| Coverage Policy Manual | |
| Policy #: | 1998051 |
| Category: | Laboratory |
| Initiated: | May 1996 |
| Last Review: | December 2023 |
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| Genetic Test: BRCA1, BRCA2 or PALB2 Mutations | |
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| Description: |
Hereditary breast and ovarian cancer (HBOC) syndrome describes the familial cancer syndromes that are related to mutations in the BRCA genes (BRCA1 located on chromosome 17q21 and BRCA2 located on chromosome 13q12-13). Families with hereditary breast and ovarian cancer syndrome have an increased susceptibility to the following types of cancer: breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer (at any age), cancer of the fallopian tube, primary peritoneal cancer, prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer.
Hereditary Breast and Ovarian Cancer Syndrome
Several genetic syndromes with an autosomal dominant pattern of inheritance that feature breast cancer have been identified. Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative variants in BRCA (breast cancer susceptibility) genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. Other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early-onset breast cancer with or without male cases, but without ovarian cancer. For this evidence review, we refer collectively to both as hereditary breast and/or ovarian cancer.
Germline variants in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in most HBOC families, especially if ovarian cancer or male breast cancer are features. However, in site-specific cancer, BRCA variants are responsible only for a proportion of affected families. BRCA gene variants are inherited in an autosomal dominant fashion through maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes to identify the specific variant in cancer cases and to identify family members at increased cancer risk. Family members without existing cancer who are found to have BRCA variants can consider preventive interventions for reducing risk and mortality.
Clinical Features Suggestive of BRCA Variant
Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 variants. Winchester (1996) estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30.1 In several studies, BRCA variants were independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35-50 years) (Winchester, 1996; Frank, 2002; Langston, 1996; Malone, 1998). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 variants is in the 40s (ford, 1998). In the Ashkenazi Jewish population, Frank et al (2002) reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA variants (Frank, 2002). In a similar study by Gershoni-Baruch et al (2000), 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA variants (Gershoni-baruch, 2000). Other studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA variants in the absence of family history in this population (Warner, 1999; Hartge, 1999; Hodgson, 1999).
As in the general population, family history of breast or ovarian cancer, particularly of early age onset, is a significant risk factor for a BRCA variant in ethnic populations characterized by founder mutations. For example, in unaffected individuals of Ashkenazi Jewish descent, 12% to 31% will have a BRCA variant depending on the extent and nature of the family history (Malone, 1998). Several other studies have documented the significant influence of family history (Gershoni-Baruch, 2000; Warner, 1999; Hartge, 1999; Hodgson, 1999; Moslehi, 2000).
In patients with “triple-negative” breast cancer (ie, negative for expression of estrogen, progesterone, and overexpression of human epidermal growth factor receptor 2 receptors), there is an increased prevalence of BRCA variants. Pathophysiologic research has suggested that the physiologic pathway for development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer (de Ruijter, 2011). In 200 randomly selected patients with triple-negative breast cancer from a tertiary care center, Kandel et al (2006) reported there was a greater than 3-fold increase in the expected rate of BRCA variants (Kandel, 2006). BRCA1 variants were found in 39.1% of patients and BRCA2 variants in 8.7%. Young et al (2009) studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing (Young, 2009). Six BRCA variants (5 BRCA1, 1 BRCA2) were found, for a variant rate of 11%. Finally, Gonzalez-Angulo et al (2011) in a study of 77 patients with triple-negative breast cancer, reported that 15 patients (19.5%) had BRCA variants (12 in BRCA1, 3 in BRCA2) (Gonzalez-Angulo, 2011).
