Protocol. Genetic Testing for Hereditary Breast and Ovarian Cancer Syndrome

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1 (20402, ) Medical Benefit Effective Date: 01/01/18 Next Review Date: 09/18 Preauthrizatin Yes Review Dates: 02/07, 01/08, 11/08, 09/09, 05/10, 05/11, 01/12, 01/13, 01/14, 05/14, 05/15, 05/16, 09/16, 03/17, 09/17 Preauthrizatin is required fr services which may be medically necessary under this prtcl. Fr tests that this prtcl cnsiders investigatinal, if the physician feels the service is medically necessary, preauthrizatin is recmmended. The fllwing prtcl cntains medical necessity criteria that apply fr this service. The criteria are als applicable t services prvided in the lcal Medicare Advantage perating area fr thse members, unless separate Medicare Advantage criteria are indicated. If the criteria are nt met, reimbursement will be denied and the patient cannt be billed. Please nte that payment fr cvered services is subject t eligibility and the limitatins nted in the patient s cntract at the time the services are rendered. Ppulatins Interventins Cmparatrs Outcmes Individuals: With cancer, r a persnal r family cancer histry and criteria suggesting a risk f hereditary breast/ varian cancer syndrme Individuals: With risk f hereditary breast/varian cancer Individuals: With risk f hereditary breast/varian cancer Individuals: With risk f hereditary breast/varian cancer Interventins f interest are: Genetic testing fr a BRCA1 r BRCA2 mutatin Interventins f interest are: Genetic testing fr a PALB2 variant Interventins f interest are: Genetic testing fr CHEK2 variant Interventins f interest are: Genetic testing fr an ATM variant Cmparatrs f interest are: N genetic testing Cmparatrs f interest are: N genetic testing Cmparatrs f interest are: N genetic testing Cmparatrs f interest are: N genetic testing Relevant utcmes include: Overall survival Disease-specific survival Test accuracy Test validity Mrbid events Quality f life Treatment-related mrbidity Relevant utcmes include: Overall survival Disease-specific survival Test accuracy Test validity Relevant utcmes include: Overall survival Disease specific survival Test accuracy Test validity Relevant utcmes include: Overall survival Disease-specific survival Test accuracy Test validity Descriptin Hereditary breast and varian cancer (HBOC) syndrme describes the familial cancer syndrmes that are related t mutatins in the BRCA genes (BRCA1 lcated n chrmsme 17q21, BRCA2 lcated n chrmsme 13q12-13). Families with HBOC syndrme have an increased susceptibility t breast cancer ccurring at a yung age, bilateral breast cancer, male breast cancer, varian cancer at any age, cancer f the fallpian tube, and primary Page 1 f 18

2 peritneal cancer as well as ther cancers, such as prstate cancer, pancreatic cancer, gastrintestinal cancers, melanma, and laryngeal cancer. Abut 3% t 5% f wmen presenting fr assessment fr hereditary breast/varian cancer risk have a variant in a gene that mderately increases the risk f cancer, rather than having ne f the well described familial breast/ varian cancer syndrmes (e.g., BRCA1, BRCA2). PALB2, CHEK2, and ATM variants are cnsidered t be f mderate penetrance and carriers have an apprximately tw t fur fld increased risk f develping breast cancer cmpared with the general ppulatin. Risk estimates may be higher in patients with a family histry f breast cancer r fr a specific variant. Summary f Evidence Fr individuals wh have cancer r a persnal r family cancer histry and meeting criteria suggesting a risk f hereditary breast and varian cancer (HBOC) syndrme wh receive genetic testing fr a BRCA1 r BRCA2 mutatin, the evidence includes a TEC Assessment and studies f mutatin prevalence and cancer risk. Relevant utcmes are verall survival, disease-specific survival, test accuracy and validity, mrbid events, quality f life, and treatment-related mrbidity. The accuracy f mutatin testing has been shwn t be high. Studies f lifetime risk f cancer fr carriers f a BRCA mutatin have shwn a risk as high as 85%. Knwledge f BRCA mutatin status in individuals at risk f a BRCA mutatin may impact health care decisins t reduce risk, including intensive surveillance, chempreventin, and/r prphylactic interventin. The evidence is sufficient t determine that the technlgy results in a meaningful imprvement in the net health utcme. Fr individuals with risk f hereditary breast/varian cancer wh receive genetic testing fr a PALB2 variant, the evidence include studies f analytic validity, variant prevalence, and multiple studies f breast cancer risk, including ne meta-analysis. Relevant utcmes are verall survival, disease-specific survival, and test accuracy and validity. The reprted evidence supprting analytic validity is nt substantial, but given current next-generatin sequencing techniques with variant cnfirmatin by cnventinal methds, high analytic sensitivity such as reprted by Judkins et al (2015) is expected in a labratry certified by the Clinical Labratry Imprvement Amendments meeting standards fr high-cmplexity mlecular diagnstics. Evidence supprting clinical validity was btained frm nine studies reprting relative risks r dds ratis (tw studies estimated penetrance). Study designs included family segregatin, kin-chrt, family-based case-cntrl, and ppulatin-based case-cntrl. The number f pathgenic variants identified in studies varied frm ne (funder variants) t 48. Relative risks fr breast cancer assciated with a PALB2 variant ranged frm 2.3 t 13.4, with the tw family-based studies reprting the lwest values. Evidence n preventive interventins in wmen with PALB2 variants is indirect, relying n studies f high-risk wmen and BRCA carriers. Cmpared with ther screening mdalities, magnetic resnance imaging (MRI) has a higher sensitivity, but increased false psitives when high-risk wmen are screened. Screening recmmendatins fr high-risk asymptmatic wmen include beginning at an earlier age and additin f MRI t mammgraphy. Hwever, there is n direct evidence and limited bservatinal data suggesting imprved utcmes. There is limited bservatinal evidence that chempreventin can decrease the risk f invasive cancers in high-risk wmen; the U.S. Preventive Services Task Frce (USPSTF) reprt and Natinal Cmprehensive Cancer Netwrk (NCCN) supprt a chempreventin ptin. In high-risk wmen, prphylactic mastectmy (bilateral r cntralateral) reduces the risk f breast cancer and breast cancer mrtality and decisin analytic mdels prject increased life-expectancy. Prphylactic mastectmy can be accmpanied by a significant risk f adverse effects and studies have fund a minrity f asymptmatic BRCA carriers chse t underg a bilateral prphylactic mastectmy. Given the penetrance f PALB2 variants, the utcmes fllwing bilateral and cntralateral prphylactic mastectmy examined in wmen with a family histry cnsistent with hereditary breast cancer (including BRCA1 and BRCA2 carriers) can be applied t wmen with PALB2 variants with the benefit t risk balance affected by penetrance. In wmen at high risk f hereditary breast cancer wh Page 2 f 18

