reduce the risk f develping breast cancer by abut 50 percent in wmen wh are at increased risk f this disease and t reduce the recurrence f breast cancer in wmen underging treatment fr a previusly diagnsed breast tumr. As a result, tamxifen was apprved by the U.S. Fd and Drug Administratin (FDA) as a breast cancer treatment and t reduce the risk f breast cancer develpment in premenpausal and pstmenpausal wmen wh are at increased risk f this disease. Few studies, hwever, have evaluated the effectiveness f tamxifen in wmen with BRCA1 r BRCA2 mutatins. Data frm three studies suggest that tamxifen may be able t help lwer the risk f breast cancer in BRCA1 and BRCA2 mutatin carriers (18 20). Tw f these studies examined the effectiveness f tamxifen in helping t reduce the develpment f cancer in the ppsite breast f wmen underging treatment fr an initial breast cancer (19, 20). Anther drug, ralxifene, was shwn in a large clinical trial spnsred by the Natinal Cancer Institute (NCI) t reduce the risk f develping invasive breast cancer in pstmenpausal wmen at increased risk f this disease by abut the same amunt as tamxifen. As a result, ralxifene was apprved by the FDA fr breast cancer risk reductin in pstmenpausal wmen. Since tamxifen and ralxifene inhibit the grwth f breast cancer cells in similar ways, ralxifene may be able t help reduce breast cancer risk in pstmenpausal BRCA1 and BRCA2 mutatin carriers. Hwever, this has nt been studied directly. 12. What are sme f the benefits f genetic testing fr breast and varian cancer risk? There can be benefits t genetic testing, whether a persn receives a psitive r a negative result. The ptential benefits f a negative result include a sense f relief and the pssibility that special preventive checkups, tests, r surgeries may nt be needed. A psitive test result can bring relief frm uncertainty and allw peple t make infrmed decisins abut their future, including taking steps t reduce their cancer risk. In additin, many peple wh have a psitive test result may be able t participate in medical research that culd, in the lng run, help reduce deaths frm breast cancer. 13. What are sme f the risks f genetic testing fr breast and varian cancer risk? The direct medical risks, r harms, f genetic testing are very small, but test results may have an effect n a persn s emtins, scial relatinships, finances, and medical chices.

7 Peple wh receive a psitive test result may feel anxius, depressed, r angry. They may chse t underg preventive measures, such as prphylactic surgery, that have serius lng-term implicatins and whse effectiveness is uncertain. Peple wh receive a negative test result may experience survivr guilt, caused by the knwledge that they likely d nt have an increased risk f develping a disease that affects ne r mre lved nes. Because genetic testing can reveal infrmatin abut mre than ne family member, the emtins caused by test results can create tensin within families. Test results can als affect persnal chices, such as marriage and childbearing. Issues surrunding the privacy and cnfidentiality f genetic test results are additinal ptential risks (see belw). 14. What can happen when genetic test results are placed in medical recrds? Clinical test results are nrmally included in a persn s medical recrds. Cnsequently, individuals cnsidering genetic testing must understand that their results might nt be kept private. Because a persn s genetic infrmatin is cnsidered health infrmatin, it is cvered by the Privacy Rule f the Health Infrmatin Prtability and Accuntability Act (HIPAA) f 1996 (21). The Privacy Rule requires that health care prviders and thers prtect the privacy f health infrmatin, sets bundaries n the use and release f health recrds, and empwers individuals t cntrl certain uses and disclsures f their health-related infrmatin. Many states als have laws t prtect the privacy and limit the release f genetic and ther health infrmatin. In 2008, the Genetic Infrmatin Nndiscriminatin Act (GINA) became Federal law (see Questin 15). GINA prhibits discriminatin based n genetic infrmatin in relatin t health insurance and emplyment, but the law des nt cver life insurance, disability insurance, and lng-term care insurance. When applying fr these types f insurance, peple may be asked t sign frms that give an insurance cmpany permissin t access their medical recrds. The insurance cmpany may take genetic test results int accunt when making decisins abut cverage. Sme physicians keep genetic test results ut f medical recrds. Hwever, even if such results are nt included in a persn s medical recrds, infrmatin abut a persn s genetic prfile can smetimes be gathered frm that persn s family medical histry. 