PALB2 Gene
The PALB2 gene (partner and localizer of BRCA2) encodes for a protein first described in 2006 by Xia et al. The gene is located at 16p12.2 [Short (p) arm of chromosome 16 at position 12.2.]and has 13 exons. PALB2 protein assists BRCA2 in DNA repair and tumor suppression. Heterozygous pathogenic PALB2 variants increase the risk of developing breast and pancreatic cancers; homozygous variants are found in Fanconi anemia. Fanconi anemia is a rare disorder, primarily affecting children, that causes bone marrow failure. Affected individuals also carry a risk of cancers including leukemia. Most pathogenic PALB2 variants are truncating frameshift or stop codons and are found throughout the gene. Pathogenic PALB2 variants are uncommon in unselected populations and prevalence varies by ethnicity and family history. For example, Antoniou et al (2014) assumed a prevalence of 8 per 10,000 in the general population when modeling breast cancer risks (Antoniou et al, 2014). Variants are more prevalent in ethnic populations where founder mutations have persisted (eg, Finns, French Canadians, Poles), while infrequently found in others (eg, Ashkenazi Jews) (Catucci et al, 2014; Casadei et al, 2011). In women with a family history of breast cancer, the prevalence of pathogenic PALB2 variants ranges between 0.9% and3.9%, (Catucci et al, 2014) or substantially higher than in an unselected general population. Depending on population prevalence, PALB2 may be responsible for as much as 2.4% of hereditary breast cancers (Catucci et al, 2014) and in populations with founder mutations cause 0.5% to 1% of all breast cancers (Cybulski et al, 2015).
Related Policies on Hereditary Cancer Syndromes
2015009 Genetic Test: Next-Generation Sequencing for Cancer Susceptibility Panels and the Assessment of Measurable Residual Disease
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Policy/ Coverage: |
Effective April 1, 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
BRCA1, BRCA2
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 variants meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
Individuals With Cancer or With a Personal History of Cancer
Individuals Without Cancer or With Other Personal History of Cancer
PALB2 Testing
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for PALB2 variants for breast cancer risk assessment in adults meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when:
POLICY GUIDELINES
Testing for BRCA1, BRCA2, and PALB2 outside of the above criteria, such as testing all individuals with triple negative breast cancer, may be indicated for guiding cancer therapies. Genetic testing for BRCA1 and BRCA2 variants in breast cancer-, pancreatic cancer-, prostate cancer-, or ovarian cancer-affected individuals who are considering systemic therapy is addressed separately in evidence reviews 2022040, 2022017, 2022043, and 2022044 respectively. Genetic testing for PALB2 variants in pancreatic cancer-affected individuals is also addressed in 2022017.
Current U.S. Preventive Services Task Force guidelines recommend screening women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutation. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing (B recommendation).
Recommended screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful variants in BRCA1 or BRCA2 are:
Close Relatives
Close relatives are blood related family members including 1st-, 2nd-, and 3rd-degree relatives on the same side of the family (maternal or paternal).
Prostate Cancer Risk Groups
Risk groups for prostate cancer in this policy include high-risk groups and very-high-risk groups.
High-risk group: no very-high-risk features and are T3a (American Joint Committee on Cancer staging T3a = tumor has extended outside of the prostate but has not spread to the seminal vesicles); OR Grade Group 4 or 5; OR prostate specific antigen of 20 ng/ mL or greater.
Very-high-risk group: T3b-T4 (tumor invades seminal vesicle(s); or tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall); OR Primary Gleason Pattern 5; OR 2 or 3 high-risk features; OR greater than 4 cores with Grade Group 4 or 5.
Recommended Testing Strategies
Individuals who meet criteria for genetic testing as outlined in the policy statements above should be tested for variants in BRCA1/BRCA2 and PALB2. Recommended strategies are listed below.
Testing strategy may also include testing individuals not meeting the above criteria who are adopted and have limited medical information on biological family members, individuals with small family structure, and individuals with presumed paternal transmission.
Comprehensive Variant Analysis
Comprehensive variant analysis currently includes sequencing the coding regions and intron and exon splice sites, as well as testing to detect large deletions and rearrangements that can be missed with sequence analysis alone. In addition, before August 2006, testing for large deletions and rearrangements was not performed, thus some individuals with familial breast cancer who had negative BRCA testing before this time may consider repeat testing for the rearrangements (see Policy section for criteria).
High-Risk Ethnic Groups
Testing of eligible individuals who belong to ethnic populations in which there are well-characterized founder mutations should begin with tests specifically for these variants. For example, founder mutations account for approximately three-quarters of the BRCA variants found in Ashkenazi Jewish populations (see Rationale section). When testing for founder mutations is negative, comprehensive variant analysis should then be performed.
