Protocol. Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (BRCA1/BRCA2)

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1 Genetic Testing fr Hereditary Breast and/r Ovarian Cancer (20402) (Frmerly ) Medical Benefit Effective Date: 07/01/15 Next Review Date: 05/16 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 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. Preauthrizatin is required. 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. 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 and BRCA2 lcated n chrmsme 13q12-13). Identificatin f patients with BRCA mutatins may lead t enhanced screening and/r surveillance that culd lead t imprved utcmes. Backgrund 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, 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 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, 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 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. FDA Status The U.S. Fd and Drug Administratin (FDA) has nt regulated these tests because t date they have been ffered as labratry-develped services, subject nly t the general labratry peratinal regulatin under CLIA f Labratries perfrming clinical tests must be certified fr high cmplexity testing under CLIA. Per the website, there are currently six CLIA-certified U.S. labratries that ffer sequence analysis f the entire cding and fur that ffer deletin/duplicatin/cpy number analysis. Page 1 f 11

2 Myriad Genetic Labratries (Salt Lake City, UT) ffers (1) Cmprehensive BRACAnalysis that includes cmplete sequencing f BRCA1/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 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/BRCA2 analysis. Quest Diagnstics (Madisn, NJ) ffers BRCAvantage that includes sequencing f BRCA1/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/BRCA2 analysis fr knwn BRCA1 r BRCA2 mutatins; a funder mutatin panel fr Ashkenazi Jewish patients (three mutatins); cmprehensive BRCA1/BRCA2 analysis (full gene sequencing plus analysis f cmmn and uncmmn large rearrangements); and deletin/duplicatin analysis f uncmmn large rearrangements nly (withut sequencing) fr use when cmprehensive analysis is negative. Related Prtcl Genetic Cancer Susceptibility Panels Using Next Generatin Sequencing Plicy 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: Cmprehensive Mutatin Analysis). Patients with Cancer r With Histry f Cancer Genetic testing fr BRCA1 and BRCA2 mutatins in cancer-affected individuals may be cnsidered medically necessary under any f the fllwing circumstances: Individual frm a family with a knwn BRCA1/BRCA2 mutatin Persnal histry f breast cancer and 1 f the fllwing: Diagnsed age 45 years Tw primary breast cancers when first breast cancer diagnsis ccurred age 50 years Diagnsed age 50 years AND: 1 1st-, 2nd-, r 3rd-degree relative a with breast cancer at any age, r Unknwn r limited family histry b Diagnsed age 60 years with a triple negative (ER, PR, HER2 ) breast cancer Diagnsed any age AND ne r mre 1st-, 2nd-, r 3rd-degree relative a with breast cancer diagnsed 50 years Diagnsed any age AND tw r mre 1st-, 2nd-, r 3rd-degree relatives a with breast cancer at any age Diagnsed any age AND ne r mre 1st-, 2nd-, r 3rd-degree relative a with epithelial varian/fallpian tube/primary peritneal CA Page 2 f 11

3 Diagnsed any age AND tw r mre 1st-, 2nd-, r 3rd-degree relatives a with pancreatic cancer r prstate cancer c at any age 1st-, 2nd-, r 3rd-degree male relative with breast cancer Ethnicity assciated with deleterius funder mutatins, e.g., Ashkenazi Jewish descent d Persnal histry f epithelial varian/fallpian tube/primary peritneal cancer Persnal histry f male breast cancer Persnal histry f pancreatic cancer r prstate cancer c at any age AND tw r mre 1st-, 2nd-, r 3rddegree relatives a with any f the fllwing at any age. Fr pancreatic cancer, if Ashkenazi Jewish ancestry, nly ne additinal affected relative is needed. Breast cancer Ovarian/fallpian tube/primary peritneal cancer Pancreatic r prstate cancer c Patients withut cancer r Withut Histry f Cancer (see Plicy Guidelines: Testing Unaffected Individuals) Genetic testing fr BRCA1 and BRCA2 mutatins f cancer-unaffected individuals may be cnsidered medically necessary under any f the fllwing circumstances: Individual frm a family with a knwn BRCA1/BRCA2 mutatin 1st- r 2nd-degree bld relative meeting any criterin listed abve fr Patients with Cancer 3rd-degree bld relative with breast cancer and/r varian/fallpian tube/primary peritneal cancer AND tw r mre 1st-, 2nd-, r 3rd-degree relatives a with breast cancer ( 1 at age 50 years) and/r varian/fallpian tube/primary peritneal cancer a Fr the purpse f familial assessment, 1st-, 2nd-, and 3rd-degree relatives are bld relatives n the same side f the family (maternal r paternal). 1st-degree relatives are parents, siblings, and children. 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings. 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cusins. b Fr example, fewer than tw first- r secnd-degree female relatives having lived beynd age 45 in either lineage. In families with a large number f unaffected female relatives, the likelihd f mutatin detectin may be very lw. c Fr the purpse f familial assessment, prstate cancer is defined as Gleasn scre 7 d Testing fr Ashkenazi Jewish r ther funder mutatin(s) shuld be perfrmed first (see Plicy Guidelines: High Risk Ethnic Grups). Unless the 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. Page 3 f 11

