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| Medical Policy: | L-203-002 |
| Topic: | BRCA Analysis |
| Section: | Laboratory |
| Effective Date: | November 13, 2017 |
| Issue Date: | November 13, 2017 |
| Last Reviewed: | March 2017 |
Hereditary breast and ovarian cancer (HBOC) is an inherited form of cancer characterized by:
People with a BRCA mutation have an increased risk of breast cancer (46-87%), ovarian cancer (16.5-63%), male breast cancer (1-9%), prostate cancer (up to 20%), pancreatic cancer (1-7%), and several other types of cancer. Individuals with a BRCA2 mutation may also be at an increased risk for melanoma. Screening and prevention options are available to specifically address the increased risk of these cancers in a person with a BRCA mutation. BRCA mutations are inherited in an autosomal dominant manner. When a parent has a BRCA mutation, each of her/his offspring has a 50% risk of inheriting the mutation. The risk for breast and ovarian cancer varies among family members and between families. |
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
| Policy Position Coverage is subject to the specific terms of the member’s benefit plan. |
This policy does not address BRCA analysis for individuals of Ashkenazi Jewish ancestry or BRCA analysis as part of multigene panels. Please refer to individual policies listed below.
BRCA analysis may be considered medically necessary when the following criteria are met:
Known Familial Mutation Analysis:
· Genetic Counseling:
o Pre- and post-test genetic counseling by an appropriate provider; and
· Previous Genetic Testing:
o No previous full sequence testing or deletion/duplication analysis; and
o Known family mutation in BRCA1/2 identified in 1st, 2nd, or 3rd degree relative(s); and
· Age 18 years or older.
Full Sequence Analysis:
· Genetic Counseling:
o Pre- and post-test genetic counseling by an appropriate provider; and
· Previous Genetic Testing: o No previous full sequencing of BRCA1/2, and
o No known mutation identified by previous BRCA analysis; and
· Age 18 years or older; and
· Diagnostic Testing for Symptomatic Individuals:
o Non-Ashkenazi Jewish descent; and
o Personal History:
§ Female with breast cancer diagnosis less than or equal to 45 years of age; and/or
§ Two breast primary tumors with first diagnosis less than or equal to 50 years of age and second diagnosis at any age (ipsilateral or bilateral); and/or
§ Diagnosed less than or equal to 60 years of age with estrogen receptor negative, progesterone receptor negative, and HER2 negative (triple negative) breast cancer; and/or
§ Diagnosed less than or equal to 50 years of age with a limited family history (NCCN provides this guidance regarding limited family history: “individuals with limited family history, such as fewer than two first- or second-degree female relatives having lived beyond 45 in either lineage, may have an underestimated probability of a familial mutation”); and/or
§ Male with breast cancer at any age; and/or
§ Epithelial ovarian, fallopian tube, or primary peritoneal cancer diagnosis at any age; and/or
§ BRCA1/2 mutation detected by tumor profiling in the absence of germline mutation analysis; or
o Personal and Family History Combination:
§ Diagnosed less than or equal to 50 years of age with at least ONE close blood relative with breast cancer diagnosed at any age; and/or
§ Diagnosed less than or equal to 50 years of age with at least ONE close blood relative with pancreatic cancer or prostate cancer (Gleason score at least 7), diagnosed at any age; and/or
§ Initial breast cancer diagnosis at any age and ONE or MORE of the following:
· Breast cancer in at least 1 close blood relative (first-, second-, or third- degree) less than or equal to 50 years of age; and/or
· Epithelial ovarian, fallopian tube, or primary peritoneal cancer in at least 1 close blood relative (first-, second-, or third- degree) at any age; and/or
· At least 2 close blood relatives (first-, second-, or third-degree on same side of family) with breast cancer, pancreatic cancer, or prostate cancer (Gleason score greater than 7) at any age; and/or
· Male close blood relative (first-, second-, or third- degree) with breast cancer; and/or
§ Personal history of pancreatic cancer or prostate cancer (Gleason score at least 7) at any age with greater than or equal to 1 close blood relatives (on the same side of the family) with ovarian cancer at any age or breast cancer less than 50 years or two close blood relatives with breast and/or pancreatic and/or prostate cancer (Gleason score at least 7) at any age; or
· Predisposition Testing for Presymptomatic/Asymptomatic Individuals
o Non-Ashkenazi Jewish descent, and ONE or MORE of the following:
§ A first or second degree relative with breast cancer at age 45 or younger; or
§ A first or second degree relative with TWO primary breast cancers, with the first diagnosis occurring at age 50 or younger; or
§ A first or second degree relative with a triple negative breast cancer (ER-, PR-, her2-) occurring at age 60 or younger; or
§ A first or second degree relative with ovarian/fallopian tube/primary peritoneal cancer at any age; or
§ A first or second degree relative with male breast cancer at any age; or
§ A combination of TWO or MORE first or second degree relatives on the same side of the family with breast cancer, ONE of whom was diagnosed at age 50 or younger; or
§ A combination of THREE or MORE first or second degree relatives on the same side of the family with breast cancer regardless of age at diagnosis; or
§ A combination of BOTH breast and ovarian/fallopian tube/primary peritoneal cancer among TWO or MORE first or second degree relatives on the same side of the family; or
§ A first or second degree relative with BOTH breast and ovarian/fallopian tube/primary peritoneal cancer at any age; or
§ A combination of THREE or MORE first or second degree relatives on the same side of the family with breast or ovarian/fallopian tube/primary peritoneal cancer and pancreatic or prostate (Gleason score greater than or equal to 7) cancer at any age; or
· Ashkenazi Jewish woman who is negative for founder mutation testing, and has a high pre-test probability of carrying a BRCA mutation; and
· Unaffected member is the most informative person to test. All affected family members are deceased, or all affected family members have been contacted and are unwilling to be tested.
