GENETIC TESTING FOR HEREDITARY BREAST AND/OR OVARIAN CANCER SYNDROME (HBOC)

CLINICAL POLICY GENETIC TESTING FOR HEREDITARY BREAST AND/OR OVARIAN CANCER SYNDROME (HBOC) Plicy Number: DIAGNOSTIC 004.22 T2 Effective Date: December 1, 2014 Table f Cntents CONDITIONS OF COVERAGE... BENEFIT CONSIDERATIONS... COVERAGE RATIONALE... APPLICABLE CODES... DESCRIPTION OF SERVICES... CLINICAL EVIDENCE... U.S. FOOD AND DRUG ADMINISTRATION... REFERENCES... POLICY HISTORY/REVISION INFORMATION... Page 1 2 2 5 5 5 10 10 12 Related Plicies: Nne The services described in Oxfrd plicies are subject t the terms, cnditins and limitatins f the Member's cntract r certificate. Unless therwise stated, Oxfrd plicies d nt apply t Medicare Advantage enrllees. Oxfrd reserves the right, in its sle discretin, t mdify plicies as necessary withut prir written ntice unless therwise required by Oxfrd's administrative prcedures r applicable state law. The term Oxfrd includes Oxfrd Health Plans, LLC and all f its subsidiaries as apprpriate fr these plicies. Certain plicies may nt be applicable t Self-Funded Members and certain insured prducts. Refer t the Member's plan f benefits r Certificate f Cverage t determine whether cverage is prvided r if there are any exclusins r benefit limitatins applicable t any f these plicies. If there is a difference between any plicy and the Member s plan f benefits r Certificate f Cverage, the plan f benefits r Certificate f Cverage will gvern. CONDITIONS OF COVERAGE Applicable Lines f Business/Prducts Benefit Type Referral Required (Des nt apply t nn-gatekeeper prducts) Authrizatin Required (Precertificatin always required fr inpatient admissin) Precertificatin with Medical Directr Review Required Applicable Site(s) f Service (If site f service is nt listed, Medical Directr review is required) Special Cnsideratins This plicy applies t Oxfrd Cmmercial plan membership. General benefits package N Yes 1 Yes 1 Labratry 1 Precertificatin with review by a Medical Directr r their designee is required. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 1

BENEFIT CONSIDERATIONS Essential Health Benefits fr Individual and Small Grup: Fr plan years beginning n r after January 1, 2014, the Affrdable Care Act f 2010 (ACA) requires fully insured nn-grandfathered individual and small grup plans (inside and utside f Exchanges) t prvide cverage fr ten categries f Essential Health Benefits ( EHBs ). Large grup plans (bth self-funded and fully insured), and small grup ASO plans, are nt subject t the requirement t ffer cverage fr EHBs. Hwever, if such plans chse t prvide cverage fr benefits which are deemed EHBs (such as maternity benefits), the ACA requires all dllar limits n thse benefits t be remved n all Grandfathered and Nn-Grandfathered plans. The determinatin f which benefits cnstitute EHBs is made n a state by state basis. As such, when using this guideline, it is imprtant t refer t the enrllee s specific plan dcument t determine benefit cverage. COVERAGE RATIONALE Definitins: Please nte, fr the purpse f this plicy: 1. Clse bld relatives are defined as fllws: A. First degree relatives include parents, sibling and ffspring B. Secnd degree relatives include half-brthers/sisters, aunts/uncles, grandparents grandchildren and nieces/nephews affected all n the same side f the family C. Third degree relatives include first cusins, great-aunts/uncles, greatgrandchildren and great grandparents affected all n same side f family 2. A breast cancer diagnsis includes either invasive r nn-invasive (ductal carcinma in situ) types. 3. Ovarian cancer als includes fallpian tube cancers and primary peritneal carcinma. 4. Limited family histry is defined as having fewer than tw knwn first-degree r secnddegree female relatives r female relatives surviving beynd 45 years f age n either r bth sides f the family. (e.g. individual wh is adpted) 5. Dcumentatin f persnal and family histry shuld be in the cntempraneus medical recrds submitted with the testing request (i.e. request frm). 6. Fr the statements that include age guidelines, a persn is cnsidered t be 45 years f age up until the day befre their 46th birthday, and a persn is cnsidered t be 50 years f age up until the day befre their 51st birthday. 7. Tw breast primary cancers include cancers appearing at the same time (synchrnus) and ne is nt a metastasis f the ther; r primary cancers develping at intervals (metachrnus r asynchrnus). The tumrs may be in ne r tw breasts. 8. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrmes (HBOC als knwn as BRACA1/BRACA2) -assciated malignancies include prstate cancer, (Gleasn scre 7), pancreatic cancer r melanma. The presence f these malignancies des nt necessarily justify BRCA testing. Fr example, a female with breast cancer ver age 50 whse sister had melanma at 40 and whse father has prstate cancer (Gleasn scre 7) wuld meet criteria. In anther example, a female with breast cancer ver age 50 whse maternal aunt had pancreatic cancer and whse paternal uncle had prstate cancer (Gleasn scre 7) wuld nt meet criteria because the aunt and uncle are n different sides f the family. 9. Triple-negative breast cancer refers t any breast cancer that des nt express the genes fr estrgen receptr (ER), prgesterne receptr (PR) r HER2/neu. This Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 2

