BRCA1 and BRCA2 Mutatins ROBERT LEVITT, MD JESSICA BERGER-WEISS, MD ADRIENNE POTTS, MD HARTAJ POWELL, MD, MPH COURTNEY LEVENSON, MD LAUREN BURNS, MSN, RN, WHNP OBGYNCWC.COM v Cancer is a cmplex disease thught t be caused by several different factrs. A few types f cancer run in families. These types, called hereditary r familial cancer, have been linked t changes in genes that can be passed frm parents t children. v Changes in genes are called mutatins. v Hereditary breast and varian cancer syndrme is a type f familial cancer. It mst cmmnly is linked t mutatins in tw genes called BRCA1 and BRCA2. Inheriting ne f these mutatins increases the risk f getting breast cancer, varian cancer, and ther types f cancer. Abut 10% f cases f varian cancer and 3 5% f cases f breast cancer are due t mutatins in BRCA1 and BRCA2. BRCA Mutatins and Cancer Cancer is a disease that affects the nrmal grwth f cells in the bdy. v Nrmal, healthy cells grw, divide, and are replaced n a regular basis. v Cancer ccurs when cells begin t grw ut f cntrl. v Cancer cells can quickly multiply and frm grwths r tumrs. v In sme types f cancer, cells spread t ther parts f the bdy, where they can grw t frm new cancerus areas. BRCA1 and BRCA2 are knwn as tumr suppressr genes. v They keep cells frm grwing t rapidly r in an uncntrlled way. v Thusands f mutatins in BRCA1 and BRCA2 have been fund. v Sme have been linked t an increased risk f cancer. Hw Cancer Genes Wrk All genes cme in pairs. 10801 LOCKWOOD DR, # 310 / 320 SILVER SPRING, MD 20901 301.681.3400 P 301.681.7982 F
v One cpy f each gene in a pair is inherited frm the mther, and the ther cpy is inherited frm the father. v Cells need bth cpies t wrk nrmally. v Inheriting ne cpy f a BRCA1 r BRCA2 mutatin increases the risk f getting cancer, but it des nt necessarily mean that yu will get cancer. v The ther cpy f the gene withut a mutatin keeps cells frm grwing ut f cntrl. But if the nrmal cpy f the gene becmes damaged, it can increase the risk that cancer will ccur. v Genes can be damaged by many factrs, including chemicals, radiatin, smking, and sun expsure. Many f the factrs that damage genes are unknwn. Wh Is Affected? Abut 1 in 300 peple carry a BRCA1 mutatin, and 1 in 800 carry a BRCA2 mutatin. These mutatins are fund mre frequently in certain ethnic grups, including peple f Ashkenazi (Eastern Eurpean) Jewish, French Canadian, and Icelandic backgrunds, but they can ccur in anyne. Effect f BRCA Mutatins n Cancer Risk All wmen have a certain risk f getting breast cancer r varian cancer at sme pint in their lives. Having a BRCA mutatin increases this risk (Table 1). v Wmen wh have a BRCA1 r BRCA2 mutatin als have an increased risk f cancer f the vary, fallpian tube, peritneum, and pancreas. v Men wh have a BRCA1 r BRCA2 mutatin have an increased risk f breast cancer and an increased risk f prstate and pancreatic cancer. Table 1. Breast Cancer and Ovarian Cancer Risk fr Wmen With BRCA Mutatins Risk With Risk With Type f Cancer Risk fr the General Ppulatin BRCA1 Mutatin BRCA2 Mutatin Breast Ovary 12% 1.4% 55 65% 39% 45% 11 17% Tests fr BRCA1 and BRCA2 Mutatins All wmen shuld be asked specific questins abut their persnal and family histry f breast cancer and varian cancer (see bx). If answers t these questins suggest that yu may have inherited ne f these mutatins, genetic testing may be ffered. Genetic testing requires a DNA sample frm bld r saliva. There are several appraches t testing that can be fllwed. DNA Sequencing
v If a relative with breast cancer r varian cancer is available, the relative s BRCA genes can be analyzed t find ut if a specific BRCA mutatin is present. This is called DNA sequencing. v Yur DNA then can be tested t see if yu have the same mutatin. v This ptin is the best way t knw if yu are at risk. v If n relative is available, and yu and yur family belng t an ethnic grup with high numbers f peple with a specific BRCA mutatin, yu can be tested fr this mutatin. v If yu are nt part f a high-risk ethnic grup, anther ptin is t have DNA sequencing f yur BRCA genes. v This ptin usually is nt the first chice because f the time and expense invlved. Befre yu have genetic testing, a health care prvider with expertise in cancer genetics can help yu understand hw the test is dne, what the results may mean, and what yu may d depending n the test results. Yu als shuld discuss current laws abut genetic discriminatin and privacy f genetic infrmatin. The Federal Genetic Infrmatin Nndiscriminatin Act f 2008 prtects peple against health and emplyment discriminatin based n genetic infrmatin. Many states have similar laws. Understanding Test Results v A psitive test result means that yu have the BRCA mutatin fr which yu have been tested. v A negative test result can mean several things, depending n the testing that yu have had perfrmed: Scenari 1 If yu were tested fr a specific BRCA mutatin linked t cancer in yur family (eg, a family member with cancer has given a DNA sample and a knwn BRCA mutatin is fund), and yu have a negative test result fr that BRCA mutatin, yu have nt inherited the gene. Yu have the same risk f breast and varian cancer as the general ppulatin. Scenari 2 If yu have a family histry f cancer but n family member with cancer has given a DNA sample, and yu have a negative test result fr a BRCA mutatin, it can mean that yur family has a gene that increases cancer risk that is nt a BRCA mutatin.