4 Plicy Guidelines The Plicy Statements abve are based n current guidelines frm the Natinal Cmprehensive Cancer Netwrk (NCCN) 1. 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. 2 (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 Patients wh meet criteria fr genetic testing as utlined in the Plicy Statements abve shuld be tested fr mutatins in BRCA1 and BRCA2. In patients with a knwn familial BRCA mutatin, targeted testing fr the specific mutatin is recmmended. In patients with unknwn familial BRCA mutatin: Nn-Ashkenazi Jewish descent T identify clinically significant mutatins, NCCN advises testing a relative wh has breast r varian cancer, especially with early-nset disease, bilateral disease, multiple primaries, r varian cancer, because that individual has the highest likelihd fr a psitive test result. If n living family member with breast r varian cancer exists, NCCN suggests testing first- r secnd-degree family members affected with cancer thught t be related t deleterius BRCA1/BRCA2 mutatins (e.g., prstate cancer, pancreatic cancer, melanma). If n familial mutatin can be identified, tw pssible testing strategies are: Full sequencing fllwed by testing fr cmmn large genmic rearrangement deletins/ duplicatins) nly if sequencing detects n mutatin (negative result). Mre than 90% f BRCA mutatins will be detected by full sequencing. 4 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. Cmprehensive testing can detect 92.5% f BRCA1/BRCA2 mutatins. 4 If cmprehensive BRCA testing is negative, testing fr uncmmn large genmic rearrangements (e.g., BART ) may be dne. Testing fr uncmmn large rearrangements shuld nt be dne unless bth sequencing and testing fr cmmn large rearrangements have been perfrmed and are negative. Page 4 f 11

5 Ashkenazi Jewish descent Amng patients with negative cmprehensive testing, BART identified a deleterius mutatin (psitive result) in less than 1%. 4 In patients 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 Mutatin Analysis, belw). Cmprehensive Mutatin Analysis 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, 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 (see Plicy Statements sectin fr criteria). High-Risk Ethnic Grups Testing in eligible individuals wh belng t ethnic ppulatins in which there are well-characterized 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. When testing fr funder mutatins is negative, cmprehensive mutatin analysis shuld then be perfrmed. Testing Unaffected Individuals In unaffected family members f ptential BRCA mutatin 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 mutatin 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 mutatin but leads t difficulties in interpreting negative test results (uninfrmative negative) r mutatins f uncertain significance because the pssibility f a causative BRCA mutatin is nt ruled ut. Prstate Cancer Patients with BRCA mutatins have an increased risk f prstate cancer, and patients with knwn BRCA mutatins 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. 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 Page 5 f 11