subtype f breast cancer is clinically characterized as mre aggressive and less respnsive t standard treatment and is assciated with prer verall patient prgnsis. It is diagnsed mre frequently in yunger wmen, wmen with BRCA1 mutatins and thse belnging t African-American and Hispanic ethnic grups. 10. Gleasn scring is a system f grading prstate cancer tissue based n hw it lks under a micrscpe. Gleasn scres range frm 2 t 10 and indicate hw likely it is that a tumr will spread. A lw Gleasn scre means the cancer tissue is similar t nrmal prstate tissue and the tumr is less likely t spread. A high Gleasn scre means the cancer tissue is very different frm nrmal and the tumr is mre likely t spread. Genetic Cunseling Genetic cunseling is strngly recmmended prir t genetic testing fr BRCA mutatins in rder t infrm persns being tested abut the advantages and limitatins f a specific genetic test as applied t a unique persn. BRCA Testing Criteria I. BRCA 1 and BRCA 2 testing is prven and medically necessary fr wmen with a persnal histry f breast cancer in the fllwing situatins: A. Breast cancer diagnsed at age 45 r yunger with r withut family histry; r B. Breast cancer diagnsed at age 50 r yunger with: 1. At least ne clse bld relative with breast cancer at any age; r 2. An unknwn r limited family histry (see Definitins sectin fr further clarificatin f limited family histry) C. Breast cancer diagnsed at any age with: 1. Tw breast primary cancers, when first breast cancer diagnsis ccurred prir t age 50; r 2. Persnal histry f varian cancer; r 3. At least ne clse bld relative with breast cancer diagnsed at age 50 r yunger; r 4. At least tw clse bld relatives n the same side f the family with breast, cancer at any age; r 5. At least ne clse bld relative with varian cancer at any age; r 6. At least tw clse bld relatives n the same side f the family with pancreatic r prstate (Gleasn scre 7) cancer at any age; r 7. Clse male bld relative with breast cancer; r 8. At least ne clse bld relative that has a BRCA1 r BRCA2 mutatin; r 9. Ashkenazi Jewish r ethnic grups assciated with funder mutatins. Testing fr Ashkenazi Jewish funder-specific mutatins shuld be perfrmed first. D. Triple negative breast cancer diagnsed at age 60 r yunger. II. III. IV. BRCA 1 and BRCA 2 testing is prven and medically necessary fr wmen with a persnal histry f varian cancer BRCA 1 and BRCA 2 testing is prven and medically necessary fr wmen and men with a persnal histry f pancreatic cancer at any age and at least tw clse bld relatives n the same side f the family with breast, varian and/r pancreatic cancer and/r aggressive prstate (Gleasn scre 7) cancer at any age. If Ashkenazi Jewish ancestry, nly ne additinal affected relative is needed. BRCA1 and BRCA2 testing is prven and medically necessary fr men with a persnal histry f prstate (Gleasn scre 7) cancer at any age and at least tw clse bld relatives n the same side f the family with breast, varian, pancreatic and/r prstate (Gleasn scre 7) cancer at any age. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 3

V. BRCA1 and BRCA2 testing is prven and medically necessary fr men with a persnal histry f breast cancer. VI. VII. BRCA 1 and BRCA 2 screening tests are prven and medically necessary fr men and wmen withut a persnal histry f breast r varian cancer with at least ne f the fllwing familial risk factrs: A. At least ne first- r secnd-degree bld relative meeting any f the abve criteria (I-V); r B. At least ne third-degree bld relative with breast cancer and/r varian cancer wh has at least 2 clse bld relatives with breast cancer (at least ne with breast cancer at age 50 r yunger) and/r varian cancer; r C. A knwn BRCA1/BRCA2 mutatin in the family (defined as first-, secnd- r thirddegree relative) Nte: Natinal Cmprehensive Cancer Netwrk (NCCN) guidelines state that significant limitatins f interpreting test results fr an unaffected individual shuld be discussed. Testing f unaffected individuals shuld nly be cnsidered when an apprpriate affected family member is unavailable fr testing. Clinical judgment shuld be used t determine if the patient has reasnable likelihd f a mutatin (NCCN, 2014). BRCA1 and/r BRCA2 testing is unprven and nt medically necessary fr all ther indicatins including 1) screening f breast r varian cancers fr individuals nt listed in the medically necessary indicatins