Testing Unaffected Individuals
In unaffected family members of potential BRCA or PALB2 variant families, most test results will be negative and uninformative. Therefore, it is strongly recommended that an affected family member be tested first whenever possible to adequately interpret the test. Should a BRCA or PALB2 variant be found in an affected family member(s), DNA from an unaffected family member can be tested specifically for the same variant of the affected family member without having to sequence the entire gene. Interpreting test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result for an established disease-associated variant but leads to difficulties in interpreting negative test results (uninformative negative) or variants of uncertain significance because the possibility of a causative BRCA or PALB2 variant is not ruled out.
Testing Minors
The use of genetic testing for BRCA/BRCA2 or PALB2 variants for identifying hereditary breast ovarian cancer syndrome has limited or no clinical utility in minors, because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious variant. In addition, there are potential harms related to stigmatization and discrimination. See policy 2015013 regarding testing of BRCA1/BRCA2, and PALB2 for Fanconi anemia. See policy 2022040 regarding genetic testing to guide targeted therapy and immunotherapy.
Prostate Cancer
Individuals with BRCA or PALB2 variants have an increased risk of prostate cancer, and individuals with known BRCA or PALB2 variants may, therefore, consider more aggressive screening approaches for prostate cancer.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017. The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes.
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 or PALB2 variants for any indication not listed above as covered does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, genetic testing for BRCA1/BRCA2 or PALB2 variants for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for BRCA1/BRCA2 or PALB2 sequence variants in minors does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, testing for BRCA1/BRCA2 or PALB2 sequence variants in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 1, 2023 through March 31, 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
BRCA1, BRCA2
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 variants meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
Individuals With Cancer or With a Personal History of Cancer
Individuals Without Cancer or With Other Personal History of Cancer
PALB2 Testing
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for PALB2 variants for breast cancer risk assessment in adults meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when:
POLICY GUIDELINES
Testing for BRCA1, BRCA2, and PALB2 outside of the above criteria, such as testing all individuals with triple negative breast cancer, may be indicated for guiding cancer therapies. Genetic testing for BRCA1 and BRCA2 variants in breast cancer-, pancreatic cancer-, prostate cancer-, or ovarian cancer-affected individuals who are considering systemic therapy is addressed separately in evidence reviews 2022040, 2022017, 2022043, and 2022044 respectively. Genetic testing for PALB2 variants in pancreatic cancer-affected individuals is also addressed in 2022017.
Current U.S. Preventive Services Task Force guidelines recommend screening women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutation. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing (B recommendation).
Recommended screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful variants in BRCA1 or BRCA2 are:
Close Relatives
Close relatives are blood related family members including 1st-, 2nd-, and 3rd-degree relatives on the same side of the family (maternal or paternal).
Prostate Cancer Risk Groups
Risk groups for prostate cancer in this policy include high-risk groups and very-high-risk groups.
High-risk group: no very-high-risk features and are T3a (American Joint Committee on Cancer staging T3a = tumor has extended outside of the prostate but has not spread to the seminal vesicles); OR Grade Group 4 or 5; OR prostate specific antigen of 20 ng/ mL or greater.
Very-high-risk group: T3b-T4 (tumor invades seminal vesicle(s); or tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall); OR Primary Gleason Pattern 5; OR 2 or 3 high-risk features; OR greater than 4 cores with Grade Group 4 or 5.
Recommended Testing Strategies
Individuals who meet criteria for genetic testing as outlined in the policy statements above should be tested for variants in BRCA1/BRCA2 and PALB2. Recommended strategies are listed below.
Testing strategy may also include testing individuals not meeting the above criteria who are adopted and have limited medical information on biological family members, individuals with small family structure, and individuals with presumed paternal transmission.
Comprehensive Variant Analysis
Comprehensive variant analysis currently includes sequencing the coding regions and intron and exon splice sites, as well as testing to detect large deletions and rearrangements that can be missed with sequence analysis alone. In addition, before August 2006, testing for large deletions and rearrangements was not performed, thus some individuals with familial breast cancer who had negative BRCA testing before this time may consider repeat testing for the rearrangements (see Policy section for criteria).
High-Risk Ethnic Groups
Testing of eligible individuals who belong to ethnic populations in which there are well-characterized founder mutations should begin with tests specifically for these variants. For example, founder mutations account for approximately three-quarters of the BRCA variants found in Ashkenazi Jewish populations (see Rationale section). When testing for founder mutations is negative, comprehensive variant analysis should then be performed.