3 wuld cnsider preventive interventins, identifying a PALB2 variant prvides a mre precise estimated risk f develping breast cancer cmpared with family histry alne and can ffer wmen a mre accurate understanding f tradeffs invlved fr any interventin. The evidence is sufficient t determine that the technlgy results in a meaningful imprvement in the net health utcme. Fr individuals with risk f hereditary breast/varian cancer wh receive genetic testing f fr a CHEK2 variant r an ATM variant, the evidence includes studies f analytic validity, variant prevalence, and studies f breast cancer risk. Relevant utcmes are verall survival, disease-specific survival, and test accuracy and validity. The available studies n clinical validity have demnstrated that bth CHEK2 and ATM2 variants are f mderate penetrance, with lwer relative risks fr breast cancer than PALB2, and cnfer a risk f breast cancer tw t fur times that f the general ppulatin. Direct evidence fr the clinical utility f genetic testing fr CHEK2 r ATM variants in individuals with risk f hereditary breast/varian cancer was nt identified. Fr wmen with high-risk hereditary cancer syndrmes, interventins t decrease breast cancer risk in high-risk wmen include screening (e.g., starting at an early age, additin f MRI t mammgraphy, and annually), chempreventin, prphylactic mastectmy, and prphylactic phrectmy. Fllwing the lgic applied in the case f PALB2, there is limited evidence that chempreventin can decrease the risk f invasive cancers in high-risk wmen; the USPSTF reprt and NCCN supprt a chempreventin ptin. In cntrast t the case f PALB2, where the penetrance appraches that f a BRCA variant, there is unlikely t be a similar benefit-t-risk calculus fr wmen with a CHEK2 variant making a decisin abut a prphylactic mastectmy. It is unclear that the relative risk assciated with the mderate penetrance variants wuld increase risk enugh beynd that already cnferred by familial risk t change screening behavir. The evidence is insufficient t determine the effects f the technlgy n health utcmes. Plicy Fr individuals frm a family with a knwn deleterius BRCA1 r BRCA2 mutatin, genetic testing fr a BRCA1 r BRCA2 mutatin may be cnsidered medically necessary. Genetic testing fr a BRCA1 and BRCA2 mutatins may be cnsidered medically necessary fr testing an individual with cancer r histry f cancer AND fr testing an unaffected individual with a strng family histry f cancer when ANY f the fllwing criteria are met: Diagnsed with breast cancer prir t 45 years f age; OR Diagnsed with tw breast cancers prir t 50 years f age; OR Diagnsed at any age and at least ne first-, secnd- r third-degree relative with breast cancer diagnsed at 50 years f age r yunger; OR Multiple primary breast cancers r bilateral breast cancer; OR Male with breast cancer; OR Triple negative breast cancer diagnsed at 60 years f age r yunger; Breast cancer and at least ne first-, secnd- r third-degree male relative with breast cancer; OR Breast cancer AND tw r mre 1st-, 2nd-, r 3rd-degree relatives n the same side f the family with breast, varian, fallpian tube, primary peritneal r pancreatic cancer; OR Ovarian, fallpian tube r primary peritneal CA; OR Page 3 f 18

4 Pancreatic cancer and tw r mre 1st-, 2nd-, r 3rd-degree relatives n the same side f the family with breast, varian, fallpian tube, primary peritneal r pancreatic cancer; OR Ashkenazi Jewish descent and has a histry f pancreatic cancer and a first-, secnd-, r third-degree relative n the same side f the family with breast, varian, fallpian tube, primary peritneal r pancreatic cancer; OR The member has a histry f breast cancer and belngs t a ppulatin at risk fr specific mutatins due t ethnic backgrund (e.g., Ashkenazi Jewish, Icelandic, Swedish, Hungarian r Dutch descent). Family histry f three r mre first-, secnd- r third-degree relatives with breast (at least ne f which has breast cancer prir t age 50), varian, fallpian tube r primary peritneal cancer. Large genmic rearrangement testing (BART) when testing fr mutatins is negative in individuals wh meet criteria fr genetic testing. Persnal histry f epithelial varian cancer Testing fr PALB2 is cnsidered medically necessary when all f the fllwing criteria are met: Age 18 years r lder Individual tested negative fr BRCA1 and/r BRCA2 Individual is at risk fr hereditary breast cancer, as indicated by any ONE f the fllwing: Persnal histry f male breast cancer diagnsed at any age Persnal histry f breast cancer Family histry f tw r mre first, secnd r third degree bld relatives with breast cancer diagnsed age 45 r yunger Family histry f tw r mre first, secnd r third degree bld relatives with varian cancer diagnsed at any age Unless criteria abve are met, genetic testing either fr thse affected by breast, varian, fallpian tube, r primary peritneal cancer r fr unaffected individuals, including thse with a family histry f pancreatic cancer, is cnsidered investigatinal. Genetic testing in minrs fr BRCA1 and BRCA2 mutatins is investigatinal. BRCA and BART testing as a screening test fr cancer in wmen in the general ppulatin are investigatinal. Testing fr CHEK2 and ATM genetic abnrmalities (mutatins, deletins, etc.) is investigatinal. BRCA and BART testing fr unaffected members f high-risk ppulatins (e.g., Ashkenazi Jewish descendant) wh have n relatives with a histry f breast, varian, fallpian tube r primary peritneal cancer at any age is investigatinal. Genetic testing using multi-gene panels is investigatinal. NGS (Next Generatin Sequencing), when used fr genetic testing fr BRCA1, BRCA2, PALB2 and CHEK2 mutatins, is investigatinal. Plicy Guidelines This testing is necessary nly nce per lifetime. Page 4 f 18

