Genetic Testing for Hereditary Breast and/or Ovarian Cancer. Original Policy Date

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1 MP Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Medical Plicy Sectin Medicine Issue 12:2013 Original Plicy Date 12:2013 Last Review Status/Date Reviewed with literature search/12:2013 Return t Medical Plicy Index Disclaimer Our medical plicies are designed fr infrmatinal purpses nly and are nt an authrizatin, r an explanatin f benefits, r a cntract. Receipt f benefits is subject t satisfactin f all terms and cnditins f the cverage. Medical technlgy is cnstantly changing, and we reserve the right t review and update ur plicies peridically. Descriptin Hereditary breast and varian cancer (HBOC) syndrme describes the familial cancer syndrmes that are related t mutatins in the BRCA genes. Identificatin f patients with BRCA mutatins may lead t enhanced screening and/r surveillance that culd lead t imprved utcmes. Several genetic syndrmes with an autsmal dminant pattern f inheritance that features breast cancer have been identified. Of these, hereditary breast and varian cancer (HBOC) and sme cases f hereditary site-specific breast cancer have in cmmn causative mutatins in BRCA 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, laryngeal cancer, ccur mre frequently in HBOC families. Hereditary sitespecific breast cancer families are characterized by early nset breast cancer with r withut male cases, but withut varian cancer. Fr this plicy, bth will be referred t cllectively as hereditary breast and/r varian cancer. Germline mutatins in the BRCA1 and BRCA2 genes are respnsible fr the cancer susceptibility in the majrity f HBOC families, especially if varian cancer r male breast cancer are features. Hwever, in site-specific breast cancer, BRCA mutatins are respnsible fr nly a prprtin f affected families, and research t date has nt yet identified ther mderate r high-penetrance gene mutatins that accunt fr disease in these 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 BRCA1and 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. 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

2 CHEK2 (cell cycle checkpint kinase2) is als invlved with DNA repair and human cancer predispsitin like BRCA1 and BRCA2. CHEK2 is nrmally activated in respnse t DNA duble-stranded breaks.chek2 regulates the functin f BRCA1 prtein in DNA repair and als exerts critical rles in cell cycle cntrl and apptsis. The CHEK2 mutatin, 1100delC in exn 10 has been assciated with familial breast cancers. Plicy Genetic testing fr BRCA1 and BRCA2 mutatins in cancer-affected individuals may be cnsideredmedically necessary under any f the fllwing circumstances: Wmen wh are affected with breast cancer r pancreatic cancer, and are frm families with a high risk f BRCA1 r BRCA2 mutatin as defined in the Plicy Guidelines, OR; Wmen wh are affected with breast cancer r pancreatic cancer wh are nt frm families with a high risk f BRCA1 r BRCA2 mutatin, as defined in Plicy Guidelines, but are affected with any ne f the fllwing: early nset breast cancer; tw breast primary cancers with the first cancer diagnsis ccurring prir t age 50 years; triple negative breast cancer (neither express estrgen receptr and prgesterne receptr, nr verexpress HER2) diagnsed at yunger than age 60; tw r mre clse bld relatives with pancreatic cancer at any age Wmen affected with epithelial varian cancer/fallpian tube /primary peritneal cancer, OR; Men affected with breast cancer at any age, OR; Thse affected with breast cancer wh are frm an ethnic backgrund, e.g., Ashkenazi Jewish descent, assciated with deleterius funder mutatins. Genetic testing fr BRCA1 and BRCA2 mutatins f unaffected adults may be cnsidered medically necessary under any f the fllwing circumstances: Unaffected individuals (male r female) frm families with a knwn BRCA1 r BRCA2 mutatin, OR; Unaffected individuals frm families with a high risk f BRCA1 r BRCA2 mutatin based n a family histry (see Plicy Guidelines), where it is nt pssible t test an affected family member fr a mutatin. Unaffected individuals in ppulatins at risk fr specific funder mutatins due t ethnic backgrund, e.g., Ashkenazi Jewish descent, and with ne r mre relatives with breast, epithelial varian, fallpian tube, r primary peritneal cancer at any age. Further, the genetic testing shuld be perfrmed in a setting that has suitably trained healthcare prviders wh can give apprpriate pre- and pst-test cunseling and that has access t a Clinical Labratry Imprvement Amendments (CLIA)-licensed labratry that ffers cmprehensive mutatin analysis (see Plicy Guidelines). 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

3 Testing fr genmic rearrangements f the BRCA1 and BRCA2 genes may be cnsidered medically necessary in patients wh meet criteria fr BRCA testing, whse testing fr pint mutatins is negative. Unless they meet the criteria abve, genetic testing fr either thse affected with breast, varian, fallpian tube, r primary peritneal cancer r fr unaffected individuals is cnsidered investigatinal. Testing fr CHEK2 abnrmality (mutatins, deletins, etc.) is cnsidered investigatinal in affected and unaffected patients with breast cancer, irrespective f the family histry. Genetic testing in minrs fr BRCA1 and BRCA2 mutatins is investigatinal. Plicy Guidelines In identifying families with a high risk f mutatin in the BRCA1 r BRCA 2 gene, bth maternal and paternal family histries are imprtant, but each lineage must be cnsidered separately. Any f the fllwing scenaris indicates a high risk f BRCA1 r BRCA2 mutatin. In assessing risk f a mutatin fr thse affected with cancer, the verall family histry (ne lineage) including the affected persn is cnsidered. The fllwing criteria fr nn-ashkenazi Jewish wmen unaffected with cancer were derived by the USPSTF in 2005 after extensive literature review by the U.S. Preventive Services Task Frce (USPSTF) (1): Three r mre first- r secnd-degree relatives with breast cancer regardless f age at diagnsis; r Tw first-degree relatives with breast cancer, ne f whm was diagnsed at age 50 years r yunger; r Cmbinatin f bth breast and varian r fallpian tube r primary peritneal cancer amng first- and secnd-degree relatives; r First-degree relative with bilateral breast cancer; r A cmbinatin f tw r mre first- r secnd-degree relatives with varian r fallpian tube r primary peritneal cancer regardless f age at diagnsis; r A first- r secnd-degree relative with bth breast and varian r fallpian tube r primary peritneal cancer at any age; r A histry f breast cancer in a male relative. Mre recent definitins f high-risk have been published, including the 2012 revised recmmendatins frm Natinal Cmprehensive Cancer Netwrk (NCCN). The fllwing highrisk criteria largely represent NCCN hereditary breast and/r varian cancer syndrme testing criteria (2) with sme mdificatins based n additinal guidelines (3) and review f evidence. A persnal r family histry suggesting genetic cancer susceptibility requires at least ne f the fllwing criteria t be present: Individual frm a family with a knwn deleterius BRCA1/BRCA2 mutatin Persnal histry f breast cancer plus ne r mre f the fllwing: 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