Testing Unaffected Individuals
In unaffected family members of potential BRCA or PALB2 variant families, most test results will be negative and uninformative. Therefore, it is strongly recommended that an affected family member be tested first whenever possible to adequately interpret the test. Should a BRCA or PALB2 variant be found in an affected family member(s), DNA from an unaffected family member can be tested specifically for the same variant of the affected family member without having to sequence the entire gene. Interpreting test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result for an established disease-associated variant but leads to difficulties in interpreting negative test results (uninformative negative) or variants of uncertain significance because the possibility of a causative BRCA or PALB2 variant is not ruled out.
Testing Minors
The use of genetic testing for BRCA/BRCA2 or PALB2 variants for identifying hereditary breast ovarian cancer syndrome has limited or no clinical utility in minors, because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious variant. In addition, there are potential harms related to stigmatization and discrimination. See policy 2015013 regarding testing of BRCA1/BRCA2, and PALB2 for Fanconi anemia. See policy 2022040 regarding genetic testing to guide targeted therapy and immunotherapy.
Prostate Cancer
Individuals with BRCA or PALB2 variants have an increased risk of prostate cancer, and individuals with known BRCA or PALB2 variants may, therefore, consider more aggressive screening approaches for prostate cancer.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017. The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes.
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 or PALB2 variants for any indication not listed above as covered does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, genetic testing for BRCA1/BRCA2 or PALB2 variants for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for BRCA1/BRCA2 or PALB2 sequence variants in minors does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, testing for BRCA1/BRCA2 or PALB2 sequence variants in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective May 2022 through February 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
*NOTE- If an unaffected individual has a family member with breast or ovarian cancer testing of the unaffected individual should only be performed if the affected family member is unavailable for testing.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for CHEK2 abnormality (mutations, deletions, etc.) in affected and unaffected patients with breast cancer, irrespective of family history does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of family history. Investigational services are specific contract exclusions.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to May 2022 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
*NOTE- If an unaffected individual has a family member with breast or ovarian cancer testing of the unaffected individual should only be performed if the affected family member is unavailable for testing.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for CHEK2 abnormality (mutations, deletions, etc.) in affected and unaffected patients with breast cancer, irrespective of family history does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of family history. Investigational services are specific contract exclusions,
Effective Prior to November 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for CHEK2 abnormality (mutations, deletions, etc.) in affected and unaffected patients with breast cancer, irrespective of family history does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of family history. Investigational services are specific contract exclusions,
Effective Prior to August 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for CHEK2 abnormality (mutations, deletions, etc.) in affected and unaffected patients with breast cancer, irrespective of family history does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of family history. Investigational services are specific contract exclusions
Effective Prior to December 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA1/BRCA2 meets ABCBS member benefit certificate Primary Coverage Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
An individual from a family with a known deleterious BRCA1/BRCA2 mutation in a 1st- or 2nd- degree relative.
*NOTE- If an unaffected individual has a family member with breast or ovarian cancer testing of the unaffected individual should only be performed if the affected family member is unavailable for testing.
Testing for genomic rearrangements of the BRCA1 and BRCA2 genes in patients who meet criteria for BRCA testing, whose testing for point mutations is negative meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for CHEK2 abnormality (mutations, deletions, etc.) in affected and unaffected patients with breast cancer, irrespective of family history does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of family history. Investigational services are specific contract exclusions
Effective Prior to March 2017
Meets Primary Coverage Criteria or Is Covered For Contracts Without Primary Coverage
Criteria
Genetic testing for BRCA1/BRCA2 meets ABCBS member benefit certificate Primary Coverage
Criteria in the following circumstances only when the results of the test will affect the individual’s treatment plan (i.e., if the test is positive, the affected person will have a prophylactic mastectomy, contra-lateral mastectomy, or oophorectomy):
*NOTE- If an unaffected individual has a family member with breast or ovarian cancer testing of the unaffected individual should only be performed if the affected family member is unavailable for testing.