5 Genetic Cunseling Genetic cunseling is primarily aimed at patients wh are at risk fr inherited disrders, and experts recmmend frmal genetic cunseling in mst cases when genetic testing fr an inherited cnditin is cnsidered. The interpretatin f the results f genetic tests and the understanding f risk factrs can be very difficult and cmplex. Therefre, genetic cunseling will assist individuals in understanding the pssible benefits and harms f genetic testing, including the pssible impact f the infrmatin n the individual s family. Genetic cunseling may alter the utilizatin f genetic testing substantially and may reduce inapprpriate testing. Genetic cunseling shuld be perfrmed by an individual with experience and expertise in genetic medicine and genetic testing methds. Hereditary breast and varian cancer Current U.S. Preventive Services Task Frce (USPSTF) guidelines recmmend screening wmen with any family histry f breast, varian, tubal, r peritneal cancer. Wmen with psitive screening results shuld receive genetic cunseling and, if indicated after cunseling, BRCA testing. (Grade B Recmmendatin) Recmmended screening tls designed t identify a family histry that may be assciated with an increased risk fr ptentially harmful mutatins in BRCA1 r BRCA2 are: Ontari Family Histry Assessment Tl (FHAT) Manchester Scring System Referral Screening Tl (RST) Pedigree Assessment Tl (PAT) Family Histry Screen (FHS-7) A Recmmended Testing Strategy In patients with knwn familial BRCA mutatin: Targeted testing fr the specific, knwn mutatin nly. In patients with unknwn familial BRCA mutatin: If mre than ne family member is affected with cancers highly assciated with a particular inherited cancer susceptibility syndrme, cnsider testing first a family member mst likely t carry a mutatin, such as the yungest age at diagnsis, bilateral disease, multiple primary cancers, r ther cancers assciated with the syndrme, r mst clsely related t the prband/patient. If n living family member with breast r varian cancer exists, NCCN suggests testing first- r secnddegree family members affected with a different cancer type that is thught t be related t deleterius BRCA1 r BRCA2 mutatins (e.g., prstate cancer, pancreatic cancer, and melanma). If n familial mutatin can be identified, tw pssible testing strategies are: Full sequencing fllwed by testing fr cmmn large genmic rearrangements (deletins/duplicatins), nly if sequencing detects n mutatin (negative result). Alternatively, simultaneus full sequencing and testing fr cmmn large genmic rearrangements (als knwn as cmprehensive BRCA testing; see Cmprehensive Mutatin Analysis, belw) may be perfrmed as is recmmended by NCCN. If fllwing full sequencing and testing fr cmmn large genmic rearrangements is negative, testing fr uncmmn large genmic rearrangements (e.g., Myriad s BART) may be dne. Page 5 f 18

6 If f Ashkenazi Jewish descent: In Ashkenazi Jewish patients, testing fr funder-specific mutatin(s) shuld be perfrmed first. Cmprehensive genetic testing may be cnsidered if ancestry als includes nn-ashkenazi Jewish relatives r if ther HBOC criteria are met. In members f knwn Ashkenazi Jewish descent, NCCN recmmends testing fr the three knwn funder mutatins (185delAG and 5182insC in BRCA1; 6174delT in BRCA2) first. If testing is negative fr funder mutatins, cmprehensive genetic testing may be cnsidered (see Cmprehensive Variant Analysis, belw). Cmprehensive Variant Analysis Cmprehensive variant analysis currently includes sequencing the cding regins and intrn and exn splice sites, as well as tests t detect cmmn large deletins and rearrangements that can be missed with sequence analysis alne. In additin, befre August 2006, testing fr large deletins and rearrangements was nt perfrmed, thus sme patients with familial breast cancer wh had negative BRCA testing befre this time may cnsider repeat testing fr the rearrangements. High-Risk Ethnic Grups Testing in eligible individuals wh belng t ethnic ppulatins in which there are well-characterized funder sequence variants shuld begin with tests specifically fr these mutatins. Fr example, funder mutatins accunt fr apprximately three quarters f the BRCA sequence variants fund in Ashkenazi Jewish ppulatins. When testing fr funder mutatins is negative, cmprehensive mutatin analysis shuld then be perfrmed. Testing Unaffected Individuals In unaffected family members f ptential BRCA sequence variant families, mst test results will be negative and uninfrmative. Therefre, it is strngly recmmended that an affected family member be tested first whenever pssible t adequately interpret the test. Shuld a BRCA mutatin be fund in an affected family member(s), DNA frm an unaffected family member can be tested specifically fr the same variant f the affected family member withut having t sequence the entire gene. Interpreting test results fr an unaffected family member withut knwing the genetic status f the family may be pssible in the case f a psitive result fr an established disease-assciated variant but leads t difficulties in interpreting negative test results (uninfrmative negative) r variants f uncertain significance because the pssibility f a causative BRCA mutatin is nt ruled ut. Prstate Cancer Patients with BRCA variants have an increased risk f prstate cancer, and patients with knwn BRCA variants may therefre cnsider mre aggressive screening appraches fr prstate cancer. Hwever, the presence f prstate cancer in an individual, r in a family, is nt itself felt t be sufficient justificatin fr BRCA testing. Backgrund Breast Cancer and Genetics In 2016, researchers anticipate breast cancer will be diagnsed in 246,660 wmen and 40,450 will die frm the disease 1 ; a wman s lifetime risk is 12.3% (seer.cancer.gv/statfacts/html/breast.html). Breast cancers can be classified as spradic, familial, r hereditary. 2 Mst are spradic (70% t 75%), ccurring in wmen withut a family histry f disease. Familial cancers (15% t 25%) aggregate within families but lack clearly discernable patterns f inheritance and are likely plygenic. Hereditary cancers have discernable inheritance patterns, ften ccur at yunger ages, may be bilateral, and cmprise between 5% and 10% f breast cancers. Pathgenic Page 6 f 18