4 Diagnsed at an early age (see definitin, fllwing) Diagnsed at age <50 years with at least ne clse bld relative (see definitin, fllwing) with breast cancer at age <50 years and/r at least ne clse bld relative with epithelial varian/fallpian tube/primary peritneal cancer at any age Tw breast primaries when the first breast cancer diagnsis ccurred prir t age 50 years Diagnsed age <60 years with a triple negative breast cancer Diagnsed age <50 years with a limited family histry Diagnsed at any age, with >2 clse bld relatives with breast and/r epithelial varian/fallpian tube/primary peritneal cancer at any age Clse male relative with breast cancer Fr an individual f ethnicity assciated with higher mutatin frequency (e.g., Ashkenazi Jewish) n additinal family histry may be required Persnal histry f epithelial varian/fallpian tube/primary peritneal cancer Persnal histry f male breast cancer Persnal histry f breast and/r varian cancer at any age with >2 clse bld relatives with pancreatic cancer at any age Persnal histry f pancreatic cancer at any age with >2 clse bld relatives with breast and/r varian cancer and/r pancreatic cancer at any age Family histry nly: Clse bld relative meeting any f the abve criteria Definitin: Early age at diagnsis refers generally t diagnsis befre age 40 t 45 years; an exact cutff fr testing affected individuals withut knwn family histry but with cancer diagnsis at an early age has nt been established, althugh guidelines f the American Cllege f Medical Genetics suggest age 45 years r yunger (see Ratinale). The decisin t test an affected individual based n age at diagnsis in the absence f family histry will depend n the risk estimate fr the individual patient (e.g., frm widely available risk assessment cmputer prgrams) and the patient tlerance fr risk, and the desire t infrm the risk f family members. Definitin: Clse bld relative typically refers t first-degree (parent, full sibling, r ffspring) and secnd-degree (grandparent, grandchild, uncle, aunt, niece, nephew, r half-sibling) relatives in diseases assciated with high penetrance gene mutatins such as BRCA1 and BRCA2 mutatins. Accmmdatin may be made t include third-degree relatives (first cusin, great grandparent r great grandchild) in sme cases, e.g., limited family histry, particularly in tracing hereditary breast and varian and related cancers in the paternal lineage. Certified genetic cunselrs r ther qualified genetics prfessinals are best able t assess exceptinal cases. As the majrity f test results will be negative and uninfrmative in unaffected family members f ptentialbrca mutatin families, it is strngly recmmended that an affected family member 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

5 be tested first whenever pssible t adequately interpret the test. Shuld a BRCA mutatin be fund in an affected family member(s), the DNA frm the unaffected family member can be tested specifically fr the same mutatin f the affected family member withut having t sequence the entire gene. Interpreting the 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 mutatin but leads t difficulties in interpreting negative test results r mutatins f uncertain significance because the pssibility f a causative BRCA mutatin is nt ruled ut. In patients with breast cancer, varian cancer, cancer f the fallpian tube, r primary peritneal cancer wh are frm high-risk families withut a knwn BRCA1 r BRCA2 gene and wh are nt frm ethnic grups with knwn funder mutatins, cmprehensive BRCA mutatin analysis shuld be perfrmed. Testing in eligible individuals wh belng t ethnic ppulatins in which there are wellcharacterized funder mutatins shuld begin with tests specifically fr these mutatins. Fr example, funder mutatins accunt fr apprximately three quarters f the BRCA mutatins fund in Ashkenazi Jewish ppulatins (see Ratinale). When the testing fr funder mutatins is negative, cmprehensive mutatin analysis shuld then be perfrmed. Patients with BRCA mutatins have an increased risk f prstate cancer, and patients with knwn BRCAmutatins 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. Cmprehensive mutatin analysis currently includes sequencing the cding regins and intrn/exn splice sites, as well as tests t detect cmmn large deletins and rearrangements that can be missed with sequence analysis alne. In additin, prir t August 2006, testing fr large deletins and rearrangements was nt perfrmed, thus sme patients with familial breast cancer wh had negativebrca testing prir t this time may cnsider repeat testing fr the rearrangements (see Plicy statement fr criteria). As nted abve, cancers f the fallpian tube and primary peritneal cancer are als cnsidered BRCA-assciated malignancies and are t be cnsidered alng with breast and varian cancer in assessing the family histry. Ratinale This plicy was develped fllwing a 1997 TEC Assessment (4) and has been updated n a regular basis with literature searches fr articles that cntained infrmatin regarding prfessinal guidelines frbrca testing, testing f unaffected family members, and testing f high-risk ethnic ppulatins. The mst recent update cvered the perid f Nvember 2010 thrugh Octber In additin, relevant prfessinal rganizatins were cnsulted fr clinical guidelines. Testing fr BRCA1 and BRCA2 in High-risk Wmen Early estimates f lifetime risk f cancer fr BRCA mutatin carriers (penetrance), based n studies f families with extensive histry f disease, have been as high as 85%. Because ther factrs that influence risk may be present in families with extensive breast and varian cancer histries, early penetrance estimates may have been biased upward. (5) Studies f funder 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