abve r 2) fr risk assessment f ther cancers. Further evidence is needed t establish the clinical utility f testing in ther ppulatins. Additinal Infrmatin: Nte: If there are n living family members with breast r varian cancer, cnsider testing family members affected with cancers thught t be assciated with BRCA1/BRCA2, prstate (Gleasn scre 7) and pancreatic cancer and melanma. Large Genmic Rearrangement Testing Certain large genmic rearrangements are nt detectable by primary sequencing assay, thereby necessitating supplementary testing, in sme cases. In these circumstances, NCCN guidelines emphasize the need fr cmprehensive testing, which encmpasses full BRCA1/2 sequencing and detectin f large gene rearrangements. I. Detectin f large genmic rearrangements is prven and medically necessary fr individuals wh meet the testing criteria fr BRCA1/BRCA2 and have n knwn familial BRCA1/BRCA2 mutatins. Nte: NCCN guidelines state that significant limitatins f interpreting test results fr an unaffected individual shuld be discussed. Testing f unaffected individuals shuld nly be cnsidered when an apprpriate affected family member is unavailable fr testing. Clinical judgment shuld be used t determine if the patient has reasnable likelihd f a mutatin (NCCN, 2014). II. Detectin f large genmic rearrangements is unprven and nt medically necessary fr the purpse f screening in the general ppulatin. There is inadequate clinical evidence that such screening reduces mrtality frm breast cancer in a nrmal risk ppulatin. APPLICABLE CODES The cdes listed in this plicy are fr reference purpses nly. Listing f a service r device cde in this plicy des nt imply that the service described by this cde is a cvered r nn-cvered health service. Cverage is determined by the Member s plan f benefits r Certificate f Cverage. This list f cdes may nt be all inclusive. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 4

Applicable CPT Cdes CPT Cde 81211 81212 81214 81215 81216 81217 Descriptin BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis and cmmn duplicatin/deletin variants in BRCA1 (i.e., exn 13 del 3.835kb, exn 13 dup 6kb, exn 14-20 del 26kb, exn 22 del 510bp, exn 8-9 del 7.1kb) BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and varian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants BRCA1 (breast cancer 1) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis and cmmn duplicatin/deletin variants (i.e., exn 13 del 3.835kb, exn 13 dup 6kb, exn 14-20 del 26kb, exn 22 del 510bp, exn 8-9 del 7.1kb) BRCA1 (breast cancer 1) (e.g., hereditary breast and varian cancer) gene analysis; knwn familial variant BRCA2 (breast cancer 2) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis BRCA2 (breast cancer 2) (e.g., hereditary breast and varian cancer) gene analysis; knwn familial variant Large Genmic Rearrangements BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and 81213 varian cancer) gene analysis; uncmmn duplicatin/deletin variants CPT is a registered trademark f the American Medical Assciatin. DESCRIPTION OF SERVICES In 5% t 10% f breast cancer cases, there is a strng family histry which includes multiple affected family members, multiple primary breast cancers in the same individual, r prevalence f bth breast and varian cancer in the same individual r family. Tw different BRCA genes have been identified, BRCA1 and BRCA2. They are nt similar in structure r functin. Wmen that carry mutatins in BRCA1 are estimated t have an almst 90% risk f develping breast cancer and a 40% t 60% risk f develping varian cancer. Wmen carrying mutatins in BRCA2 are estimated t have an 85% lifetime risk f breast cancer and a 10% t 20% risk f develping varian cancer. In cmparisn, an average wman withut mutatins in the BRCA genes has a 10% lifetime risk f breast cancer and a 1.7% risk f varian cancer (ECRI Htline 2011a). Ethnic-specific cmmn variants include funder effects fr a few ppulatins, especially Ashkenazi Jewish, fr which assays are variant-specific and the test ppulatin is mre clearly defined. Cmprehensive genetic testing may be perfrmed n individuals at exceptinally high risk wh test negative with cnventinal (sequencing assay) BRCA1/BRCA2 testing. Accrding t the NCCN, cmprehensive genetic testing includes full sequencing f BRCA1/BRCA2 and detectin f large genmic rearrangements (NCCN, 2014). CLINICAL EVIDENCE A GeneReviews chapter n hereditary breast and varian cancer addresses BRCA mutatins and the risk f develping certain cancers. An increased likelihd f a BRCA1 r BRCA2 mutatin is suspected n the basis f certain persnal and family histry characteristics and varius clinical criteria (Petrucelli et al., 2013). In a Cchrane systematic review, Hilgart et al. (2012) evaluated the impact f cancer genetic riskassessment services n patients at risk f familial breast cancer. In this update, the authrs Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 5