7 BRCA1 and BRCA2 variants appear respnsible fr 20% t 25% f hereditary breast cancers a, while small prprtins are attributed t pathgenic variants in ther highly penetrant genes (e.g., TP53, CDH1, PTEN, STK11). a Hereditary breast and varian cancer Several genetic syndrmes with an autsmal dminant pattern f inheritance that feature breast cancer have been identified. Of these, HBOC and sme cases f hereditary site-specific breast cancer have in cmmn causative mutatins in BRCA (breast cancer susceptibility) genes. Families suspected f having HBOC syndrme are characterized by an increased susceptibility t breast cancer ccurring at a yung age, bilateral breast cancer, male breast cancer, varian cancer at any age, as well as cancer f the fallpian tube and primary peritneal cancer. Other cancers, such as prstate cancer, pancreatic cancer, gastrintestinal cancers, melanma, and laryngeal cancer, ccur mre frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early nset breast cancer with r withut male cases, but withut varian cancer. Fr this prtcl, we refer cllectively t bth as hereditary breast and/r varian cancer. Germline mutatins in the BRCA1 and BRCA2 genes are respnsible fr the cancer susceptibility in mst HBOC families, especially if varian cancer r male breast cancer are features. Hwever, in site-specific breast cancer, BRCA mutatins are respnsible nly fr a prprtin f affected families. BRCA gene mutatins are inherited in an autsmal dminant fashin thrugh either the maternal r paternal lineage. It is pssible t test fr abnrmalities in BRCA1 and BRCA2 genes t identify the specific mutatin in cancer cases and t identify family members with increased cancer risk. Family members withut existing cancer wh are fund t have BRCA mutatins can cnsider preventive interventins fr reducing risk and mrtality. Penetrance f Pathgenic Variants Penetrance is the risk cnferred by a pathgenic variant, r the prprtin f individuals with the variant expected t develp cancer. Variant penetrance is cnsidered high, mderate, r lw accrding t lifetime risk: high (> 50%), mderate (20% t 50%), and lw (< 20%) (crrespnding relative risks f apprximately 5, 1.5 t 5, and < ). Variants in nly a few breast cancer-susceptibility genes (BRCA1 and BRCA2 [hereditary breast/ varian cancer syndrme], TP53 [Li-Fraumeni syndrme], PTEN [Cwden syndrme], CDH1 [hereditary diffuse gastric cancer], STK11 [Peutz-Jeghers syndrme]) are cnsidered highly penetrant. Fr example, a wman with a BRCA1 r BRCA2 variant has rughly a 75% lifetime risk f develping breast cancer and a relative risk f 11 t 12 cmpared with the general ppulatin. 4 Penetrance can be mdified by envirnmental factrs and by family histry, which is a particularly imprtant mdifier fr lw- and mderate-penetrance genes. In additin, specific pathgenic variants within a gene may cnfer smewhat different risks. In cntrast, abut 3% t 5% f wmen presenting fr hereditary breast/varian cancer risk assessment have sequence variants in a mderate penetrance gene. Determining Variant Pathgenicity Determining the pathgenicity f variants in a cancer-susceptibility gene mst cmmnly detected (e.g., funder sequence variants) is generally straightfrward because assciatins are repeatedly bserved. Fr uncmmnly identified variants, such as thse fund in a few individuals r families, defining pathgenicity can be mre difficult. Fr example, predicting the pathgenicity f previusly unidentified variants typically requires in silic (cmputatinal) analysis predicting prtein structure/functin, evlutinary cnservatin, and splice site predictin. 5 The apprach t defining pathgenicity is clearly utlined in standards and reprting guidelines. 5 Still, distinctins between a variant f uncertain significance and a pathgenic ne frm different labratries may nt always be identical. 6 Page 7 f 18

8 Genes Assciated With a Mderate Penetrance f Breast Cancer PALB2 The PALB2 gene (partner and lcalizer f BRCA2) encdes fr a prtein first described in The gene is lcated at 16p12.2 a and has 13 exns ( The PALB2 prtein assists BRCA2 in DNA repair and tumr suppressin. Heterzygus pathgenic PALB2 variants increase the risk f develping breast and pancreatic cancers; hmzygus variants are fund in Fancni anemia b. PALB2 variants are truncating frameshift r stp cdns, and are fund thrughut the gene. Pathgenic PALB2 variants are uncmmn in unselected ppulatins and prevalence varies by ethnicity and family histry. Fr example, Antniu et al (2014) assumed a prevalence f eight per 10,000 in the general ppulatin when mdeling breast cancer risks. 8 Variants are mre prevalent in ethnic ppulatins where funder variants have persisted (e.g., Finns, French Canadians, Ples), while infrequently fund in thers (e.g., in Ashkenazi Jews 9, 10 ). In wmen with a family histry f breast cancer, the prevalence f pathgenic PALB2 variants ranges between 0.9% and 3.9%, 8 r substantially higher than in an unselected general ppulatin. Depending n ppulatin prevalence, PALB2 may be respnsible fr as much as 2.4% f hereditary breast cancers 8 ; and in ppulatins with funder variants cause 0.5% t 1% f all breast cancers. 11 Prtein-truncating PALB2 variants appear respnsible fr sme cases f familial pancreatic cancers, but the prprtin is unclear. Whether screening asymptmatic high-risk patients fr pancreatic cancer can imprve health utcmes is uncertain. CHEK2 Gene The CHEK2 (checkpint kinase 2) gene is activated in respnse t DNA duble-strand breakage and plays a rle in cell-cycle cntrl, DNA repair, and apptsis. In 2002, a single recurrent truncating mutatin in the CHEK2 gene (c.1100delc) was first reprted as a cause f breast cancer, and studies have since cnfirmed this. The incidence f CHEK2 variants varies widely amng ppulatins. It is mst prevalent in Eastern and Nrthern Eurpe, where the ppulatin frequency f the c.1100delc allele ranges frm 0.5% t 1.4%; the allele is less frequent in Nrth America and virtually absent in Spain and India. Althugh mst data fr truncating CHEK2 variants are limited t the c.1100delc variant, three ther funder variants f CHEK2 (IVS2+1G>A, del5395, I157T) have been assciated with breast cancer in Eastern Eurpe. IVS2+1G>A and del5395 are prtein-truncating variants, and I157T is a missense variant. The truncating variants are assciated with breast cancer in the Slavic ppulatins f Pland, Belarus, Russia, and the Czech Republic. The I157T variant has a wider gegraphic distributin, and has been reprted t be assciated with breast cancer in Pland, Finland, Germany, and Belarus. 12 ATM Gene ATM (ataxia-telangiectasia [AT] mutated), lcated n chrmsme 11q22.3, is assciated with the autsmal recessive cnditin AT. This cnditin is characterized by prgressive cerebellar ataxia with nset between the ages f ne and fur years, telangiectasias f the cnjunctivae, culmtr apraxia, immune defects, and cancer predispsitin. Female ATM heterzygtes carriers have a risk f breast cancer abut twice as high as that f the general ppulatin, but d nt appear t have an elevated varian cancer risk. Identifying Wmen at Risk f an Inherited Susceptibility t Breast Cancer Breast cancer risk can be affected by genetic and nngenetic factrs. Risk is increased in wmen experiencing an earlier age at menarche, nulliparity, late age f first pregnancy, fewer births, late menpause, prliferative breast disease, menpausal hrmne therapy, alchl, besity, inactivity, and radiatin. 13 A family histry f breast cancer cnfers between a tw and a fur fld increased risk varying accrding t the number and clse- Page 8 f 18