15. What is genetic discriminatin, and are there laws t prtect peple frm this type f discriminatin? Genetic discriminatin ccurs when peple are treated differently by insurance cmpanies r emplyers because they have a gene mutatin that increases their risk f a disease, such as cancer. Hwever, in 2008, GINA was enacted t prtect U.S. citizens against discriminatin based n their genetic infrmatin in relatin t health insurance and emplyment (22, 23). The parts f the law relating t health insurers will take effect between May 2009 and May 2010, and thse relating t emplyers will take effect by Nvember The law des nt cver life insurance, disability insurance, and lngterm care insurance. In additin, the law des nt cver members f the military. Sme f the prtectins under GINA with regard t health insurance include the fllwing:

8 Premiums r cntributins t a grup health plan cannt be increased based n the genetic infrmatin f an individual(s) enrlled in the plan. Insurers cannt require an individual r family member t underg a genetic test befre enrllment in a grup health plan. Insurers cannt request, require, r purchase genetic infrmatin abut an individual befre the persn s enrllment in a grup health plan r in cnnectin with that persn s enrllment in the plan. Health insurers cannt use genetic infrmatin as the nly basis upn which t claim a pre-existing cnditin is present and, therefre, t deny cverage. Sme f the prtectins under GINA with regard t emplyment include the fllwing: Emplyers cannt refuse t hire and cannt fire individuals based n their genetic infrmatin. Emplyers cannt discriminate against emplyees with regard t salary, terms and cnditins f emplyment, privileges, and pprtunities fr the future because f their genetic infrmatin. Emplyers cannt request, require, r purchase genetic infrmatin abut an emplyee except under specific circumstances. Emplyers cannt disclse an emplyee's genetic infrmatin except under specific circumstances. Befre GINA was passed, many states enacted laws against genetic discriminatin. The amunt f prtectin prvided by these laws varies widely frm state t state. GINA sets a minimum standard f prtectin that must be met by all states. It des nt weaken the prtectins prvided by any state law. 16. In general, what factrs increase r decrease the chance f develping breast cancer and/r varian cancer? The fllwing factrs have been assciated with increased r decreased risk f develping breast and/r varian cancer in the general ppulatin. It is nt yet knwn exactly hw these factrs influence risk in peple with BRCA1 r BRCA2 mutatins. In additin, a significant prtin f hereditary breast cancers are nt assciated with BRCA1 r BRCA2 mutatins (8). Age The risks f breast and varian cancer increase with age. Mst breast and varian cancers ccur in wmen ver the age f 50. Wmen with harmful BRCA1 r BRCA2 mutatins ften develp breast r varian cancer befre age 50. Family Histry Wmen wh have a first-degree relative (mther, sister, r daughter) r ther clse relative with breast and/r varian cancer may be at increased risk f develping these cancers. In additin, wmen with relatives wh have had cln cancer may be at increased risk f develping varian cancer. Medical Histry Wmen wh have already had breast cancer are at increased risk f develping breast cancer again, r f develping varian cancer. Hrmnal Influences Estrgen is a hrmne that is naturally prduced by the bdy and stimulates the nrmal grwth f breast tissue. It is thught that excess estrgen may cntribute t breast cancer risk because f its natural rle in stimulating breast cell grwth. Wmen wh had their first menstrual perid befre the age f 12 r experienced menpause after age 55 have a slightly increased risk f breast cancer, as d wmen wh had their first child after age 30. Each f these