6 mutatins in ethnic ppulatins (e.g., Ashkenazi Jewish, Plish, and Icelandic ppulatins) unselected fr family histry indicated lwer penetrance estimates, in the range f 40 60% fr BRCA1 and 25 40% fr BRCA2. (6-9) Hwever, a gentyping study f Ashkenazi Jewish wmen with incident, invasive breast cancer, selected regardless f family histry f cancer, and their family members resulted in an 82% lifetime risk f breast cancer fr carriers f any f 3 BRCA funder mutatins.(10) Imprtantly, the risk f cancer in mutatin carriers frm families with little histry f cancer (~50% f all carriers) was nt significantly different. Lifetime risks f varian cancer were 54% fr BRCA1 and 23% fr BRCA2 mutatin carriers. Wmen with a histry f breast cancer and a BRCA mutatin have a significant risk f cntralateral breast cancer; in ne study the risk was 29.5% at 10 years fr wmen with initial stage I r II disease. (11) Thus, the risk f cancer in a BRCA mutatin carrier is significant, and knwledge f mutatin status in individuals at ptentially increased risk f a BRCA mutatin may impact healthcare decisins t reduce risk. (12-19) Risk-reducing ptins include intensive surveillance, chemprphylaxis, prphylactic mastectmy, r prphylactic phrectmy. Prphylactic mastectmy reduces the risk f breast cancer in high-risk wmen (based n family histry) by 90% r mre but is invasive and disfiguring. (13) Prphylactic phrectmy significantly reduces the risk f varian cancer t less than 10% (16, 17) and reduces the risk f breast cancer by apprximately 50%. (17) In wmen wh have already had breast cancer, prphylactic phrectmy reduces the risk f cancer relapse. (15) Studies indicate that gentyping results significantly influence treatment chices. (14, 18, 19) The prevalence f BRCA mutatins is apprximately % in the general ppulatin. Prevalence may be much higher fr particular ethnic grups with characterized funder mutatins (e.g., 2.5% [1 in 40] in the Ashkenazi Jewish ppulatin). Family histry f breast and varian cancer is an imprtant risk factr fr BRCA mutatin. Age and, in sme cases, ethnic backgrund can als be independent risk factrs. Yung age f nset f breast cancer, even in the absence f family histry, has been demnstrated t be a risk factr fr BRCA1 mutatins. Winchester (20) estimated that hereditary breast cancer accunts fr 36 85% f patients diagnsed befre age 30. In several studies, BRCA mutatins are independently predicted by early age at nset, being present in 6 10% f breast cancer cases diagnsed at ages yunger than varius premenpausal age cutffs (ages years). (20-23) In cancer-prne families, the mean age f breast cancer diagnsis amng wmen carrying BRCA1 r BRCA2 mutatins is in the 40s. (24) In the Ashkenazi Jewish ppulatin, Frank et al. (21) reprted that 13% f 248 cases with n knwn family histry and diagnsed befre 50 years f age had BRCA mutatins. In a similar study, 31% f Ashkenazi Jewish wmen, unselected fr family histry, diagnsed with breast cancer at yunger than 42 years f age had BRCA mutatins. (25) Additinal studies indicate that early age f breast cancer diagnsis is a significant predictr f BRCA mutatins in the absence f family histry in this ppulatin. (9, 26, 27) As in the general ppulatin, family histry f breast r varian cancer, particularly f early age nset, is a significant risk factr fr a BRCA mutatin in ethnic ppulatins characterized by funder mutatins. Fr example, in unaffected individuals f Ashkenazi Jewish descent, 12 31% will have a BRCA mutatin depending n the extent and nature f the family histry. (23) Several ther studies dcument the significant influence f family histry. (6, 9, 25-27) 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

7 In patients with breast cancer that is triple-negative, i.e., negative fr expressin f estrgen and prgesterne receptrs and fr verexpressin f HER2 receptrs, there is an increased incidence fbrca mutatins. Pathphysilgic research has suggested that the physilgic pathway fr develpment f triple-negative breast cancer is similar t that fr BRCA-assciated breast cancer (28). In 200 randmly selected patients with triple-negative breast cancer frm a tertiary care center, (29) there was a greater than 3-fld increase in the expected rate f BRCA mutatins. BRCA1 mutatins were fund in 39.1% f patients and BRCA2 mutatins in 8.7%. Yung et al. (30) studied 54 wmen with high-grade, triple-negative breast cancer with n family histry f breast r varian cancer, representing a grup that previusly was nt recmmended fr BRCA testing. A ttal f 6 BRCA mutatins, 5 BRCA1 and 1 BRCA2, were fund fr a mutatin rate f 11%. Finally, in a study f 77 patients with triple-negative breast cancer, 15 patients (19.5%) had BRCA mutatins: 12 in BRCA1 and 3 in BRCA2. (31) Unaffected individuals with a family histry suggestive f hereditary breast and/r varian cancer but unknwn family mutatin may btain interpretable results in mst cases f a psitive test. Mst BRCA1and BRCA2 mutatins reprted t date cnsist f frameshift deletins, insertins, r nnsense mutatins leading t premature truncatin f prtein transcriptin. These are invariably deleterius and thus are infrmative in the absence f an established familial mutatin. (21, 32) In additin, specific missense mutatins and nncding intervening sequence mutatins may be interpreted as deleterius n the basis f accumulated data r frm specific functinal r bichemical studies. Hwever, sme BRCAmutatins may have uncertain significance in the absence f a family study, and negative results ffer n useful infrmatin, i.e., the patient may still be at increased risk f a disease-assciated mutatin in an as yet undiscvered gene. Unaffected individuals may als be at high risk due t ther patterns f nn-breast cancer malignancies. A persnal histry f pancreatic cancer is estimated t raise the risk f a BRCA mutatin by fld ver the general ppulatin. (33) Cuch et al. (34) reprted n screening fr BRCA in 2 chrts f families at high risk fr pancreatic cancer. In the first chrt f high-risk families, there were a ttal f 5 BRCAmutatins in 151 prbands, and in the secnd chrt, there were anther 5 BRCA mutatins in 29 prbands. The cmbined BRCA mutatin rate fr these 2 chrts was 6% (10/180). Ferrne et al. (35) tested 187 Ashkenazi Jewish patients with pancreatic cancer fr BRCA mutatins and fund that 5.5% (8/187) had a BRCA mutatin. Wmen with a persnal histry f varian cancer als have an increased rate f BRCA mutatins. In a systematic review f 23 studies, Trainer et al. (36) estimated the rate f BRCA mutatins fr wmen with varian cancer t be in the range f 3-15%. In this review, there were 3 studies that were perfrmed in the United States and tested fr bth BRCA1 and BRCA2. The incidence f BRCA mutatins in these studies was 11.3%, 15.3%, and 9.5%. In a ppulatin-based study f 1,342 unselected patients with invasive varian cancer perfrmed in Canada, (37) there were 176 wmen with BRCA mutatins, fr a rate f 13.3%. The prevalence f mutatins was higher fr wmen in their 40s (24.0%) and in wmen with serus varian cancer (18.0%). Ethnicity was als an additinal risk factr fr BRCA, with higher rates seen in wmen f Italian (43.5%), Jewish (30.0%), and Ind- Pakistani rigin (29.4%). A clinical apprach t these patients was recently published by Rbsn and Offit. (38) Phillips et al. reprted that while uptake f prphylactic surgery and screening was assciated with knwing ne s mutatin status, in their chrt f 70 unaffected female mutatin carriers wh had 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