9 ness f affected relatives, age at which cancers develped, whether breast cancers were bilateral, and if ther cancers ccurred (e.g., varian). 14 Fr a wman withut breast cancer, the prbability f detecting a pathgenic variant can be estimated frm a detailed multigeneratinal pedigree (e.g., Breast and Ovarian Analysis f Disease Incidence and Carrier Estimatin Algrithm), 15 screening tls (e.g., BRCAPRO, 16 Ontari Family Histry Assessment Tl, Manchester Scring System, Referral Screening Tl, Pedigree Assessment Tl, Family Histry Screen 17, 18 ), r by referring t guidelines that define specific family histry criteria (see Table 1). Fr wmen with breast cancer, family histry als affects the likelihd f carrying a pathgenic variant, althugh smewhat different criteria are applied (see Table 2) as is risk assessment frm a pedigree. 15 Table 1. NCCN Criteria fr Genetic Risk Evaluatin f an Individual Withut a Histry f Breast Cancer 2 Individual Withut a Histry f Breast Cancer A clse relative with any f the fllwing: A knwn mutatin in a cancer susceptibility gene within the family 2 breast cancer primaries in a single individual 2 individuals with breast cancer primaries n the same side f family with at least ne diagnsed 50 years Ovarian cancer Male breast cancer First- r secnd-degree relative with breast cancer 45 years Family histry f three r mre f the fllwing (especially if early nset and can include multiple primary cancers in same individual): breast, pancreatic cancer, prstate cancer (Gleasn scre 7), melanma, sarcma, adrencrtical carcinma, brain tumrs, leukemia, diffuse gastric cancer, cln cancer, endmetrial cancer, thyrid cancer, kidney cancer, dermatlgic manifestatins, and/r macrcephaly, hamartmatus plyps f GI tract GI: gastrintestinal; NCCN: Natinal Cmprehensive Cancer Netwrk. Table 2. NCCN Criteria fr Genetic Risk Evaluatin f an Individual With Breast Cancer 2 Individual With Breast Cancer A knwn sequence variant in a cancer susceptibility gene within the family: Early-age-nset breast cancer Triple negative (ER-, PR-, HER2-) breast cancer diagnsed 60 years Tw breast cancer primaries in a single individual Breast cancer at any age, and 1 clse bld relative with breast cancer 50 years, r 1 clse bld relative with invasive varian cancer at any age, r 2 clse bld relatives with breast cancer and/r pancreatic cancer at any age, r Frm a ppulatin at increased risk Male breast cancer An individual f Ashkenazi Jewish descent with breast, varian, r pancreatic cancer at any age An individual with a persnal and/r family histry f three r mre f the fllwing (especially if early nset and can include multiple primary cancers in same individual): breast, pancreatic cancer, prstate cancer (Gleasn scre 7), melanma, sarcma, adrencrtical carcinma, brain tumrs, leukemia, diffuse gastric cancer, cln cancer, endmetrial cancer, thyrid cancer, kidney cancer, dermatlgic manifestatins, and/r macrcephaly, hamartmatus plyps f gastrintestinal (GI) tract. An individual with an varian cancer ER: estrgen receptr; HER2: human epidermal grwth factr receptr 2; NCCN: Natinal Cmprehensive Cancer Netwrk; PR: prgesterne receptr. Patient Ppulatins Genetic testing can be cnsidered fr wmen at increased risk f develping hereditary breast cancer based n their family histry, r in wmen with breast cancer whse family histry r cancer characteristics (e.g., triplenegative disease, yung age) increase the likelihd that the breast cancer is hereditary. Testing may als be cnsidered fr wmen frm families with knwn variants. Ptential benefit derives frm interventins (screen- Page 9 f 18

10 ing, chempreventin, risk reducing surgery) that can prevent a first breast cancer, a cntralateral breast cancer, r cancer in a different rgan caused by the same variant. Whether benefit utweighs harms depends n the risk f develping breast cancer (a first cancer r a cntralateral ne), the effectiveness and the harms f interventins. Assessing the net health utcme requires: 1. that a test accurately identifies variants and pathgenicity can be determined; 2. that a variant alters (increasing r decreasing) a wman s risk f develping breast cancer (including cntralateral disease in wmen already diagnsed) sufficient t change decisin making, and f a magnitude that 3. management changes infrmed by testing can lead t imprved health utcmes. Additinally, if a familial pathgenic variant is identified, asymptmatic at-risk family members may benefit frm cascade testing fr the knwn variant. If that variant is identified in an at-risk relative, then risk-reducing management ptins culd be ffered; if the familial variant is nt identified, then the relative may be cnsidered near ppulatin risk and culd avid increased surveillance fr breast cancer and risk reducing ptins wuld nt be cnsidered. Regulatry Status Clinical labratries may develp and validate tests in-huse and market them as a labratry service; labratry-develped tests (LDTs) must meet the general regulatry standards f the Clinical Labratry Imprvement Act (CLIA). PALB2, CHEK2, and ATM testing are available under the auspices f CLIA (a list f labratries ffering testing is available at NCBI s Genetic Testing Registry Labratries that ffer LDTs must be licensed by CLIA fr high-cmplexity testing. T date, the U.S. Fd and Drug Administratin has chsen nt t require any regulatry review f these tests. Myriad Genetic Labratries (Salt Lake City, UT) ffers: (1) Cmprehensive BRACAnalysis that includes cmplete sequencing f BRCA1 and BRCA2 and gap plymerase chain reactin fr five cmmn rearrangements (deletins/duplicatins) in BRCA1; (2) BRACAnalysis Large Rearrangement Test (BART ), which may be rdered as a reflex test fr patients wh test negative fr Cmprehensive BRACAnalysis t detect uncmmn large rearrangements in BRCA1 and BRCA2; and (3) Integrated BRACAnalysis, which includes BART as part f BRCA1 r BRCA2 analysis. Per the website there are currently six CLIA-certified U.S. labratries that ffer sequence analysis f the entire gene cding and fur that ffer deletin. Quest Diagnstics (Madisn, NJ) ffers BRCAvantage that includes sequencing f BRCA1 and BRCA2 and a multiplex ligatin-dependent prbe amplificatin assay t detect bth cmmn and uncmmn gene rearrangements. LabCrp (Burlingtn, NC) ffers the BRCAssure SM suite f tests which includes: targeted BRCA1 and BRCA2 analysis; a funder mutatin panel fr Ashkenazi Jewish patients (three mutatins); cmprehensive BRCA1 and BRCA2 analysis (full gene sequencing plus analysis f cmmn and uncmmn large rearrangements); and deletin/duplicatin analysis f uncmmn large rearrangements nly (withut sequencing) when cmprehensive analysis is negative. Custmized next-generatin sequencing panels prvide simultaneus analysis f multiple cancer predispsitin genes, and typically include bth mderate and high-penetrant genes. Page 10 f 18