*First-degree relatives (parents, siblings, children); second-degree relatives (aunts, uncles, grandparents, grandchildren, nieces, nephews and half-siblings); and third-degree relatives (great-grandparents, great-aunts, great-uncles, and first cousins) on the same side of the family.
These criteria may only be applied to a single BRCA sequencing CPT code.
If BRCA gene testing will be performed as part of an expanded hereditary cancer syndrome panel, refer to medical policy L-184 Hereditary Cancer Syndrome Multigene Panels.
Deletion/Duplication Analysis
· Genetic Counseling:
o Pre- and post-test genetic counseling by an appropriate provider; and
· Previous Genetic Testing:
o No previous BRCA deletion/duplication analysis; and
o Meets criteria for full sequence analysis of BRCA1/2.
If BRCA1/2 deletion/duplication analysis will be performed concurrently with BRCA1/2 gene sequencing, CPT code 81162 is likely most appropriate.
If BRCA gene testing will be performed as part of an expanded hereditary cancer syndrome panel, refer to medical policy L-184 Hereditary Cancer Syndrome Multigene Panels.
Test information
Four types of BRCA testing are available. Each may be appropriate for different clinical situations.
· Full sequence analysis of BRCA1/2 genes looks at all of the coding regions of the BRCA1/2 genes, and often includes analysis of five common BRCA1/2 gene duplications and deletions.
o Full sequence testing is typically appropriate as an initial test for people who meet criteria (See Guidelines below) and do NOT have Ashkenazi Jewish ancestry.
· Deletion/duplication analysis looks for large rearrangements, duplications, and deletions in the BRCA1/2 genes.
· Known familial mutation testing looks for a specific mutation in either the BRCA1/2 gene previously identified in a family member.
o This test is appropriate for those who have a known BRCA mutation in the family AND are not Ashkenazi Jewish.
o It is important to note that founder mutation testing may be appropriate for those with Ashkenazi Jewish ancestry, even with a known familial mutation, since these mutations are common enough that multiple mutations can be found in the same Ashkenazi Jewish individual or family. If the familial mutation is not one of the three Ashkenazi Jewish mutations, then known familial mutation analysis for that mutation should be performed in addition to the founder mutation panel.
· Ashkenazi Jewish founder mutation testing includes the three mutations most commonly found in the Ashkenazi Jewish population: 187delAG and 5385insC in BRCA1 and 6174delT in BRCA2.
Cancer Multigene Panels- BRCA1/2 gene testing is also available in the form of multigene panels for individuals with a personal and/or family history of cancer suggestive of more than one hereditary cancer syndrome. (See related summary for guidance).