Or, it can mean that yur family has a BRCA mutatin that cannt be fund with current tests. With these tw pssibilities, it remains unclear whether yu have an inherited predispsitin fr cancer. A third pssibility is that yur family des nt have a gene that increases the risk f cancer. v Yu als can have an unclear test result. This means there is a change in a BRCA gene, but it is nt knwn whether the change increases the risk f cancer. v Researchers are cntinuing t study many mre BRCA mutatins t determine hw they may r may nt influence cancer risk. v If yu have a negative result r an unclear result, a genetic cunselr may be able t determine which scenari is mst likely fr yu and what risk- reductin strategies may be apprpriate. What a Psitive Test Result Means fr Yu and Yur Family A psitive test result fr a BRCA mutatin assciated with cancer means that yu have an increased risk f getting cancer. It des nt mean that yu will get cancer. v There is n test currently available that can tell which wmen with a BRCA mutatin will develp cancer r at what age. It is imprtant t discuss yur results with yur health care prvider and learn abut preventive strategies that may be available t yu t decrease yur risk f cancer v Having a BRCA mutatin means that yu can pass the gene t yur children. Each child has a 50% chance f getting the gene. v Yur siblings als may be at risk f having the gene. Each f yur siblings has a 50% chance f having inherited the gene. v Whether t tell family members that yu have a BRCA1 r BRCA2 mutatin is yur chice. Yur health care prvider cannt disclse this infrmatin t them. Yu are nt bligated t tell yur family members, but it ften is a gd idea t d s. Sharing this infrmatin allws yur family members t decide whether they want t be tested and t get apprpriate preventive care if they als have a mutatin. Shuld Yu Be Tested? If yu answer yes t any f the fllwing questins, genetic risk assessment IS recmmended: v D yu have a persnal histry f breast cancer and varian cancer?*
v D yu have a persnal histry f varian cancer* and a clse relative with varian cancer r premenpausal breast cancer r bth? v D yu have a persnal histry f varian cancer* and are yu f Ashkenazi Jewish ancestry? v Have yu had a breast cancer diagnsis at age 50 years r yunger and d yu have a clse relative with varian cancer * r male breast cancer at any age? v Are yu f Ashkenazi Jewish ancestry and have yu had a breast cancer diagnsis at age 40 years r yunger? v D yu have a clse relative with a knwn BRCA1 r BRCA2 mutatin? If yu answer yes t any f the fllwing questins, genetic risk assessment MAY BE helpful: v Have yu had a breast cancer diagnsis at age 40 years r yunger? v D yu have a persnal histry f varian cancer, primary peritneal cancer, r fallpian tube cancer f high-grade, serus histlgy that was diagnsed at any age? v D yu have a persnal histry f bilateral breast cancer (particularly if the first case f breast cancer was diagnsed at age 50 years r yunger)? v Have yu had a breast cancer diagnsis at age 50 years r yunger and d yu als have a clse relative with breast cancer diagnsed at age 50 years r yunger? v Are yu f Ashkenazi Jewish ancestry and have yu had a breast cancer diagnsis at age 50 years r yunger? v D yu have a persnal histry f breast cancer diagnsed at any age and tw r mre clse relatives with breast cancer at any age (particularly if at least ne case f breast cancer was diagnsed at age 50 years r yunger)? v Have yu never had breast r varian cancer but have a clse relative that meets ne f the previus criteria? *Cancer f the peritneum and fallpian tubes shuld be cnsidered a part f the spectrum f the hereditary breast and varian cancer syndrme. Clse relative is defined as a first-degree relative (parent r sibling) r secnd-degree relative (grandparent, grandchild, aunt, uncle, niece, nephew). Cancer Preventin if Yu Have a BRCA Mutatin If yu test psitive fr a BRCA mutatin, yu may want t discuss preventive strategies with yur health care prvider. Preventin includes screening tests, medicatins, and surgery.