6 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. NCCN Clinical Practive Guidelines in Onclgy. Genetic/familial high-risk assessment: breast and varian (discussin update in prgress), versin Accessed September 16, Myer VA. Risk assessment, genetic cunseling, and genetic testing fr BRCA-related cancer in wmen: U.S. Preventive Services Task Frce recmmendatin statement. Ann Intern Med. Feb ; 160(4): PMID U.S. Preventive Services Task Frce. Risk Assessment, Genetic Cunseling, and Genetic Testing fr BRCARelated Cancer in Wmen, December Accessed September 16, Myriad Genetics. Myriad PRO. BRACAnalysis large rearrangement test (BART): BART prevalence table and FAQ Accessed Octber 16, 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 4. PMID 6. Nelsn HD, Fu R, Gddard K et al. Risk Assessment, Genetic Cunseling, and Genetic Testing fr BRCA Related Cancer: Systematic Review t Update the U.S. Preventive Services Task Frce Recmmendatin. Evidence Synthesis N AHRQ Publicatin N EF-1. Rckville, MD: Agency fr Healthcare Research and Quality; 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 USA. Sep ; 111(39): PMID King MC, Levy-Lahad E, Lahad A. Ppulatin-based screening fr BRCA1 and BRCA2: 2014 Lasker Award. JAMA. Sep ; 312(11): PMID Stein R. Researcher urges wider genetic screening fr breast cancer. Natinal Public Radi Shts: health news frm NPR, 09/08/ aign=stryshare&utm_term. Accessed Octber 13, Begg CB. On the use f familial aggregatin in ppulatin-based case prbands fr calculating penetrance. J Natl Cancer Inst. 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. Am J Hum Genet. 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 Page 6 f 11

7 13. 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 Metcalfe K, Lynch HT, Ghadirian P, et al. Cntralateral breast cancer in BRCA1 and BRCA2 mutatin carriers. J Clin Oncl. Jun ; 22(12): PMID Mavaddat N, Peck S, Frst D, et al. Cancer risks fr BRCA1 and BRCA2 mutatin carriers: results frm prspective analysis f EMBRACE. Jurnal f the Natinal Cancer Institute. Jun ; 105(11): PMID Grann VR, Whang W, Jacbsn JS, et al. Benefits and csts f screening Ashkenazi Jewish wmen fr BRCA1 and BRCA2. Jurnal f clinical nclgy: fficial jurnal f the American Sciety f Clinical Onclgy. Feb 1999; 17(2): PMID Hartmann LC, Schaid DJ, Wds JE, et al. Efficacy f bilateral prphylactic mastectmy in wmen with a family histry f breast cancer. The New England jurnal f medicine. Jan ; 340(2): PMID Menkiszak J, Rzepka-Grska I, Grski B, et al. Attitudes tward preventive phrectmy amng BRCA1 mutatin carriers in Pland. Eurpean jurnal f gynaeclgical nclgy. 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. Internatinal jurnal f cancer. Jurnal internatinal du cancer. Oct ; 101(6): PMID Olpade OI, Artili G. Efficacy f risk-reducing salping-phrectmy in wmen with BRCA-1 and BRCA-2 mutatins. The breast jurnal. Jan-Feb 2004; 10 Suppl 1:S5-9. PMID Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prphylactic phrectmy in carriers f BRCA1 r BRCA2 mutatins. The New England jurnal f medicine. May 23, 2002; 346(21): PMID Scheuer L, Kauff N, Rbsn M, et al. Outcme f preventive surgery and screening fr breast and varian cancer in BRCA mutatin carriers. Jurnal f clinical nclgy: fficial jurnal f the American Sciety f Clinical Onclgy. Mar ; 20(5): PMID Weitzel JN, McCaffrey SM, Nedelcu R, et al. Effect f genetic cancer risk assessment n surgical decisins at breast cancer diagnsis. Archives f surgery. Dec 2003; 138(12): ; discussin PMID 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 research. Aug ; 66(16): PMID Winchester DP. Breast cancer in yung wmen. The Surgical clinics f Nrth America. Apr 1996; 76(2): PMID Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics f individuals with germline mutatins in BRCA1 and BRCA2: analysis f 10,000 individuals. Jurnal f clinical nclgy: fficial jurnal f the American Sciety f Clinical Onclgy. Mar ; 20(6): PMID Page 7 f 11