Does Not Meet Primary Coverage Criteria or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for BRCA mutations for any indication not listed above as covered as well as testing in minors is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for CHEK2 abnormality (mutations, deletions, etc.) in affected and unaffected patients with breast cancer, irrespective of family history does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, testing for CHEK2 abnormality (mutations, deletions, etc.) is considered investigational in affected and unaffected patients with breast cancer, irrespective of family history. Investigational services are specific contract exclusions
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| Rationale: |
High Risk families for harboring a BRCA1 or BRCA2 mutation are those in which the incidence of breast or ovarian cancer in first- or second-degree relatives suggests an autosomal dominant inheritance, i.e., about half the family members are affected. However, this criterion identifies only a subset of mutation carriers, and may not adequately cover the possibility of paternal transmission of a BRCA1 or BRCA2 mutation. Men rarely develop breast cancer and thus there may not be an affected first-degree relative, and the size of the family may not permit analysis of possible autosomal dominant inheritance. Moreover, a recent study in the Ashkenazi Jewish population, in which 2% of women have a founder BRCA mutation, showed that approximately 50% of mutation carriers came from families in which the incidence of cancer is low and not suggestive of hereditary breast cancer.
Early age at diagnosis refers to diagnosis at a premenopausal age; an exact cutoff for testing affected individuals without known family history but with cancer diagnosis at an early age has not been established, although guidelines of the American College of Medical Genetics suggest age 45 or younger. The decision to test an affected individual based on age at diagnosis in the absence of family history will depend on the risk estimate for the individual patient (e.g., from widely available risk assessment computer programs) and the patient tolerance for risk.
As the majority of test results will be negative and uninformative in unaffected family members of potential BRCA mutation families, it is strongly recommended that an affected family member be tested first whenever possible to adequately interpret the test. Should a BRCA mutation be found in an affected family member(s), the DNA from the unaffected family member can be tested specifically for the same mutation of the affected family member without having to sequence the entire gene. Interpreting the test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result, but leads to difficulties in interpreting negative test results because the possibility of a BRCA mutation is not ruled out.
In patients with breast or ovarian cancer who are from high-risk families without a known BRCA1 or BRCA2 gene, the entire gene must be sequenced to identify possible mutations.
Testing in eligible individuals who belong to ethnic populations in which there are well-characterized founder mutation should begin with tests specifically for these mutations. For example, founder mutations account for approximately three quarters of the BRCA mutations found in Ashkenazi Jewish populations. When the testing for founder mutations is negative, full gene sequencing should then be performed.
The U.S. Preventive Services Task Force (USPSTF), in 2005, recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2).
“The USPSTF found fair evidence that women without certain specific family history patterns, termed here ‘increased risk family history’ have a low risk for developing breast or ovarian cancer associated with BRCA1 or BRCA2 mutations. Thus, any benefit to routine screening of these women for BRCA1 or BRCA2 mutations, or routine referral for genetic counseling, would be small or zero.”
The USPSTF recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BrCA2 genes be referred for genetic counseling and evaluation for BRCA testing. (Reprints of the USPSTF full recommendations are available from the USPSTF Web site [www.preventiveservices.ahrq.gov] and in print through the Agency for Healthcare Research and Quality Publications Clearinghouse @ 800/358-9295).
The Genetic Risk assessment and BRCA Testing for Breast and Ovarian Cancer Susceptibility, the 2008 recommendations from the U.S. Preventive Services Task Force, are unchanged from 2005. High-risk parameters were added to the coverage field for clarification.
2009 Update
Coverage for BRCA1/2 testing for men has been added based on recommendations by the National Comprehensive Cancer Network (NCCN). The U. S. Preventive Heatlh Services Task Force is silent on this issue.
2012 Update
This policy is updated with a literature search of the MEDLINE database. A summary of the relevant literature is included below.
In patients with breast cancer that is “triple-negative”, i.e., negative for expression of estrogen and progesterone receptors and for overexpression of HER2 receptors, there is an increased incidence of BRCA mutations. Pathophysiologic research has suggested that the physiologic pathway for development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer (de Ruijter, 2011). In 200 randomly selected patients with triple-negative breast cancer from a tertiary care center, (Kandel, 2006) there was a greater than 3-fold increase in the expected rate of BRCA mutations. BRCA1 mutations were found in 39.1% of patients and BRCA2 mutations in 8.7%. Young et al. studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing (Young, 2009). A total of 6 BRCA mutations, 5 BRCA1 and 1 BRCA2, were found for a mutation rate of 11%. Finally, in a study of 77 patients with triple-negative breast cancer, 15 patients (19.5%) had BRCA mutations: 12 in BRCA1 and 3 in BRCA2 (Gonzalez, 2011). Therefore, “triple-negative” breast cancer is added as an indication in the coverage statement.