8 chsen t receive results, the minrity utilized risk-reducing surgery (11% had bilateral mastectmy and 29% bilateral phrectmy) r chempreventin. (39) Rennert and clleagues reprted that breast cancer-specific rates f death amng Israeli wmen were similar fr carriers f a BRCA funder mutatin and nncarriers. (40) Malne and clleagues reprted n racial and ethnic differences in the prevalence fbrca1 and BRCA2 in American wmen. (41) Amng their cases, 2.4% and 2.3% carried deleterius mutatins in BRCA1 and BRCA2, respectively. BRCA1 mutatins were significantly mre cmmn in white (2.9%) versus black (1.4%) cases and in Jewish (10.2%) versus nn-jewish (2.0%) cases;brca2 mutatins were slightly mre frequent in black (2.6%) versus white (2.1%) cases. Cuch et al. studied familial pancreatic cancer and nted that BRCA2 mutatins accunted fr 6% f mderate and high-risk pancreatic cancer families. (34) A number f studies have indicated that BRCA mutatins are assciated with increased risk f prstate cancer in men. In a study f 832 Ashkenazi Jewish men diagnsed with lcalized prstate cancer, and 454 Ashkenazi Jewish men withut prstate cancer, the presence f a BRCA2 mutatin was assciated with a mre than 3-fld increased risk f prstate cancer (dds rati [OR]: 3.18, 95% cnfidence interval [CI: ). (42) In a similar ppulatin f 251 Ashkenazi Jewish men with prstate cancer and 1,472 vlunteers withut prstate cancer, the presence f a BRCA mutatin was assciated with a 3.41 times higher risk f prstate cancer (95% CI: ). (43) When brken dwn by type f BRCA mutatin, BRCA2 was assciated with a 4.82 times increased risk (95% CI: ), while BRCA1 mutatins were nt assciated with an increased risk. Other studies have lked at the results f prstate cancer screening in men with BRCA mutatins. The IMPACT study evaluated the results f screening in 205 men years f age wh were BRCAmutatin carriers and 95 cntrl patients. (44) At the baseline screen, bipsies were perfrmed in 7.0% f patients with a prstate-specific antigen (PSA) greater than 3.0, and prstate cancer was identified in 3.3%. This resulted in a psitive predictive value f 47.6%, which is cnsiderably higher than that estimated fr nrmal risk men. Als, the grade f tumr identified was intermediate in 67% f cancers and high in 11%. This differs frm the expected distributin f cancer grade in average risk men, with mre than 60% expected t have lw-grade cancer. There has been interest in further risk-stratifying patients with knwn BRCA mutatins in rder t further assist in clinical decisin making. Numerus recent publicatins have identified a large number f candidate mdifier genes, (45-51) and there have als been nn-genetic mdifying factrs examined. Antniu et al. (45) examined the risk f breast cancer assciated with 9 genetic plymrphisms, the majrity f which had previusly shwn an increase cancer risk amng BRCA carriers. Seven f the 9 plymrphisms were cnfirmed t increase breast cancer risk. The magnitude f increased risk varied by whether the patient was a BRCA1 versus a BRCA2 carrier, and the plymrphisms appeared t interact multiplicatively t increase risk. Kleibl et al. (49) reprted that the AIB1 gentype in general did nt influence breast cancer risk in BRCAcarriers but that the specific gentype AIB1 cnsisting f 28/28 glutamine repeats cnferred a decreased risk f breast cancer (hazard rati [HR]: 0.64, 95% cnfidence interval [CI]: , p=0.045). Zhu et al. (52) reprted an increased risk f cancer in BRCA carriers wh als had the RAD51 135G>C plymrphism (dds rati [OR]: 1.34, 95% CI: , p=0.04). Metcalfe et al. (53) reprted that family histry prvided additinal predictive infrmatin in BRCA carriers. Fr each first-degree relative with breast cancer, there was a 1.7- fld increase in risk f cancer fr BRCA carriers. 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