9 factrs increases the amunt f time a wman s bdy is expsed t estrgen. Remval f a wman s varies, which are the main surce f estrgen prductin, reduces the risk f breast cancer. Breast-feeding als reduces breast cancer risk and is thught t exert its effects thrugh hrmnal mechanisms (24). Birth Cntrl Pills (Oral Cntraceptives) Mst studies have shwn a slight increase r n change in risk f breast cancer amng wmen taking birth cntrl pills (24). In cntrast, numerus studies have shwn that taking birth cntrl pills decreases a wman s risk f develping varian cancer (25). This prtective benefit appears t increase with the duratin f ral cntraceptive use and persists up t 25 years after discntinuing use. It als appears that the use f birth cntrl pills lwers the risk f varian cancer in wmen wh carry harmful BRCA1 r BRCA2 mutatins (26). Hrmne Replacement Therapy Dctrs may prescribe hrmne replacement therapy (HRT) t reduce the discmfrt f certain symptms f menpause, such as ht flashes. Hwever, the results f the Wmen s Health Initiative (WHI), a large clinical study cnducted by the Natinal Heart, Lung, and Bld Institute, part f the Natinal Institutes f Health (NIH), shwed that HRT with the hrmnes estrgen and prgestin is assciated with harmful side effects, including an increased risk f breast cancer and increased risks f heart attack, bld clts, and strke. The WHI als shwed that HRT with estrgen alne was assciated with increased risks f bld clts and strke, but the effect n breast cancer risk was uncertain (27). In additin, the WHI shwed an increase in varian cancer risk amng wmen wh received estrgen and prgestin HRT, but this finding was nt statistically significant (28). Because f these ptential harmful side effects, the FDA has recmmended that HRT be used nly at the lwest dses fr the shrtest perid f time needed t achieve treatment gals. N data have been reprted t date regarding the effects f HRT n breast cancer risk amng wmen carrying harmful BRCA1 r BRCA2 mutatins, and nly limited data are available regarding HRT use and varian cancer risk amng such wmen. In ne study, HRT use did nt appear t affect varian cancer risk amng wmen with BRCA1 r BRCA2 mutatins (29). When cnsidering HRT use, bth the ptential harms and benefits f this type f treatment shuld be discussed carefully by a wman and her health care prvider. Obesity Substantial evidence indicates that besity is assciated with an increased risk f breast cancer, especially amng pstmenpausal wmen wh have nt used HRT (24). Evidence als suggests that besity is assciated with increased mrtality (death) frm varian cancer (30). Physical Activity Numerus studies have examined the relatinship between physical activity and breast cancer risk, and mst f these studies have shwn that physical activity, especially strenuus physical activity, is assciated with reduced risk. This decrease in risk appears t be mre prnunced in premenpausal wmen and wmen with lwer-than-nrmal bdy weight (24). Alchl There is substantial evidence that alchl cnsumptin is assciated with increased breast cancer risk. Hwever, it is uncertain whether reducing alchl cnsumptin wuld decrease breast cancer risk (24).

10 Dietary Fat Althugh early studies suggested a pssible assciatin between a high-fat diet and increased breast cancer risk, mre recent studies have been incnclusive. In the WHI, a lw-fat diet did nt help reduce breast cancer risk (31). 17. Where can peple get mre infrmatin abut genetic testing fr cancer risk? A persn wh is cnsidering genetic testing shuld speak with a prfessinal trained in genetics befre deciding whether t be tested. These prfessinals may include dctrs, genetic cunselrs, and ther health care wrkers trained in genetics (such as nurses, psychlgists, r scial wrkers). Fr help finding a health care prfessinal trained in genetics, please visit NCI s Cancer Genetics Services Directry at n the Internet. Alternatively, please cntact NCI s Cancer Infrmatin Service (CIS) (see belw fr cntact infrmatin). The CIS can prvide mre infrmatin abut genetic testing and help in finding a health care prfessinal trained in genetics. 18. What research is currently being dne t help individuals with harmful BRCA1 r BRCA2 mutatins? Research studies are being cnducted t find newer and better ways f detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutatin carriers. Additinal studies are fcused n imprving genetic cunseling methds and utcmes. Our knwledge in these areas is evlving rapidly. Infrmatin abut active clinical trials (research studies with peple) fr individuals with BRCA1 r BRCA2 mutatins is available n NCI s Web site. The fllwing links will initiate searches f NCI s clinical trials database and retrieve lists f trials pen t individuals with BRCA1 r BRCA2 mutatins. BRCA1 mutatin carriers BRCA2 mutatin carriers In additin, NCI s CIS can prvide infrmatin abut clinical trials and help with clinical trial searches (see belw fr cntact infrmatin).