included five new trials, bringing the ttal number f included studies t eight. The included trials prvided data n 1973 participants and assessed the impact f cancer genetic risk assessment n utcmes including perceived risk f inherited cancer, and psychlgical distress. The review suggests that cancer genetic risk-assessment services help t reduce distress, imprve the accuracy f the perceived risk f breast cancer and increase knwledge abut breast cancer and genetics. The review fund favrable utcmes fr patients after risk assessment fr familial breast cancer. Hwever, there were t few studies t make any significant cnclusins abut hw best t deliver cancer genetic risk-assessment services. Further research is needed assessing the best means f delivering cancer risk assessment, by different health prfessinals, in different ways and in alternative lcatins. A task frce cnvened by the Cancer Genetics Studies Cnsrtium (CGSC) and rganized by the Natinal Human Genme Research Institute develped recmmendatins fr fllw-up care f individuals with a predispsitin t cancer due t BRCA1 r BRCA2 mutatins (Burke et al., 1997). Althugh the efficacy f cancer surveillance r ther measures t reduce risk in these individuals is unknwn, early breast and varian cancer screening was recmmended fr individuals with BRCA1 mutatins, and early breast cancer screening fr thse individuals with BRCA2 mutatins. N recmmendatins were made fr r against prphylactic surgery, as evidence f benefit was lacking. Warlam-Rdenhuis et al. (2005) cmpleted a 1000 patient prspective study t determine predictive factrs linked t BRCA1/BRCA2. The family histry f breast cancer was the highest predictive factr f a psitive BRCA test. The next highest predictive factr was age. Nearly 30% f BRCA carriers had n family histry f breast r varian cancer and an additinal 50% f the mutatin carriers had n affected first-degree relatives with breast cancer suggesting that BRCA screening based n family histry alne wuld miss a cnsiderable prprtin f mutatin carriers. The frequency f BRCA mutatins in patients diagnsed befre the age f 45 years indicated that this age was a useful selectin criterin. ECRI cncluded that the diagnstic test characteristics f BRCA gene mutatin testing have nt been studied fr the average ppulatin. Mst patients with breast cancer d nt have a familial frm f the disease. Thus, screening f the general ppulatin is unwarranted (ECRI, 2011a). The Natinal Institute fr Health and Care Excellence (NICE) published guidelines addressing the classificatin and care f peple at risk f familial breast cancer and management f breast cancer and related risks in peple with a family histry f breast cancer (NICE, 2013). The U.S. Preventive Services Task Frce (USPSTF, 2013) recmmends that primary care prviders screen wmen wh have family members with breast, varian, tubal r peritneal cancer with ne f several screening tls designed t identify a family histry that may be assciated with an increased risk fr ptentially harmful mutatins in breast cancer susceptibility genes (BRCA1 r BRCA2). Wmen with psitive screening results shuld receive genetic cunseling and, if indicated after cunseling, BRCA testing (Grade B). Grade B recmmendatin: The USPSTF recmmends the service. There is high certainty that the net benefit is mderate r there is mderate certainty that the net benefit is mderate t substantial. The USPSTF recmmends against rutine genetic cunseling r BRCA testing fr wmen whse family histry is nt assciated with an increased risk fr ptentially harmful mutatins in the BRCA1 r BRCA2 genes (Grade D). Grade D recmmendatin: The USPSTF recmmends against the service. There is mderate r high certainty that the service has n net benefit r that the harms utweigh the benefits. The USPSTF cncluded that the benefits f referring wmen with an increased risk family histry t suitably trained healthcare prviders utweigh the harms. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 6

Germline mutatins in the tumr suppressr genes BRCA1 and BRCA2 have been prven t indicate a drastically increased lifetime risk f breast and varian cancers in the individuals wh carry them. A number f studies have shwn that the third mst cmmn cancer assciated with these mutatins is pancreatic cancer (Greer and Whitcmb, 2007). Of 211 Ashkenazi Jewish breast cancer prbands with a family histry f pancreatic cancer, Stadler et al. (2011) fund that 30 (14.2%) harbred a BRCA mutatin. Furteen (47%) f the mutatins were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnsed with breast cancer at age 50 years were fund t have a higher BRCA1/2 mutatin prevalence than prbands with breast cancer wh were diagnsed at age > 50 years (21.1% vs 6.9%). In patients with a first-, secnd-, r third-degree relative with pancreatic