9 The use f genetic testing fr BRCA mutatins has limited r n clinical utility in minrs. This is because there is n change in management fr minrs as a result f knwledge f the presence r absence f a deleterius mutatin. In additin, there are ptential harms related t stigmatizatin and discriminatin. Testing fr Large BRCA Rearrangements Over the past few years, a number f studies have shwn that a significant percentage f wmen with a strng family histry f breast cancer and negative tests fr BRCA mutatins have large genmic rearrangements (including deletins r duplicatins) in ne f these genes. Fr example, in 2006 Walsh and clleagues reprted n prbands frm 300 U.S. families with 4 r mre cases f breast r varian cancer but with negative (wild-type) cmmercial genetic tests fr BRCA1 and BRCA2. (54) These patients underwent screening with additinal multiple DNAbased and RNA-based methds. Of these 300 patients, 17% carried previusly undetected mutatins, including 35 (12%) with genmic rearrangement f BRCA1 r BRCA2. A mre recent study evaluated 251 patients with an estimated BRCA mutatin using the Myriad II mdel f 10% r greater. (55) In the 136 nn-ashkenazi Jewish prbands, 36 (26%) had BRCA pint mutatins and 8 (6%) had genmic rearrangements, 7 in BRCA1 and 1 in BRCA2. N genmic rearrangements were identified in the 115 Ashkenazi Jewish prbands, but 47 f the 115 (40%) had pint mutatins. In this ppulatin genmic rearrangements cnstituted 18% f all identified BRCA mutatins. The authrs als indicated that the estimated prevalence f a mutatin was nt predictive f the presence f a genmic rearrangement. Based n these published studies, a substantial minrity f clinically significant BRCA mutatins will be large genmic rearrangements that are nt detected by sequence analysis. These mutatins will be missed if BART testing (BRACAnalysis Rearrangement Test) is nt perfrmed. Cmmercial labratries began t ffer expanded testing in August 2006 (56); BRCA testing dne befre this starting time did nt include analysis fr genmic rearrangement. Subsequent t that, based n infrmatin available frm the labratry, this additinal testing is cnducted n a subset f patients, and additinal infrmatin n breast cancer risk may be requested in sme cases. Clinical guidelines, such as NCCN, cnsider BART testing as part f cmprehensive BRCA testing and d nt require additinal criteria ther than a negative sequence result. Therefre, testing fr genmic rearrangements f BRCA1 and BRCA2with BART may be cnsidered medically necessary as part f cmprehensive BRCA analysis, when testing fr standard mutatins n sequence analysis is negative. CHEK2and Other Mutatins A number f publicatins have als described the assciatin f CHEK2 (cell cycle checkpint kinase 2) mutatins with hereditary breast cancer. The prevalence f this finding varies greatly by gegraphic regins, being mst cmmn in nrthern and eastern Eurpe. It has been detected in 4% f early breast cancer patients in the Netherlands, in 2.3% f such patients in Germany, but has been nted t be rare in these patients in Spain r Australia. In the U.S., this mutatin is much less cmmn than BRCAmutatins and BRCA rearrangements. Fr example, in the study by Walsh et al. (54) cited abve, 14 (4.7%) f the 300 patients with a psitive family histry f breast cancer (4 affected relatives) wh were negative by standard BRCA testing, were psitive fr CHECK2 mutatins. The lw frequency makes evaluatin f risk and treatment 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

10 implicatins less precise. In general, the risk f breast cancer assciated with this mutatin is less that that assciated with either BRCA1 r BRCA2. A meta-analysis by Weischer et al. cncluded that fr familial breast cancer, the cumulative risk at age 70 years fr CHEK2*1100delC mutatin was 37% (95% CI: 26% t 56%). (57) This risk is lwer than cumulative risk at age 70 f 57% fr BRCA1 and 49% fr BRCA2. In an accmpanying editrial, Offit and Garber raise a number f questins abut ptential use f this assay. (58) In particular, they raise questins abut the breast cancer risk estimates presented in the Weischer study; a number f the questins relate t the variable methds f ascertainment used in the studies in this meta-analysis. They als nte that ther mutatins, such as CHEK2*S428F, are bserved in ther ppulatins. The varying frequency is mentined, with the mutatin nted in % f the ppulatin in nrthern and eastern Eurpe cmpared with % in the U.S. Finally, they raise cncerns abut the implicatins f the lw penetrance f this mutatin. They cncluded that n the basis f data available at this time, there is nt cmpelling evidence t justify rutine clinical testing fr CHEK2 t guide the management f families affected with breast cancer. Thus, based n a number f cncerns, testing fr CHEK2 mutatins is cnsidered investigatinal because the impact n net health utcme is uncertain. Since the meta-analysis by Weischer, there have been additinal studies lking at the risk f breast cancer assciated with the CHEK2 mutatin. Myszka et al. (59) examined 284 breast cancer patients, 113 varian cancer patients, and 287 healthy wmen frm a chrt f Plish individuals. The CHEK2 mutatin rate was nt higher amng patients with breast r varian cancer cmpared t healthy wmen. Zhang et al. (60) perfrmed a systematic review f candidate-gene assciatin studies, identifying mre than 1,000 published articles. Meta-analysis was perfrmed fr a ttal f 279 genetic variants in 128 genes that were identified by at least 3 different researchers. Significant assciatins with the risk f breast cancer were fund fr 29 variants in 20 genes. The assciatin was strng fr 10 variants in 6 genes, 4 f which were lcated in the CHEK2 gene. There was als a strng assciatin fund fr tw variants f the ATM gene and an additinal 4 genes that had a single variant with a strng assciatin (CASP8, CTLA4, NBN, and TP53). Peng et al. (61) perfrmed an verview f systematic reviews and pled analyses n the assciatin f genetic variants with breast cancer. A ttal f 87 analyses were identified, which examined 145 candidate gene variants and fund that 46 variants were significantly assciated with breast cancer. The dds ratis fr these assciatins ranged frm 0.66 t Using the methd f false-psitive reprt prbability, there were 10 assciatins in 7 genes that were ntewrthy. These genes were CASP8, CHEK2, CTLA4, FGFR2, ILIB, LSP1, and MAP3K1. A recent publicatin described the high rate f ccult fallpian tube cancers in at-risk wmen having prphylactic bilateral salping-phrectmy. (62) In this prspective series f 45 wmen, 4 (9%) were fund t have fallpian tube malignancies. The authrs nted that this supprts ther studies that have demnstrated the fimbrial end f the fallpian tube as an imprtant site f cancer in thse with BRCA1 rbrca2 mutatins. Similarly, the current NCCN guidelines fr assessing high risk in breast and varian cancer (2) include bth fallpian tube and primary peritneal cancer as ther malignancies that shuld be asked abut when assessing family histry t make a decisin regarding testing fr BRCA1 and BRCA2. Thus, these 2 cnditins are added t the plicy statements and plicy guidelines. 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