11 Related Prtcl Genetic Cancer Susceptibility Panels Using Next-Generatin Sequencing Genetic Testing fr Li-Fraumeni Services that are the subject f a clinical trial d nt meet ur Technlgy Assessment Prtcl criteria and are cnsidered investigatinal. Fr explanatin f experimental and investigatinal, please refer t the Technlgy Assessment Prtcl. It is expected that nly apprpriate and medically necessary services will be rendered. We reserve the right t cnduct prepayment and pstpayment reviews t assess the medical apprpriateness f the abve-referenced prcedures. Sme f this prtcl may nt pertain t the patients yu prvide care t, as it may relate t prducts that are nt available in yur gegraphic area. References We are nt respnsible fr the cntinuing viability f web site addresses that may be listed in any references belw. 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, CA Cancer J Clin. Jan-Feb 2016; 66(1):7-30. PMID Natinal Cmprehensive Cancer Netwrk (NCCN). NCCN Clinical Practice Guidelines in Onclgy: Genetic/ Familial High-Risk Assessment: Breast and Ovarian. Versin Accessed December 1, Apstlu P, Fstira F. Hereditary breast cancer: the era f new susceptibility genes. Bimed Res Int. 2013; 2013: PMID Eastn DF, Pharah PD, Antniu AC, et al. Gene-panel sequencing and the predictin f breast-cancer risk. N Engl J Med. Jun ; 372(23): PMID Richards S, Aziz N, Bale S, et al. Standards and guidelines fr the interpretatin f sequence variants: a jint cnsensus recmmendatin f the American Cllege f Medical Genetics and Genmics and the Assciatin fr Mlecular Pathlgy. Genet Med. May 2015; 17(5): PMID Kurian AW, Antniu AC, Dmchek SM. Refining breast cancer risk stratificatin: additinal genes, additinal infrmatin. Am Sc Clin Oncl Educ Bk. 2016; 35: PMID Xia B, Sheng Q, Nakanishi K, et al. Cntrl f BRCA2 cellular and clinical functins by a nuclear partner, PALB2. Ml Cell. Jun ; 22(6): PMID Antniu AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutatins in PALB2. N Engl J Med. Aug ; 371(6): PMID Catucci I, Peterlng P, Ciceri S, et al. PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutatin recurrent in the prvince f Bergam. Genet Med. Sep 2014; 16(9): PMID Casadei S, Nrquist BM, Walsh T, et al. Cntributin f inherited mutatins in the BRCA2-interacting prtein PALB2 t familial breast cancer. Cancer Res. Mar ; 71(6): PMID Cybulski C, Kluzniak W, Huzarski T, et al. Clinical utcmes in wmen with breast cancer and a PALB2 mutatin: a prspective chrt analysis. Lancet Oncl. Jun 2015; 16(6): PMID Page 11 f 18

12 12. Cybulski C, Wklrczyk D, Jakubwska A, et al. Risk f breast cancer in wmen with a CHEK2 mutatin with and withut a family histry f breast cancer. J Clin Oncl. Oct ; 29(28): PMID Schttenfeld D, Fraumeni JF. Cancer epidemilgy and preventin. 3rd ed. New Yrk: Oxfrd University Press; Singletary SE. Rating the risk factrs fr breast cancer. Ann Surg. Apr 2003; 237(4): PMID Antniu AC, Pharah PP, Smith P, et al. The BOADICEA mdel f genetic susceptibility t breast and varian cancer. Br J Cancer. Oct ; 91(8): PMID Berry DA, Iversen ES, Jr., Gudbjartssn DF, et al. BRCAPRO validatin, sensitivity f genetic testing f BRCA1/ BRCA2, and prevalence f ther breast cancer susceptibility genes. J Clin Oncl. Jun ; 20(11): PMID Nelsn HD, Fu R, Gddard K, et al. Risk Assessment, Genetic Cunseling, and Genetic Testing fr BRCA- Related Cancer (AHRQ Publicatin N EF-1). Rckville (MD): Agency fr Healthcare Research and Quality; Nelsn HD, Pappas M, Zakher B, et al. Risk assessment, genetic cunseling, and genetic testing fr BRCArelated cancer in wmen: a systematic review t update the U.S. Preventive Services Task Frce recmmendatin. Ann Intern Med. Feb ; 160(4): PMID Gldfeder RL, Priest JR, Zk JM, et al. Medical implicatins f technical accuracy in genme sequencing. Genme Med. Mar ; 8(1):24. PMID Rehm HL, Bale SJ, Bayrak-Tydemir P, et al. ACMG clinical labratry standards fr next-generatin sequencing. Genet Med. Sep 2013; 15(9): PMID Mu W, Lu HM, Chen J, et al. Sanger cnfirmatin is required t achieve ptimal sensitivity and specificity in next-generatin sequencing panel testing. J Ml Diagn. Nv 2016; 18(6): PMID Blue Crss Blue Shield Asssciatin. Genetic Testing fr Inherited BRCA1 r BRCA2 Mutatins. Technl Eval Cent Assess Prgram Exec Summ. June 1997; 12(4): Judkins T, Leclair B, Bwles K, et al. Develpment and analytical validatin f a 25-gene next generatin sequencing panel that includes the BRCA1 and BRCA2 genes t assess hereditary cancer risk. BMC Cancer. 2015; 15(1):215. PMID Erkk H, Dwty JG, Nikkila J, et al. Penetrance analysis f the PALB2 c.1592delt funder mutatin. Clin Cancer Res. Jul ; 14(14): PMID Heikkinen T, Karkkainen H, Aaltnen K, et al. The breast cancer susceptibility mutatin PALB2 1592delT is assciated with an aggressive tumr phentype. Clin Cancer Res. May 1, 2009; 15(9): PMID Rahman N, Seal S, Thmpsn D, et al. PALB2, which encdes a BRCA2-interacting prtein, is a breast cancer susceptibility gene. Nat Genet. Feb 2007; 39(2): PMID Thmpsn ER, Grringe KL, Rwley SM, et al. Prevalence f PALB2 mutatins in Australian familial breast cancer cases and cntrls. Breast Cancer Res. 2015; 17(1):111. PMID Suthey MC, Gldgar DE, Winqvist R, et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data frm COGS. J Med Genet. Dec 2016; 53(12): PMID Antniu AC, Fulkes WD, Tischkwitz M, et al. Breast cancer risk in wmen with PALB2 mutatins in different ppulatins. Lancet Oncl. Aug 2015; 16(8):e PMID Balmana J, Digivanni L, Gaddam P, et al. Cnflicting Interpretatin f genetic variants and cancer risk by cmmercial labratries as assessed by the prspective registry f multiplex testing. J Clin Oncl. Dec 2016; 34(34): PMID Gabai-Kapara E, Lahad A, Kaufman B, et al. Ppulatin-based screening fr breast and varian cancer risk due t BRCA1 and BRCA2. Prc Natl Acad Sci U S A. Sep ; 111(39): PMID Page 12 f 18