cancer, mutatin prevalences were 15.4%, 15.3% and 8.6%, respectively. The authrs fund that BRCA1 and BRCA2 mutatins are bserved with nearly equal distributin in Ashkenazi Jewish breast-pancreas cancer families, suggesting that bth genes are assciated with pancreatic cancer risk. Ferrne et al. (2009) lked at the prevalence f BRCA1 and BRCA2 in an unselected grup f Jewish patients and cmpared patients with resected BRCA mutatin-assciated pancreatic adencarcinma (PAC) t PAC patients withut mutatins. Of the 187 Jewish patients wh underwent resectin fr PAC, tissue was available fr 145 patients. Funder mutatins fr BRCA1 and BRCA2 were identified in 5.5% f patients (tw with BRCA1 [1.3%] and six with BRCA2 [4.1%]). A previus cancer was reprted by 24% (35 f 145) f patients with the mst cmmn sites being breast cancer (9 f 35; 74%) and prstate cancer (8 f 35; 23%). Large Genmic Rearrangement Testing The prevalence f BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histries and ancestries that were referred fr clinical mlecular testing fr suspicin f hereditary breast and varian cancer. Prevalence data was analyzed fr patients frm different risk and ethnic grups. Patients were designated as high-risk (n=25,535) if their clinical histry predicted a high prir prbability. Fr these patients, large rearrangement (LR) testing was perfrmed autmatically in cnjunctin with sequencing. Elective patients (n=22,921) did nt meet the highrisk criteria, but underwent LR testing if BRCA1/2 sequencing indicated n knwn mutatins. Overall BRCA1/2 mutatin prevalence amng high-risk patients was 23.8% versus 8.2% fr the elective grup. The mutatin prfile fr high-risk patients was 90.1% sequencing mutatins versus 9.9% LRs, and fr elective patients, 94.1% sequencing versus 5.9% LRs. The authrs nted that this difference may reflect the bias in high-risk patients t carry mutatins in BRCA1, which has a higher penetrance and frequency f LRs cmpared with BRCA2. Significant differences in the prevalence and types f LRs were fund in patients f different ancestries. LR mutatins were significantly mre cmmn in Latin American/Caribbean patients (Judkins et al., 2012). A study (Walsh, 2006) fund that the nly genetic test cmmercially available in the United States t determine risk fr develpment f hereditary breast cancer failed t detect BRCA1 and BRCA2 mutatins in apprximately 12% f breast cancer patients (n=300) wh were members f a family with at least 4 cases f breast cancer and/r varian cancer. In this study, researchers retested participants fr carrier status f genetic mutatins knwn t influence risk fr develpment f breast cancer using a mlecular methd nt currently cleared fr market in the United States knwn as multiplex ligatin-dependent prbe amplificatin (MLPA). Prir t enrllment, all participants had received a negative result frm the breast cancer genetic test (Myriad Genetics Inc.) used rutinely in the United States. The results f MLPA analysis indicated that 17% f study participants were, in fact, carriers f breast cancer-relevant genetic mutatin, with 12% fund t have alteratins f BRCA1 r BRCA2. Inherited alteratins f BRCA1 were mre frequent amng participants wh were diagnsed with breast cancer prir t 40 years f age (16%) than amng thse wh were lder when diagnsed (6.5%). The clinical implicatins f these findings cannt be generalized t ther ppulatins, but results strngly suggest that imprved methds fr determining breast cancer risk are needed fr individuals with strng family histries f breast and/r varian cancer. Unger et al. (2000) assessed the frequency f genmic rearrangements in BRCA1 was in 42 Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 7

American families with breast and varian cancer wh were seeking genetic testing and wh were subsequently fund t be negative fr BRCA1 and BRCA2 cding-regin mutatins. The exn 13 duplicatin was detected in ne family, and fur families had ther genmic rearrangements. A ttal f 5 (11. 9%) f the 42 families with breast/varian cancer wh did nt have BRCA1 and BRCA2 cding-regin mutatins had mutatins in BRCA1 that were missed by cnfrmatin-sensitive gel electrphresis r sequencing. Fur f five families with BRCA1 genmic rearrangements included at least ne individual with bth breast and varian cancer; therefre, 4 (30.8%) f 13 families with a case f multiple primary breast and varian cancer had a genmic rearrangement in BRCA1. Families with genmic rearrangements had prir prbabilities f having a BRCA1 mutatin, ranging frm 33% t 97% (mean 70%). In cntrast, in families withut rearrangements, prir prbabilities f having a BRCA1 mutatin ranged frm 7% t 92% (mean 37%). Triple Negative Breast Cancer The triple-negative breast cancer phentype, which carries an adverse prgnsis, accunts fr 80% t 90% f BRCA1-assciated breast cancers. A study f 54 wmen with triple-negative breast