Screening Tests Enhanced breast cancer screening fr wmen with BRCA mutatins is recmmended. Enhanced breast cancer screening may include the fllwing tests: v Clinical breast exam by a health care prvider twice a year v Annual mammgraphy and annual breast magnetic resnance imaging (MRI) starting at age 25 years r yunger based n the earliest age at which breast cancer was diagnsed in the family v breast self-awareness: It is als helpful t be aware f hw yur breasts nrmally lk and feel and reprt any changes t yur health care prvider. This is called breast self-awareness. Screening fr varian cancer in wmen with BRCA mutatins als may be recmmended. Current screening tests include v peridic bld tests fr CA 125 (a substance that is made by varian cancer cells) and an ultrasund exam f the varies. v Testing can begin between the ages f 30 years and 35 years r 5 10 years earlier than the age at which varian cancer was diagnsed in the yungest affected relative. v These screening tests have a limited ability t find varian cancer at an earlier, mre treatable stage. v Test results may be nrmal even when cancer is present. v There als is a high rate f false- psitive results (a psitive test result in smene wh des nt have varian cancer). Medicatins The use f drugs t help reduce the risk f r delay the ccurrence f cancer is called chempreventin. v Taking a medicatin called tamxifen has been shwn t reduce the risk f breast cancer in wmen with BRCA2 mutatins. v Tamxifen is a drug that is used t treat and prevent estrgen-psitive breast cancer. Estrgen-psitive means that the cancer cells respnd t the hrmne estrgen. Estrgen in the bldstream can cause the cancer cells t grw. Tamxifen blcks the effects f estrgen n these cancer cells. Tamxifen wrks well in wmen with BRCA2 mutatins because abut 70% f breast cancer tumrs in this grup are estrgen-psitive. Less than 25% f tumrs in wmen with BRCA1 mutatins are estrgen-psitive. Tamxifen des nt appear t reduce breast cancer risk in wmen with BRCA1 mutatins.
v Cmbined hrmnal birth cntrl pills (thse that cntain estrgen and anther hrmne called prgestin) may reduce the risk f varian cancer and fallpian tube cancer in wmen with BRCA mutatins. If yu are thinking abut using cmbined hrmnal birth cntrl pills, yu shuld carefully weigh the risks and benefits fr chempreventin and birth cntrl. Surgery Surgery is anther preventive ptin fr wmen with BRCA1 and BRCA2 mutatins. This type f surgery is called risk-reducing surgery. v Risk-reducing bilateral salping- phrectmy is the remval f bth varies and bth fallpian tubes. It can significantly reduce the risk f varian cancer, fallpian tube cancer, and peritneal cancer in wmen with a BRCA mutatin. If it is dne befre menpause, having this surgery als can reduce the risk f breast cancer. Wmen with these mutatins shuld cnsider having this surgery befre age 40 years r after they have cmpleted their families. An imprtant cnsideratin t think abut is that salping-phrectmy perfrmed befre menpause will cause yu t experience menpause immediately, rather than ver several years. Signs and symptms f menpause ften can be managed with hrmne therapy and ther treatments. Yu can discuss these treatment ptins with yur health care prvider befre yur surgery. v Bilateral mastectmy (surgical remval f bth breasts) reduces the risk f breast cancer by mre than 90 95%. The type f mastectmy is imprtant in reducing risk. v Ttal mastectmy, in which the entire breast tissue is remved, including the nipple and arela, is the mst effective risk-reducing surgery fr breast cancer. Mastectmy that remves the breast tissue and leaves the nipple and arela als can be cnsidered. If yu are thinking abut having preventive surgery, yu and yur health care prvider will cnsider the risks and benefits. Yu shuld discuss the psychlgical effects as well as shrt- and lng-term cmplicatins.
Timing f surgery shuld be based n yur needs, yur desire t have children, and the effect that surgery will have n yur well- being. Finding Mre Infrmatin If yu have a persnal r family histry f breast cancer r varian cancer, getting tested fr BRCA mutatins may be smething that yu want t cnsider. Talk t yur health care prvider abut screening and testing ptins. The fllwing rganizatins ffer additinal infrmatin abut BRCA and cancer risk: American Cancer Sciety Genetics and Cancer www.cancer.rg/cancer/cancercauses/geneticsandcancer/genetics-and-cancer-landing Centers fr Disease Cntrl and Preventin KNOW: BRCA www.cdc.gv/cancer/breast/yung_wmen/knwbrca.htm Natinal Cancer Institute: BRCA1 and BRCA2: Cancer Risk and Genetic Testing www.cancer.gv/cancertpics/factsheet/risk/brca