11 Clinical Input Received thrugh Physician Specialty Scieties and Academic Medical Centers In respnse t requests, input was received thrugh 3 Physician Specialty Scieties (5 reviews) and 3 Academic Medical Centers (5 reviews) while this plicy was under review fr January While the varius Physician Specialty Scieties and Academic Medical Centers may cllabrate with and make recmmendatins during this prcess, thrugh the prvisin f apprpriate reviewers, input received des nt represent an endrsement r psitin statement by the Physician Specialty Scieties r Academic Medical Centers, unless therwise nted. Thse prviding input were in general agreement with the plicy statements cnsidering testing fr genmic rearrangements f BRCA1 and BRCA2 as medically necessary, with the statement cnsidering CHEK2 testing as investigatinal, and with adding fallpian tube and primary peritneal cancer as additinal BRCA-assciated malignancies t assess when btaining the family histry. Summary The presence f a BRCA1 r BRCA2 mutatin cnfers a high lifetime risk fr breast and varian cancer amng affected wmen. These mutatins may be gene sequence variatins r large rearrangements/deletins. Knwledge f mutatin status in individuals at risk f a BRCA mutatin may impact healthcare decisins t reduce risk. Risk-reducing ptins include intensive surveillance, chemprphylaxis, prphylactic mastectmy, r prphylactic phrectmy. Criteria fr testing high-risk wmen have been develped by Natinal Cmprehensive Cancer Netwrk (NCCN), the U.S. Preventive Services Task Frce (USPSTF) and ther review bdies. Definitins f high-risk vary smewhat, and there is nt widespread agreement n the ptimal criteria that shuld be used fr defining high-risk. When testing highrisk wmen, health utcmes are imprved, therefre, testing high-risk wmen fr BRCA1and BRCA2 mutatins may be cnsidered medically necessary. Mutatins ther than BRCA1 and BRCA2 have been reprted t be assciated with an increased risk f breast cancer. While a number f these, fr example the CHEK2 mutatin, have been cnfirmed t be assciated with increased risk, clinical utility f testing fr these nn- BRCA mutatins has nt been demnstrated. Therefre, genetic testing fr mutatins ther than BRCA1 and BRCA2 t determine risk f breast and/r varian cancer is cnsidered investigatinal. Practice Guidelines and Psitin Statements The Natinal Cmprehensive Cancer Netwrk (NCCN) guidelines n genetic/familial high-risk assessment fr breast and varian cancer were updated in (2) Criteria fr genetic testing fr the hereditary breast and/r varian cancer syndrme included 3 factrs: 1) there is a persnal r family histry suggesting genetic cancer susceptibility; 2) the test can be adequately interpreted; and 3) the results will aid in the diagnsis r influence the medical r surgical management f the patient r family members at hereditary risk f cancer. The NCCN definitin f a persnal r family histry suggesting genetic cancer susceptibility requires at least ne f the fllwing criteria t be present: Individual frm a family with a knwn deleterius BRCA1/BRCA2 mutatin Persnal histry f breast cancer plus ne r mre f the fllwing: 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

12 Diagnsed at age <45 years Diagnsed at age <50 years with at least ne clse bld relative with breast cancer at age <50 years and/r at least ne clse bld relative with epithelial varian/fallpian tube/primary peritneal cancer at any age Tw breast primaries when the first breast cancer diagnsis ccurred prir t age 50 years Diagnsed age <60 years with a triple negative breast cancer Diagnsed age <50 years with a limited family histry Diagnsed at any age, with >2 clse bld relatives with breast and/r epithelial varian/fallpian tube/primary peritneal cancer at any age Diagnsed at any age, with >2 clse bld relatives with pancreatic cancer at any age Clse male relative with breast cancer Fr an individual f ethnicity assciated with higher mutatin frequency (e.g., Ashkenazi Jewish) n additinal family histry may be required Persnal histry f epithelial varian/fallpian tube/primary peritneal cancer Persnal histry f male breast cancer Persnal histry f breast and/r varian cancer at any age with >2 clse bld relatives with pancreatic cancer at any age Persnal histry f pancreatic cancer at any age with >2 clse bld relatives with breast and/r varian cancer at any age and/r pancreatic cancer at any age Family histry nly: First- r secnd-degree bld relative meeting any f the abve criteria Third-degree bld relative with breast cancer and/r varian/fallpian tube/primary peritneal cancer with >2 clse bld relatives with breast cancer (at least ne with breast cancer <50 years) and/r varian cancer Accrding t the NCCN guidelines, patients wh meet the criteria fr genetic testing shuld be tested fr mutatins in BRCA1 and BRCA2. The guidelines d nt address measurement f the CHEK2 mutatins. The U.S. Preventive Services Task Frce (USPSTF) published guidelines fr genetic testing fbrca1/brca2 in (1) Their recmmendatins were as fllws: The USPSTF recmmends against rutine referral fr genetic cunseling r rutine breast cancer susceptibility gene (BRCA) testing fr wmen whse family histry is nt assciated with an increased risk fr deleterius mutatins in breast cancer susceptibility gene 1 ( BRCA1) r breast cancer susceptibility gene 2 (BRCA2). (Grade D recmmendatin) 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