cancer aged 40 years r yunger, wh were nt cnsidered candidates fr BRCA testing because f the lack f a strng family histry, shwed five with BRCA1 mutatins and ne with a BRCA2 mutatin (11% mutatin prevalence) (Natinal Cancer Institute, 2014; Yung et al. 2009). Several studies have shwn that BRCA1 breast cancer is mre likely t be characterized as triple negative. Studies have reprted BRCA1 mutatins in 11-28% f patients with triple negative breast cancer. In additin, it appears that amng patients with triple negative disease, BRCA mutatin carriers were diagnsed at a yunger age cmpared with nn-carriers (NCCN, 2013). In a chrt f triple negative breast cancer patients, Gnzalez-Angul et al. (2011) fund a 19.5% incidence f BRCA mutatins. Median age was 51 years (27-83 years). The authrs recmmend that genetic testing be discussed with patients with triple negative breast cancer. Almst 10% f wmen with breast cancer wh are yunger than age 50 have BRCA mutatins. Mst f the BRCA-psitive wmen d nt have persnal r family histries f breast r varian cancer and are nt f Ashkenazi Jewish ancestry. Using a simulatin mdel, Kwn et al. (2010) evaluated six ppulatins f wmen yunger than 50 with breast cancer, lking at csts and health benefits. The results led the authrs t cnclude that testing wmen with triple negative breast cancers wh were yunger than 50 years fr BRCA mutatins shuld be adpted int current guidelines fr genetic testing. The Natinal Cmprehensive Cancer Netwrk (NCCN) recmmends the fllwing testing criteria fr hereditary breast and/r varian cancer syndrme: Individual frm a family with a knwn BRCA1/BRCA2 mutatin Persnal histry f breast cancer AND ne r mre f the fllwing: Diagnsed age 45 years Diagnsed age 50 years with at least 1 clse bld relative with breast cancer diagnsed at any age Tw breast primaries when first breast cancer diagnsis ccurred age 50 years Diagnsed age 60 years with a triple negative breast cancer Diagnsed age 50 years with an unknwn r limited family histry Diagnsed at any age, with at least 1 clse bld relative with breast cancer diagnsed at age 50 years Diagnsed at any age, with at least 2 clse bld relatives with breast cancer diagnsed at any age Diagnsed at any age, with at least 1 clse bld relative with epithelial varian/fallpian tube/primary peritneal cancer Diagnsed at any age, with at least 2 clse bld relatives with pancreatic r prstate (Gleasn scre 7) cancer at any age Clse male bld relative with breast cancer Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 8

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 pancreatic cancer r prstate (Gleasn scre 7) cancer at any age with at least 2 clse bld relatives with breast, varian, pancreatic and/r prstate (Gleasn scre 7) cancer at any age Family histry nly (significant limitatins f interpreting test results fr an unaffected individual shuld be discussed): 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 at least 2 clse bld relatives with breast cancer (at least ne with breast cancer diagnsed at 50 years) and/r varian cancer Clinical judgment shuld be used t determine if the patient has reasnable likelihd f a mutatin, cnsidering the unaffected patient s current age and the age f female unaffected relatives wh link the patient with the affected relatives. Testing f unaffected individuals shuld nly be cnsidered when an apprpriate affected family member is unavailable fr testing (NCCN, 2014). Large Genmic Rearrangements NCCN recmmends cmprehensive genetic testing in individuals wh meet the testing criteria fr BRCA1/BRCA2 and have n knwn familial BRCA1/BRCA2 mutatins. The guidelines recmmend cmprehensive testing f patient, r if unaffected, test family member with the highest likelihd f a BRCA1/BRCA2 mutatin (see additinal ntes belw). Cmprehensive genetic testing includes full sequencing f BRCA1/BRCA2 and detectin f large genmic rearrangements. Testing f unaffected family members when n affected member is available shuld be cnsidered. Significant limitatins f interpreting test results shuld be discussed. If mre than ne affected family member, first cnsider: yungest age at diagnsis, bilateral disease, multiple primaries, varian cancer, mst clsely related t the prband/patient. If n living family member with breast r varian cancer, cnsider testing first- r secnd-degree family members affected with cancers thught t be related t BRCA1/BRCA2 (e.g., prstate, pancreas r melanma). Fr bth affected and unaffected individuals f Ashkenazi Jewish descent with n knwn familial mutatin, first test fr the three cmmn mutatins. If negative, and ancestry als includes nn-ashkenazi Jewish relatives r ther HBOC criteria are met, cnsider cmprehensive genetic testing. Fr bth affected and unaffected individuals wh are nn- Ashkenazi Jewish and wh have n knwn familial mutatin, cmprehensive genetic testing is the apprach, if testing is dne (NCCN, 2014). Prfessinal Scieties American Cllege f Obstetricians and Gyneclgists (ACOG) In a 2009 practice bulletin (reaffirmed 2013), the ACOG recmmended criteria fr genetic risk assessment f hereditary breast and varian cancer syndrme (HBOC). These recmmendatins cnclude: 1. BRCA psitive wmen shuld be ffered salping-phrectmy by age 40 r when childbearing is cmpleted 2. Fr a risk reducing bilateral salping-phrectmy, all tissue frm the varies and fallpian tubes shuld be remved. Thrugh visualizatin f the peritneal surfaces with pelvic washings shuld be perfrmed. Cmplete, serial sectining f the varies and fallpian tubes is necessary, with micrscpic examinatin fr ccult cancer. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 9

3. Genetic risk assessment is recmmended fr patients with a greater than an apprximate 20-25% chance f having an inherited predispsitin t breast cancer and varian cancer. This includes wmen with the fllwing: A clse relative (mther, sister, daughter, grandmther, granddaughter, aunt r niece) with a knwn BRCA mutatin Persnal histry f bth breast and varian cancer Ovarian cancer and a clse relative with varian cancer r premenpausal breast cancer r bth Ovarian cancer and Ashkenazi Jewish ancestry Breast cancer by age 40 years and Ashkenazi Jewish ancestry Breast cancer by age 50 years and a clse relative with varian cancer r male breast cancer American Sciety f Clinical Onclgy (ASCO) An ASCO plicy statement recmmends that genetic testing fr cancer susceptibility be perfrmed when the fllwing three criteria are met: the individual being tested has a persnal r family histry suggestive f genetic cancer susceptibility; the test can be adequately interpreted; and the test results have accepted clinical utility (ASCO, 2003; Rbsn et al., 2010). Natinal Sciety f Genetic Cunselrs (NSGC) The NSGC recmmends that genetic testing be perfrmed in the cntext f an infrmed decisinmaking prcess (Berliner et al., 2013). The prcess f cancer risk assessment and genetic cunseling fr hereditary breast and varian cancer syndrme requires many steps, including the fllwing: Gathering persnal medical and family histry data Psychscial assessment Discussin f cancer and mutatin risk and hw persnalized risk estimates are derived Facilitatin f the infrmed cnsent prcess thrugh discussin f the risks, benefits, limitatins, and likelihd f identifying a mutatin with genetic susceptibility testing Results disclsure (if applicable) Discussin f medical management ptins Review f issues related t genetic discriminatin U.S. FOOD AND DRUG ADMINISTRATION (FDA) Genetic tests are regulated under the Clinical Labratry Imprvement Amendments (CLIA) Act f 1988. Mre infrmatin is available at: http://www.fda.gv/medicaldevices/deviceregulatinandguidance/ivdregulatryassistance/uc m124105.htm. Accessed August 19, 2014. Additinal Prducts BRACAnalysis (Myriad Genetics, Inc.) BRCAdvantage (Quest Diagnstics, Inc.) BRCAssure (LabCrp) REFERENCES The freging Oxfrd plicy has been adapted frm an existing UnitedHealthcare natinal plicy that was researched, develped and apprved by UnitedHealthcare Medical Technlgy Assessment Cmmittee. [2014T0009R] American Cllege f Obstetricians and Gyneclgists. Practice Bulletin number 103. Hereditary breast and varian cancer syndrme. Obstetrics and Gyneclgy April 2009: 113:957-66. Reaffirmed 2013. American Sciety f Clinical Onclgy. ASCO plicy statement update: genetic testing fr cancer susceptibility. J Clin Oncl. 2003 Jun 15; 21(12):2397-406. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 10

Berliner JL, Fay AM, Cummings SA, et al. Natinal Sciety f Genetic Cunselrs (NSGC) practice guideline: risk assessment and genetic cunseling fr hereditary breast and varian cancer. J Genet Cuns. 2013 Apr; 22(2):155-63. Burke W, Daly M, Garber J, et al. Recmmendatins fr fllw-up care f individuals with an inherited predispsitin t cancer. II. BRCA1 and BRCA2. JAMA. 1997; 277:997-1003. ECRI Institute. Htline Service. Testing and genetic risk assessment fr BRCA genetic mutatins and develpment f breast and varian cancer. June 2013. ECRI Institute. Prduct Brief. BRACAnalysis test (Myriad Genetics, Inc.) fr assessing hereditary breast and varian cancer risk. June 2013. ECRI Institute. Htline Service. Genetic testing fr BRCA1 and BRCA2 mutatins fr assessing breast cancer risk. March 2011a. ECRI Institute. Htline Service. Genetic testing fr BRCA1 and BRCA2 mutatins fr assessing varian cancer risk. March 2011b. Ferrne CR, Levine DA, Tang LH, et al. BRCA germline mutatins in Jewish patients with pancreatic adencarcinma. J Clin Oncl. 2009 Jan 20; 27(3):433-8. 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 Mar 1; 17(5):1082-9. Greer JB, Whitcmb DC. Rle f BRCA1 and BRCA2 mutatins in pancreatic cancer. Gut. 2007 May; 56(5):601-5. Hilgart JS, Cles B, Iredale R. Cancer genetic risk assessment fr individuals at risk f familial breast cancer. Cchrane Database Syst Rev. 2012 Feb 15; 2:CD003721. Judkins T, Rsenthal E, Arnell C, et al. Clinical significance f large rearrangements in BRCA1 and BRCA2. Cancer. 