13 32. Natinal Cmprehensive Cancer Netwrk (NCCN). NCCN Clinical Practice Guidelines in Onclgy: Breast Cancer Risk Reductin. Versin Accessed September, Natinal Institute fr Health and Care Excellence (NICE). Familial breast cancer: classifificatin, care and managing breast cancer and related risks in peple with a family histry f breast cancer [CG164]. 2013; updated 2015; Accessed May 12, Lee CH, Dershaw DD, Kpans D, et al. Breast cancer screening with imaging: recmmendatins frm the Sciety f Breast Imaging and the ACR n the use f mammgraphy, breast MRI, breast ultrasund, and ther technlgies fr the detectin f clinically ccult breast cancer. J Am Cll Radil. Jan 2010; 7(1): PMID Phi XA, Saadatmand S, De Bck GH, et al. Cntributin f mammgraphy t MRI screening in BRCA mutatin carriers by BRCA status and age: individual patient data meta-analysis. Br J Cancer. Mar ; 114(6): PMID Seil E, Jack B. Breast magnetic resnance imaging (MRI) fr screening f high-risk wmen. MSAC applicatin n Assessment reprt Saadatmand S, Obdeijn IM, Rutgers EJ, et al. Survival benefit in wmen with BRCA1 mutatin r familial risk in the MRI screening study (MRISC). Int J Cancer. Oct ; 137(7): PMID Phillips KA, Milne RL, Rkus MA, et al. Tamxifen and risk f cntralateral breast cancer fr BRCA1 and BRCA2 mutatin carriers. J Clin Oncl. Sep ; 31(25): PMID Finch AP, Lubinski J, Mller P, et al. Impact f phrectmy n cancer incidence and mrtality in wmen with a BRCA1 r BRCA2 mutatin. J Clin Oncl. May 20, 2014; 32(15): PMID Kauff ND, Satagpan JM, Rbsn ME, et al. Risk-reducing salping-phrectmy in wmen with a BRCA1 r BRCA2 mutatin. N Engl J Med. May 23, 2002; 346(21): PMID Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prphylactic phrectmy in carriers f BRCA1 r BRCA2 mutatins. N Engl J Med. May 23, 2002; 346(21): PMID Hartmann LC, Lindr NM. The rle f risk-reducing surgery in hereditary breast and varian cancer. N Engl J Med. Feb ; 374(5): PMID Dmchek SM, Friebel TM, Singer CF, et al. Assciatin f risk-reducing surgery in BRCA1 r BRCA2 mutatin carriers with cancer risk and mrtality. JAMA. Sep ; 304(9): PMID Evans DG, Baildam AD, Andersn E, et al. Risk reducing mastectmy: utcmes in 10 Eurpean centres. J Med Genet. Apr 2009; 46(4): PMID Hartmann LC, Schaid DJ, Wds JE, et al. Efficacy f bilateral prphylactic mastectmy in wmen with a family histry f breast cancer. N Engl J Med. Jan ; 340(2): PMID Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy f bilateral prphylactic mastectmy in BRCA1 and BRCA2 gene mutatin carriers. J Natl Cancer Inst. Nv ; 93(21): PMID Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, et al. Prphylactic mastectmy in BRCA1/2 mutatin carriers and wmen at risk f hereditary breast cancer: lng-term experiences at the Rtterdam Family Cancer Clinic. Ann Surg Oncl. Dec 2007; 14(12): PMID Meijers-Heijber H, van Geel B, van Putten WL, et al. Breast cancer after prphylactic bilateral mastectmy in wmen with a BRCA1 r BRCA2 mutatin. N Engl J Med. Jul ; 345(3): PMID Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prphylactic mastectmy reduces breast cancer risk in BRCA1 and BRCA2 mutatin carriers: the PROSE Study Grup. J Clin Oncl. Mar ; 22(6): PMID Skytte AB, Cruger D, Gerster M, et al. Breast cancer after bilateral risk-reducing mastectmy. Clin Genet. May 2011; 79(5): PMID Lstumb L, Carbine NE, Wallace J. Prphylactic mastectmy fr the preventin f breast cancer. Cchrane Database Syst Rev. 2010(11):CD PMID Page 13 f 18