13 The USPSTF recmmends that wmen whse family histry is assciated with an increased risk fr deleterius mutatins in BRCA1 r BRCA2 genes be referred fr genetic cunseling and evaluatin fr BRCA testing. (Grade B recmmendatin) The American Sciety f Clinical Onclgy (ASCO) recmmended in 2003 (63) that cancer predispsitin testing be ffered when 1) the persn has a strng family histry f cancer r very early age f nset f disease, 2) the test can be adequately interpreted, and 3) the results will influence the medical management f the patient r family member. In 1999, the American Cllege f Medical Genetics (ACMG) (64) published guidelines fr BRCA testing under the auspices f a grant frm the New Yrk State Department f Health t the ACMG Fundatin. The guidelines suggest that increased risk fr a mutatin in a knwn cancer susceptibility gene is evident if: There are three r mre affected first r secnd degree relatives n the same side f the family, regardless f age at diagnsis, r References: There are fewer than three affected relatives, but the patient was diagnsed at 45 years f age r less, r a family member has been identified with a detectable mutatin, r there are ne r mre cases f varian cancer at any age, and ne r mre members n the same side f the family with breast cancer at any age, r there are multiple primary r bilateral breast cancers in the patient r ne family member, r there is breast cancer in a male patient, r in a male relative, r the patient is at increased risk fr specific mutatin(s) due t ethnic backgrund (fr instance: Ashkenazi Jewish descent) and has ne r mre relatives with breast cancer r varian cancer at any age. 1. Genetic risk assessment and BRCA mutatin testing fr breast and varian cancer susceptibility.us Preventive Services Task Frce. Available nline at: Last accessed September 29, Genetic/Familial High-Risk Assessment: Breast and Ovarian (V ). Natinal Cmprehensive Cancer Netwrk (NCCN) Clinical Practice Guidelines in Onclgy. Available nline at: Last accessed Octber, ACOG Practice Bulletin N. 103: Hereditary breast and varian cancer syndrme. Obstet Gynecl 2009; 113(4): Blue Crss and Blue Shield Assciatin Technlgy Evaluatin Center (TEC). BRCA1 and BRCA2 testing t determine the risk f breast and varian cancer. TEC Assessments 1997; vlume 12, tab Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

14 5. Begg CB. On the use f familial aggregatin in ppulatin-based case prbands fr calculating penetrance. J Natl Cancer Inst 2002; 94(16): Mslehi R, Chu W, Karlan B et al. BRCA1 and BRCA2 mutatin analysis f 208 Ashkenazi Jewish wmen with varian cancer. Am J Hum Genet 2000; 66(4): 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 2001; 10(5): Thrlacius S, Struewing JP, Hartge P et al. Ppulatin-based study f risk f breast cancer in carriers f BRCA2 mutatin. Lancet 1998; 352(9137): 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 1999; 91(14): King MC, Marks JH, Mandell JB. Breast and varian cancer risks due t inherited mutatins in BRCA1 and BRCA2. Science 2003; 302(5645): Metcalfe K, Lynch HT, Ghadirian P et al. Cntralateral breast cancer in BRCA1 and BRCA2 mutatin carriers. J Clin Oncl 2004; 22(12): Grann VR, Whang W, Jacbsn JS et al. Benefits and csts f screening Ashkenazi Jewish wmen fr BRCA1 and BRCA2. J Clin Oncl 1999; 17(2): 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 1999; 340(2): 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): 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 2002; 101(6): Olpade OI, Artili G. Efficacy f risk-reducing salping-phrectmy in wmen with BRCA-1 and BRCA-2 mutatins. Breast J 2004; 10 Suppl 1:S Rebbeck TR, Lynch HT, Neuhausen SL et al. Prphylactic phrectmy in carriers f BRCA1 r BRCA2 mutatins. N Engl J Med 2002; 346(21): 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 2002; 20(5): Weitzel JN, McCaffrey SM, Nedelcu R et al. Effect f genetic cancer risk assessment n surgical decisins at breast cancer diagnsis. Arch Surg 2003; 138(12):1323-8; discussin Winchester DP. Breast cancer in yung wmen. Surg Clin Nrth Am 1996; 76(2): Frank TS, Deffenbaugh AM, Reid JE et al. Clinical characteristics f individuals with germline mutatins in BRCA1 and BRCA2: analysis f 10,000 individuals. J Clin Oncl 2002; 20(6): Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

15 22. Langstn AA, Malne KE, Thmpsn JD et al. BRCA1 mutatins in a ppulatin-based sample f yung wmen with breast cancer. N Engl J Med 1996; 334(3): Malne KE, Daling JR, Thmpsn JD et al. BRCA1 mutatins and breast cancer in the general ppulatin: analyses in wmen befre age 35 years and in wmen befre age 45 years with first-degree family histry. JAMA 1998; 279(12): Frd D, Eastn DF, Strattn M et al. Genetic hetergeneity and penetrance analysis f the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Cnsrtium. Am J Hum Genet 1998; 62(3): Gershni-Baruch R, Patael Y, Dagan et al. Assciatin f the I1307K APC mutatin with hereditary and spradic breast/varian cancer: mre questins than answers. Br J Cancer 2000; 83(2): Hartge P, Struewing JP, Wachlder S et al. The prevalence f cmmn BRCA1 and BRCA2 mutatins amng Ashkenazi Jews. Am J Hum Genet 1999; 64(4): Hdgsn SV, Heap E, Camern J et al. Risk factrs fr detecting germline BRCA1 and BRCA2 funder mutatins in Ashkenazi Jewish wmen with breast r varian cancer. J Med Genet 1999; 36(5): de Ruijter TC, Veeck J, de Hn JP et al. Characteristics f triple-negative breast cancer. J Cancer Res Clin Oncl 2011; 137(2): Kandel MJ, Stadler Z, Masciari S et al. Prevalence f BRCA1 mutatins in triple negative breast cancer (BC). J Clin Oncl 2006; 24(18S): Yung SR, Pilarski RT, Dnenberg T et al. The prevalence f BRCA1 mutatins amng yung wmen with triple-negative breast cancer. BMC Cancer 2009; 9: Gnzalez-Angul AM, Timms KM, Liu S et al. Incidence and utcme f BRCA mutatins in unselected patients with triple receptr-negative breast cancer. Clin Cancer Res 2011; 17(5): Nard SA, Fulkes WD. BRCA1 and BRCA2: 1994 and beynd. Nat Rev Cancer 2004; 4(9): Hruban RH, Cant MI, Gggins M et al. Update n familial pancreatic cancer. Adv Surg 2010; 44: Cuch FJ, Jhnsn MR, Rabe KG et al. The prevalence f BRCA2 mutatins in familial pancreatic cancer. Cancer Epidemil Bimarkers Prev 2007; 16(2): Ferrne CR, Levine DA, Tang LH et al. BRCA germline mutatins in Jewish patients with pancreatic adencarcinma. J Clin Oncl 2009; 27(3): Trainer AH, Meiser B, Watts K et al. Mving tward persnalized medicine: treatmentfcused genetic testing f wmen newly diagnsed with varian cancer. Int J Gynecl Cancer 2010; 20(5): Zhang S, Ryer R, Li S et al. Frequencies f BRCA1 and BRCA2 mutatins amng 1,342 unselected patients with invasive varian cancer. Gynecl Oncl 2011; 121(2): Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