2012 Nv 1; 118(21):5210-6. Kwn JS, Gutierrez-Barrera AM, Yung D, et al. Expanding the criteria fr BRCA mutatin testing in breast cancer survivrs. J Clin Oncl. 2010 Sep 20;28(27):4214-20. Natinal Cancer Institute. Genetics f breast and varian cancer (PDQ ). July 2014. Available at: http://www.cancer.gv/cancertpics/pdq/genetics/breast-and-varian/healthprfessinal. Accessed August 19, 2014. Natinal Cmprehensive Cancer Netwrk. NCCN Clinical Practice Guidelines in Onclgy. Genetic/familial high-risk assessment: breast and varian. V1.2014. Natinal Institute fr Health and Care Excellence (NICE). Clinical guideline #164. Familial breast cancer. June 2013. Available at: http://guidance.nice.rg.uk/cg164/niceguidance/pdf/english. Accessed August 19, 2014. Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 hereditary breast and varian cancer. September 1998. Updated September 2013. In: Pagn RA, Adam MP, Ardinger HH, et al., editrs. GeneReviews [Internet]. Seattle (WA): University f Washingtn, Seattle; 1993-2014. Available frm: http://www.ncbi.nlm.nih.gv/bks/nbk1247/. Accessed August 19, 2014. Rbsn ME, Strm CD, Weitzel J, et al. American Sciety f Clinical Onclgy plicy statement update: genetic and genmic testing fr cancer susceptibility. J Clin Oncl. 2010 Feb 10;28(5):893-901. Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 11

Stadler ZK, Sal-Mullen E, Patil SM, et al. Prevalence f BRCA1 and BRCA2 mutatins in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer. 2012 Jan 15;118(2):493-9. Unger MA, Nathansn KL, Calzne K, Antin-Ozerkis D, Shih HA, Martin AM, et al. Screening fr genmic rearrangements in families with breast and varian cancer identifies BRCA1 mutatins previusly missed by cnfrmatin sensitive gel electrphresis r sequencing. Am J Hum Genet. 2000;67:841-50. U.S. Preventive Services Task Frce (USPSTF). Risk assessment, genetic cunseling and genetic testing fr BRCA-related cancer in wmen. December 2013. Available at: http://www.uspreventiveservicestaskfrce.rg/uspstf/uspsbrgen.htm. Accessed August 19, 2014. 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):1379-1388. Warlam-Rdenhuis CC et al. A prspective study n predictive factrs linked t the presence f BRCA1 and BRCA2 mutatins in breast cancer patients. Eurpean Jurnal f Cancer 41 (2005) 1409-1415. Yung SR, Pilarski RT, Dnenberg T, et al. The prevalence f BRCA1 mutatins amng yung wmen with triple-negative breast cancer. BMC Cancer. 2009 Mar 19;9:86. POLICY HISTORY/REVISION INFORMATION Date 12/01/2014 Actin/Descriptin Rerganized plicy cntent; Remved references t BRACAnalysis Large Rearrangement Test (BART) Added benefit cnsideratins language fr Essential Health Benefits fr Individual and Small Grup plans t indicate: Fr plan years beginning n r after January 1, 2014, the Affrdable Care Act f 2010 (ACA) requires fully insured nngrandfathered individual and small grup plans (inside and utside f Exchanges) t prvide cverage fr ten categries f Essential Health Benefits ( EHBs ) Large grup plans (bth self-funded and fully insured), and small grup ASO plans, are nt subject t the requirement t ffer cverage fr EHBs; hwever, if such plans chse t prvide cverage fr benefits which are deemed EHBs (such as maternity benefits), the ACA requires all dllar limits n thse benefits t be remved n all Grandfathered and Nn- Grandfathered plans The determinatin f which benefits cnstitute EHBs is made n a state by state basis; as such, when using this guideline, it is imprtant t refer t the member s specific plan dcument t determine benefit cverage Revised cverage ratinale: Refrmatted and relcated infrmatin pertaining t medical necessity review; added language t indicate if service is prven r unprven t applicable medically necessary/nt medically necessary statement Replaced references t aggressive prstate cancer with prstate cancer Updated BRCA testing criteria fr wmen with a persnal histry f breast cancer/ breast cancer diagnsis at age 50 r yunger: Replaced criterin requiring limited family histry f breast cancer with an unknwn r limited family histry Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 12

f breast cancer Updated cverage guidelines fr men and wmen with a persnal histry f pancreatic cancer; updated criteria t indicate patients f Ashkenazi Jewish ancestry require nly ne additinal affected relative Updated supprting infrmatin t reflect the mst current clinical evidence, FDA infrmatin, and references Archived previus plicy versin DIAGNOSTIC 004.20 T2 Genetic Testing fr Hereditary Breast and/r Ovarian Cancer Syndrme (HBOC): Clinical Plicy (Effective 12/01/2014) 1996-2014, Oxfrd Health Plans, LLC 13