8 29. Langstn AA, Malne KE, Thmpsn JD, et al. BRCA1 mutatins in a ppulatin-based sample f yung wmen with breast cancer. The New England jurnal f medicine. Jan ; 334(3): PMID 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: the jurnal f the American Medical Assciatin. Mar ; 279(12): PMID 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. American jurnal f human genetics. Mar 1998; 62(3): PMID 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. British jurnal f cancer. Jul 2000; 83(2): PMID Hartge P, Struewing JP, Wachlder S, et al. The prevalence f cmmn BRCA1 and BRCA2 mutatins amng Ashkenazi Jews. American jurnal f human genetics. Apr 1999; 64(4): PMID 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. Jurnal f medical genetics. May 1999; 36(5): PMID de Ruijter TC VJ, de Hn JPJ, et al. Characteristics f triple-negative breast cancer. J Cancer Res Clin Oncl. 2011; 137: PMID 36. Kandel MJ SD, Masciari S et al. Prevalence f BRCA1 mutatins in triple negative breast cancer (BC). J Clin Onc. 2006; 24(18S):508. PMID 37. Yung SR, Pilarski RT, Dnenberg T, et al. The prevalence f BRCA1 mutatins amng yung wmen with triple-negative breast cancer. BMC cancer. 2009; 9:86. PMID Gnzalez-Angul AM, Timms KM, Liu S, et al. Incidence and utcme f BRCA mutatins in unselected patients with triple receptr-negative breast cancer. Clinical cancer research: an fficial jurnal f the American Assciatin fr Cancer Research. Mar ; 17(5): PMID Nard SA, Fulkes WD. BRCA1 and BRCA2: 1994 and beynd. Nat Rev Cancer. Sep 2004; 4(9): PMID Hruban RH, Cant MI, Gggins M, et al. Update n familial pancreatic cancer. Advances in surgery. 2010; 44: PMID Cuch FJ, Jhnsn MR, Rabe KG, et al. The prevalence f BRCA2 mutatins in familial pancreatic cancer. Cancer epidemilgy, bimarkers & preventin: a publicatin f the American Assciatin fr Cancer Research, cspnsred by the American Sciety f Preventive Onclgy. Feb 2007; 16(2): PMID Ferrne CR, Levine DA, Tang LH, et al. BRCA germline mutatins in Jewish patients with pancreatic adencarcinma. Jurnal f clinical nclgy: fficial jurnal f the American Sciety f Clinical Onclgy. Jan ; 27(3): PMID Trainer AH, Meiser B, Watts K, et al. Mving tward persnalized medicine: treatment-fcused genetic testing f wmen newly diagnsed with varian cancer. Internatinal jurnal f gyneclgical cancer: fficial jurnal f the Internatinal Gyneclgical Cancer Sciety. Jul 2010; 20(5): PMID Page 8 f 11

9 44. Zhang S, Ryer R, Li S, et al. Frequencies f BRCA1 and BRCA2 mutatins amng 1,342 unselected patients with invasive varian cancer. Gyneclgic nclgy. May 1, 2011; 121(2): PMID Hirst JE, Gard GB, McIllry K, et al. High rates f ccult fallpian tube cancer diagnsed at prphylactic bilateral salping-phrectmy. Internatinal jurnal f gyneclgical cancer: fficial jurnal f the Internatinal Gyneclgical Cancer Sciety. Jul 2009; 19(5): PMID Pwell CB, Swisher EM, Cass I, et al. Lng term fllw up f BRCA1 and BRCA2 mutatin carriers with unsuspected neplasia identified at risk reducing salping-phrectmy. Gyneclgic nclgy. May 2013; 129(2): PMID Rbsn M, Offit K. Clinical practice. Management f an inherited predispsitin t breast cancer. The New England jurnal f medicine. Jul ; 357(2): PMID 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. Clinical genetics. Sep 2006; 70(3): PMID Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical utcmes f breast cancer in carriers f BRCA1 and BRCA2 mutatins. The New England jurnal f medicine. Jul ; 357(2): PMID Lesnck JL, Darcy KM, Tian C, et al. BRCA1 expressin and imprved survival in varian cancer patients treated with intraperitneal cisplatin and paclitaxel: a Gyneclgic Onclgy Grup Study. British jurnal f cancer. Apr ; 108(6): PMID 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 Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutatins dente a clinicpathlgic subset f prstate cancer. Clinical cancer research: an fficial jurnal f the American Assciatin fr Cancer Research. Apr ; 16(7): PMID Kirchhff T, Kauff ND, Mitra N, et al. BRCA mutatins and risk f prstate cancer in Ashkenazi Jews. Clinical cancer research: an fficial jurnal f the American Assciatin fr Cancer Research. May 1, 2004; 10(9): PMID Castr E, Gh C, Olms D, et al. Germline BRCA mutatins are assciated with higher risk f ndal invlvement, distant metastasis, and pr survival utcmes in prstate cancer. Jurnal f clinical nclgy: fficial jurnal f the American Sciety f Clinical Onclgy. May 10, 2013; 31(14): PMID 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. Jan 2011; 107(1): PMID 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 research. Dec ; 70(23): PMID Casadei S, Nrquist BM, Walsh T, et al. Cntributin f inherited mutatins in the BRCA2-interacting prtein PALB2 t familial breast cancer. Cancer research. Mar ; 71(6): PMID Page 9 f 11