14 52. Fayanju OM, Stll CR, Fwler S, et al. Cntralateral prphylactic mastectmy after unilateral breast cancer: a systematic review and meta-analysis. Ann Surg. Dec 2014; 260(6): PMID Metcalfe K, Lynch HT, Ghadirian P, et al. Cntralateral breast cancer in BRCA1 and BRCA2 mutatin carriers. J Clin Oncl. Jun ; 22(12): PMID van Sprundel TC, Schmidt MK, Rkus MA, et al. Risk reductin f cntralateral breast cancer and survival after cntralateral prphylactic mastectmy in BRCA1 r BRCA2 mutatin carriers. Br J Cancer. Aug ; 93(3): PMID Evans DG, Ingham SL, Baildam A, et al. Cntralateral mastectmy imprves survival in wmen with BRCA1/ 2-assciated breast cancer. Breast Cancer Res Treat. Jul 2013; 140(1): PMID Metcalfe K, Gershman S, Ghadirian P, et al. Cntralateral mastectmy and survival after breast cancer in carriers f BRCA1 and BRCA2 mutatins: retrspective analysis. BMJ. Feb ; 348:g226. PMID Bughey JC, Attai DJ, Chen SL, et al. Cntralateral prphylactic mastectmy (CPM) cnsensus statement frm the American Sciety f Breast Surgens: data n CPM utcmes and risks. Ann Surg Oncl. Oct 2016; 23(10): PMID Silva AK, Lapin B, Ya KA, et al. The effect f cntralateral prphylactic mastectmy n periperative cmplicatins in wmen underging immediate breast recnstructin: A NSQIP analysis. Ann Surg Oncl. Oct 2015; 22(11): PMID Prtschy PR, Kuntz KM, Tuttle TM. Survival utcmes after cntralateral prphylactic mastectmy: a decisin analysis. J Natl Cancer Inst. Aug 2014; 106(8). PMID Schrag D, Kuntz KM, Garber JE, et al. Decisin analysis--effects f prphylactic mastectmy and phrectmy n life expectancy amng wmen with BRCA1 r BRCA2 mutatins. N Engl J Med. May 15, 1997; 336(20): PMID Schrag D, Kuntz KM, Garber JE, et al. Life expectancy gains frm cancer preventin strategies fr wmen with breast cancer and BRCA1 r BRCA2 mutatins. JAMA. Feb ; 283(5): PMID Yang Y, Zhang F, Wang Y, et al. CHEK2 1100delC variant and breast cancer risk in Caucasians: a metaanalysis based n 25 studies with 29,154 cases and 37,064 cntrls. Asian Pac J Cancer Prev. 2012; 13(7): PMID Weischer M, Bjesen SE, Ellervik C, et al. CHEK2*1100delC gentyping fr clinical assessment f breast cancer risk: meta-analyses f 26,000 patient cases and 27,000 cntrls. J Clin Oncl. Feb ; 26(4): PMID Huzarski T, Cybulski C, Wklrczyk D, et al. Survival frm breast cancer in patients with CHEK2 mutatins. Breast Cancer Res Treat. Apr 2014; 144(2): PMID Kriege M, Hllestelle A, Jager A, et al. Survival and cntralateral breast cancer in CHEK2 1100delC breast cancer patients: impact f adjuvant chemtherapy. Br J Cancer. Aug ; 111(5): PMID Weischer M, Nrdestgaard BG, Pharah P, et al. CHEK2*1100delC heterzygsity in wmen with breast cancer assciated with early death, breast cancer-specific death, and increased risk f a secnd breast cancer. J Clin Oncl. Dec ; 30(35): PMID Marabelli M, Cheng SC, Parmigiani G. Penetrance f ATM gene mutatins in breast cancer: a meta-analysis f different measures f risk. Genet Epidemil. Jul 2016; 40(5): PMID Thmpsn D, Duedal S, Kirner J, et al. Cancer risks and mrtality in heterzygus ATM mutatin carriers. J Natl Cancer Inst. Jun ; 97(11): PMID Renwick A, Thmpsn D, Seal S, et al. ATM mutatins that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. Aug 2006; 38(8): PMID Rbsn ME, Bradbury AR, Arun B, et al. American Sciety f Clinical Onclgy Plicy statement update: genetic and genmic testing fr cancer susceptibility. J Clin Oncl. Nv ; 33(31): PMID Page 14 f 18

15 71. Natinal Cmprehensive Cancer Netwrk (NCCN). NCCN Clinical Practice Guidelines in Onclgy: Breast Cancer Screening and Diagnsis. Versin Accessed December 1, Natinal Cmprehensive Cancer Netwrk (NCCN). NCCN Clinical Practice Guidelines in Onclgy: Pancreatic Adencarcinma. Versin Accessed December 1, King MC, Levy-Lahad E, Lahad A. Ppulatin-based screening fr BRCA1 and BRCA2: 2014 Lasker Award. JAMA: the jurnal f the American Medical Assciatin. Sep ; 312(11): PMID Rhiem K, Schmutzler R. Impact f prphylactic mastectmy in BRCA1/2 mutatin carriers. Breast Care (Basel). Dec 2014; 9(6): PMID Begg CB. On the use f familial aggregatin in ppulatin-based case prbands fr calculating penetrance. Jurnal f the Natinal Cancer Institute. Aug ; 94(16): PMID Mslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutatin analysis f 208 Ashkenazi Jewish wmen with varian cancer. American jurnal f human genetics. Apr 2000; 66(4): PMID Satagpan JM, Offit K, Fulkes W, et al. The lifetime risks f breast cancer in Ashkenazi Jewish carriers f BRCA1 and BRCA2 mutatins. Cancer Epidemil Bimarkers Prev. May 2001; 10(5): PMID Thrlacius S, Struewing JP, Hartge P, et al. Ppulatin-based study f risk f breast cancer in carriers f BRCA2 mutatin. Lancet. Oct ; 352(9137): PMID Warner E, Fulkes W, Gdwin P, et al. Prevalence and penetrance f BRCA1 and BRCA2 gene mutatins in unselected Ashkenazi Jewish wmen with breast cancer. J Natl Cancer Inst. Jul ; 91(14): PMID King MC, Marks JH, Mandell JB. Breast and varian cancer risks due t inherited mutatins in BRCA1 and BRCA2. Science. Oct ; 302(5645): PMID Mavaddat N, Peck S, Frst D, et al. Cancer risks fr BRCA1 and BRCA2 mutatin carriers: results frm prspective analysis f EMBRACE. J Natl Cancer Inst. Jun ; 105(11): PMID Xu K, Yang S, Zha Y. Prgnstic significance f BRCA mutatins in varian cancer: an updated systematic review with meta-analysis. Onctarget. Sep PMID Yang D, Khan S, Sun Y, et al. Assciatin f BRCA1 and BRCA2 mutatins with survival, chemtherapy sensitivity, and gene mutatr phentype in patients with varian cancer. JAMA. Oct ; 306(14): PMID Candid-ds-Reis FJ, Sng H, Gde EL, et al. Germline mutatin in BRCA1 r BRCA2 and ten-year survival fr wmen diagnsed with epithelial varian cancer. Clin Cancer Res. Feb ; 21(3): PMID Zhu Y, Wu J, Zhang C, et al. BRCA mutatins and survival in breast cancer: an updated systematic review and meta-analysis. Onctarget. Sep PMID Grann VR, Whang W, Jacbsn JS, et al. Benefits and csts f screening Ashkenazi Jewish wmen fr BRCA1 and BRCA2. J Clin Oncl. Feb 1999; 17(2): PMID Menkiszak J, Rzepka-Grska I, Grski B, et al. Attitudes tward preventive phrectmy amng BRCA1 mutatin carriers in Pland. Eur J Gynaecl Oncl. 2004; 25(1): PMID Mller P, Brg A, Evans DG, et al. Survival in prspectively ascertained familial breast cancer: analysis f a series stratified by tumur characteristics, BRCA mutatins and phrectmy. Int J Cancer. Oct ; 101(6): PMID Olpade OI, Artili G. Efficacy f risk-reducing salping-phrectmy in wmen with BRCA-1 and BRCA-2 mutatins. Breast J. Jan-Feb 2004; 10 Suppl 1:S5-9. PMID Scheuer L, Kauff N, Rbsn M, et al. Outcme f preventive surgery and screening fr breast and varian cancer in BRCA mutatin carriers. J Clin Oncl. Mar ; 20(5): PMID Page 15 f 18