Refer to the following medical policies for additional information:
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| Professional Statements and Societal Positions |
Guidelines and Evidence
The National Comprehensive Cancer Network (NCCN, 2017) evidence and consensus-based guidelines address test indications for those with a personal history of HBOC-related cancers, those with a known mutation in the family, and unaffected individuals with a family history of HBOC-related cancer. · Based on these guidelines, and the recommendations of the National Society of Genetic Counselors (2013), BRCA sequence analysis is appropriate in individuals with a personal and/or family history of cancer when ANY of the following criteria are met: o Personal history of breast cancer plus at least ONE of the following in non-Ashkenazi Jewish individuals: § Diagnosed at age 45 years or younger; or § Diagnosed at age 50 or younger with at least one close blood relative with breast cancer diagnosed at any age; or § Diagnosed at age 60 years or younger with a triple negative (ER-, PR-, HER2-) breast cancer; or § Two breast primaries when the first breast cancer diagnosis occurred at age 50 or younger; or § Diagnosed at any age with at least one close blood relative* with breast cancer diagnosed at age 50 years or younger and/or at least one close blood relative* diagnosed with epithelial ovarian, fallopian tube or primary peritoneal cancer at any age; or § Diagnosed at any age with two or more close blood relatives* with breast cancer, pancreatic cancer, or prostate cancer (Gleason score less than 7) at any age; or § Diagnosed at 50 or younger with at least one close blood relative* with pancreatic cancer or prostate cancer (Gleason score at least 7); or § Diagnosed at age 50 years or younger with an unknown or limited** family history § Diagnosed at any age with a close male relative* with breast cancer. o Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer (without history of breast cancer). o Personal history of male breast cancer. o Personal history of pancreatic cancer or prostate cancer (Gleason score at least 7) at any age with at least one close blood relative* with ovarian cancer at any age or breast cancer less than 50 years or two close blood relatives with breast and/or pancreatic or prostate cancer (Gleason score at least 7) at any age. o Family history only, no personal diagnosis of cancer plus ONE of the following: § First- or second- degree blood relative meeting any of the above criteria; or § Third-degree blood relative with breast and/or ovarian cancer and 2 or MORE close blood relatives* with breast cancer (at least one diagnosed at or before age 50) and/or ovarian, primary peritoneal, or fallopian tube cancer. Ashkenazi Jewish women who are negative for founder mutation testing, and have a high pre-test probability of carrying a BRCA mutation. § BRCA1/2 mutation detected by tumor profiling in the absence of germline mutation analysis. · NCCN states "Testing of unaffected individuals should only be considered when an appropriate affected family member is unavailable for testing." They caution that the significant limitations in interpreting results from unaffected relatives must be discussed. · *Close blood relatives include: first-degree relatives (parents, siblings, children); second-degree relatives (aunts, uncles, grandparents, grandchildren, nieces, nephews and half-siblings); and third-degree relatives (great-grandparents, great-aunts, great-uncles, and first cousins) on the same side of the family. · **Limited family history is defined as “fewer than two first- or second-degree female relatives having lived beyond age 45 in either lineage.” · These recommendations are Category 2A, defined as "lower-level evidence with uniform NCCN consensus.
The National Comprehensive Cancer Network (2017) guidelines state that: "Unless the affected individual is a member of an ethnic group for which particular founder gene mutations are known, comprehensive genetic testing (i.e., full sequencing of the genes and detection of large gene rearrangements) should be performed.
The National Society of Genetic Counselors (2013) guidelines also state that: "[For patients with negative sequencing results], it may be appropriate to request additional analysis to detect large genomic rearrangements in both BRCA1 and BRCA2 genes." In non-Ashkenazi Jewish individuals: If no mutation or inconclusive results are reported after sequence analysis, testing for large deletions/duplications in BRCA1/2 should be considered. · Frequency of gene rearrangements is reviewed in a 2010 study by Stadler et al: o "Genomic rearrangements in the BRCA1 gene are found in 1.3- 5.1% of families with histories highly suggestive of an inherited predisposition, accounting for 8-19% of all BRCA1 mutations." o "The prevalence of genomic rearrangements in the BRCA2 gene appears to be lower, with such alterations accounting for 0-11% of all BRCA2 mutations." o In their series of 108 patients with a qualifying history and negative results from BRCA1/2 sequencing, none had mutations found by rearrangement testing. The authors conclude: "Major gene rearrangements involving the BRCA1/2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.” · Jackson et al 2014 addresses the characteristics of individuals who are more likely to have a large rearrangements in BRCA1/2: o Latin American/Caribbean ancestry o Number of first-degree relatives with breast cancer (1 or MORE) o Younger age at first breast cancer diagnosis (average age of 39.8 years) o More likely to have ER- and PR- breast cancers o More likely to have more two breast cancers as well as ovarian cancer o More likely to have infiltrating ductal carcinoma with ductal carcinoma in situ features.
The U.S. Preventive Services Task Force (USPSTF, 2013) recommendations address women who do not have a personal history of breast and/or ovarian cancer, but rather have a family history of these cancer types. The USPSTF guideline recommends: · "That primary care providers screen women who have family members with breast, ovarian, tubal (fallopian tube), or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1/2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing." · The USPSTF considers this a Grade B recommendation: "The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms." · The USPSTF guidelines no longer make explicit recommendations as to who should have BRCA1/2 gene testing -- only genetic counseling. In general, women identified as high risk by these screening tools have ONE or MORE of the following characteristics: o A first or second degree relative with breast cancer before 50 years old o A first or second degree relative with ovarian cancer o A first or second degree relative with bilateral/multifocal breast cancer o A first or second degree male relative with breast cancer o A first or second degree relative with both breast and ovarian cancers o Two or more relatives (first, second, third degree) with breast and/or ovarian cancer o Two or more relatives (first, second, third degree) with breast and/or prostate/pancreatic cancer o Presence of Ashkenazi Jewish ancestry with any of the above. |
| Place of Service: Outpatient |
BRCA analysis is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.
| The policy position applies to all commercial lines of business |
| Denial Statements |
Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.
| Links |
- Link to Provider Resource Center for the Medical Policy Update
05/2017, REMINDER: Molecular and Genomic Testing
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