10 58. 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. Human mlecular genetics. Sep PMID 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 epidemilgy, bimarkers & preventin: a publicatin f the American Assciatin fr Cancer Research, cspnsred by the American Sciety f Preventive Onclgy. Nv 2010; 19(11): PMID Kleibl Z, Havranek O, Krmunda S, et al. The AIB1 gene plyglutamine repeat length plymrphism and the risk f breast cancer develpment. Jurnal f cancer research and clinical nclgy. Feb 2011; 137(2): PMID 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. British jurnal f cancer. Apr ; 104(8): PMID Ramus SJ, Kartsnaki C, Gayther SA, et al. Genetic variatin at 9p22.2 and varian cancer risk fr BRCA1 and BRCA2 mutatin carriers. Jurnal f the Natinal Cancer Institute. Jan ; 103(2): PMID Bianc A, Quaresima B, Pileggi C, et al. Plymrphic repeat length in the AIB1 gene and breast cancer risk in BRCA1 and BRCA2 mutatin carriers: a meta-analysis f bservatinal studies. PLS One. 2013; 8(3):e PMID Zhu GW, Hu J, Peng XD, et al. RAD51 135G>C plymrphism and breast cancer risk: a meta-analysis. Breast cancer research and treatment. Jan 2011; 125(2): PMID Metcalfe K, Lubinski J, Lynch HT, et al. Family histry f cancer and cancer risks in wmen with BRCA1 r BRCA2 mutatins. Jurnal f the Natinal Cancer Institute. Dec ; 102(24): PMID Lancaster JM, Pwell CB, Chen LM, et al. Statement n risk assessment fr inherited gyneclgic cancer predispsitins. Gyneclgic nclgy. Sep PMID 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: the jurnal f the American Medical Assciatin. Mar ; 295(12): PMID 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 research. Sep ; 68(17): PMID Armstrng J, Tscan M, Ktchk N, et al. American BRCA Outcmes and Utilizatin f Testing (ABOUT) Study: A Pragmatic Research Mdel that Incrprates Persnalized Medicine/Patient-Centered Outcmes in a Real Wrld Setting. J Genet Cuns. Sep PMID American Sciety f Clinical Onclgy plicy statement update: genetic testing fr cancer susceptibility. Jurnal f clinical nclgy: fficial jurnal f the American Sciety f Clinical Onclgy. Jun ; 21(12): PMID Rbsn ME, Strm CD, Weitzel J, et al. American Sciety f Clinical Onclgy Plicy Statement Update: Genetic and Genmic Testing fr Cancer Susceptibility. Jurnal f Clinical Onclgy. February 10, 2010; 28(5): PMID Page 10 f 11

11 72. Genetic Susceptibility t Breast and Ovarian Cancer: Assessment, Cunseling and Testing Guidelines. The American Cllege f Medical Genetics, Practice Guideline: 1999; Accessed September 16, Palmett GBA. MlDX apprved gene testing (M00041), last updated 09/17/ Tpic~Cvered%20Tests~9BMLRK6738?pen&navmenu=Brwse%5eBy%5eTpic. Accessed Octber 15, Page 11 f 11