16 38. Rbsn M, Offit K. Clinical practice. Management f an inherited predispsitin t breast cancer. N Engl J Med 2007; 357(2): Phillips KA, Jenkins MA, Lindeman GJ et al. Risk-reducing surgery, screening and chempreventin practices f BRCA1 and BRCA2 mutatin carriers: a prspective chrt study. Clin Genet 2006; 70(3): Rennert G, Bisland-Naggan S, Barnett-Griness O et al. Clinical utcmes f breast cancer in carriers f BRCA1 and BRCA2 mutatins. N Engl J Med 2007; 357(2): Malne KE, Daling JR, Ddy DR et al. Prevalence and predictrs f BRCA1 and BRCA2 mutatins in a ppulatin-based study f breast cancer in white and black American wmen ages 35 t 64 years. Cancer Res 2006; 66(16): Gallagher DJ, Gaudet MM, Pal P et al. Germline BRCA mutatins dente a clinicpathlgic subset f prstate cancer. Clin Cancer Res 2010; 16(7): Kirchhff T, Kauff ND, Mitra N et al. BRCA mutatins and risk f prstate cancer in Ashkenazi Jews. Clin Cancer Res 2004; 10(9): Mitra AV, Bancrft EK, Barbachan Y et al. Targeted prstate cancer screening in men with mutatins in BRCA1 and BRCA2 detects aggressive prstate cancer: preliminary analysis f the results f the IMPACT study. BJU Int 2011; 107(1): Antniu AC, Beesley J, McGuffg L et al. Cmmn breast cancer susceptibility alleles and the risk f breast cancer fr BRCA1 and BRCA2 mutatin carriers: implicatins fr risk predictin. Cancer Res 2010; 70(23): Casadei S, Nrquist BM, Walsh T et al. Cntributin f inherited mutatins in the BRCA2-interacting prtein PALB2 t familial breast cancer. Cancer Res 2011; 71(6): Cx DG, Simard J, Sinnett D et al. Cmmn variants f the BRCA1 wild-type allele mdify the risk f breast cancer in BRCA1 mutatin carriers. Hum Ml Genet 2011; 20(23): Engel C, Versmld B, Wappenschmidt B et al. Assciatin f the variants CASP8 D302H and CASP10 V410I with breast and varian cancer risk in BRCA1 and BRCA2 mutatin carriers. Cancer Epidemil Bimarkers Prev 2010; 19(11): Kleibl Z, Havranek O, Krmunda S et al. The AIB1 gene plyglutamine repeat length plymrphism and the risk f breast cancer develpment. J Cancer Res Clin Oncl 2011; 137(2): Osri A, Milne RL, Alns R et al. Evaluatin f the XRCC1 gene as a phentypic mdifier in BRCA1/2 mutatin carriers. Results frm the cnsrtium f investigatrs f mdifiers f BRCA1/BRCA2. Br J Cancer 2011; 104(8): Ramus SJ, Kartsnaki C, Gayther SA et al. Genetic variatin at 9p22.2 and varian cancer risk fr BRCA1 and BRCA2 mutatin carriers. J Natl Cancer Inst 2011; 103(2): Zhu GW, Hu J, Peng XD et al. RAD51 135G>C plymrphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 2011; 125(2): Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f

17 53. Metcalfe K, Lubinski J, Lynch HT et al. Family histry f cancer and cancer risks in wmen with BRCA1 r BRCA2 mutatins. J Natl Cancer Inst 2010; 102(24): Walsh T, Casadei S, Cats KH et al. Spectrum f mutatins in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk f breast cancer. JAMA 2006; 295(12): Palma MD, Dmchek SM, Stpfer J et al. The relative cntributin f pint mutatins and genmic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 2008; 68(17): Myriad Website. Available nline at: Resurce-Guide-BART-Criteria.pdf and Last accessed September 2, 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 2008; 26(4): Offit K, Garber JE. Time t check CHEK2 in families with breast cancer? J Clin Oncl 2008; 26(4): Myszka A, Karpinski P, Slezak R et al. Irrelevance f CHEK2 variants t diagnsis f breast/varian cancer predispsitin in Plish chrt. J Appl Genet 2011; 52(2): Zhang B, Beeghly-Fadiel A, Lng J et al. Genetic variants assciated with breast-cancer risk: cmprehensive research synpsis, meta-analysis, and epidemilgical evidence. Lancet Oncl 2011; 12(5): Peng S, Lu B, Ruan W et al. Genetic plymrphisms and breast cancer risk: evidence frm meta-analyses, pled analyses, and genme-wide assciatin studies. Breast Cancer Res Treat 2011; 127(2): Hirst JE, Gard GB, McIllry K et al. High rates f ccult fallpian tube cancer diagnsed at prphylactic bilateral salping-phrectmy. Int J Gynecl Cancer 2009; 19(5): American Sciety f Clinical Onclgy plicy statement update: genetic testing fr cancer susceptibility. J Clin Oncl 2003; 21(12): Genetic Susceptibility t Breast and Ovarian Cancer: Assessment, Cunseling and Testing Guidelines. The American Cllege f Medical Genetics, Plicy Statement: Available nline at: Last accessed Nvember Cdes Number Descriptin CPT 81211, 81212, 81213, 81214, 81215, 81216, BRCA1 and BRCA2 testing, cde range (new cdes effective 1/1/12) Cde range, Mlecular diagnstics; DNA islatin, amplificatin r analysis (New r revised 1999 CPT cdes) 42 Memrial Drive Suite 1 Pinehurst, N.C Phne (910) Fax (910) FirstCarlinaCare Insurance Cmpany, Inc. is a whlly-wned subsidiary f