Unaffected individuals with a family history suggestive of hereditary breast and/or ovarian cancer but unknown family mutation may obtain interpretable results in most cases of a positive test. Most BRCA1 and BRCA2 mutations reported to date consist of frameshift deletions, insertions, or nonsense mutations leading to premature truncation of protein transcription. These are invariably deleterious and thus are informative in the absence of an established familial mutation (Frank, 2002) (Narod, 2004). In addition, specific missense mutations and noncoding intervening sequence mutations may be interpreted as deleterious on the basis of accumulated data or from specific functional or biochemical studies. However, some BRCA mutations may have uncertain significance in the absence of a family study, and negative results offer no useful information, i.e., the patient may still be at increased risk of a disease-associated mutation in an as yet undiscovered gene.
Unaffected individuals may also be at high risk due to other patterns of non-breast cancer malignancies. A personal history of pancreatic cancer is estimated to raise the risk of a BRCA mutation by 3.5-10-fold over the general population (Hruban, 2010). Couch et al. reported on screening for BRCA in 2 cohorts of families at high risk for pancreatic cancer (Couch, 2007). In the first cohort of high-risk families, there were a total of 5 BRCA mutations in 151 probands, and in the second cohort, there were another 5 BRCA mutations in 29 probands. The combined BRCA mutation rate for these 2 cohorts was 6% (10/180). Ferrone et al. tested 187 Ashkenasi Jewish patients with pancreatic cancer for BRCA mutations and found that 5.5% (8/187) had a BRCA mutation (Ferrone. 2009).
Women with a personal history of ovarian cancer also have an increased rate of BRCA mutations. In a systematic review of 23 studies, Trainer et al. estimated the rate of BRCA mutations for women with ovarian cancer to be in the range of 3-15% (Trainer, 2010). In this review, there were 3 studies that were performed in the United States and tested for both BRCA1 and BRCA2. The incidence of BRCA mutations in these studies was 11.3%, 15.3%, and 9.5%. In a population-based study of 1,342 unselected patients with invasive ovarian cancer performed in Canada, (Zhang, 2011) there were 176 women with BRCA mutations, for a rate of 13.3%. The prevalence of mutations was higher for women in their 40s and in women with serous ovarian cancer. Ethnicity was also an additional risk factor for BRCA, with higher rates seen in women of Italian, Jewish, and Indo-Pakistani origin.
There has been interest in further risk-stratifying patients with known BRCA mutations in order to further assist in clinical decision making. Numerous recent publications have identified a large number of candidate modifier genes, and there have also been non-genetic modifying factors examined. Antoniou et al. examined the risk of breast cancer associated with nine genetic polymorphisms, the majority of which had previously shown an increase cancer risk among BRCA carriers (Antoniou, 2010). Seven of the nine polymorphisms were confirmed to increase breast cancer risk. The magnitude of increased risk varied by whether the patient was a BRCA1 versus a BRCA2 carrier, and the polymorphisms appeared to interact multiplicatively to increase risk.
Kleibl et al. reported that the AIB1 genotype in general did not influence breast cancer risk in BRCA carriers but that the specific genotype AIB1 consisting of 28/28 glutamine repeats conferred a decreased risk of breast cancer (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.41-0.99, p=0.045) (Kleibl, 2011). Zhou et al. reported an increased risk of cancer in BRCA carriers who also had the RAD51 135G>C polymorphism (odds ratio [OR]: 1.34, 95% CI: 1.01-1.78, p=0.04) (Zhou, 2011). Metcalfe et al. reported that family history provided additional predictive information in BRCA carriers (Metcalfe, 2010). For each first-degree relative with breast cancer, there was a 1.7-fold increase in risk of cancer for BRCA carriers.
CHEK2 and Other Mutations
A number of publications have also described the association of CHEK2 (cell cycle checkpoint kinase 2) mutations with hereditary breast cancer. The prevalence of this finding varies greatly by geographic regions, being most common in northern and eastern Europe. It has been detected in 4% of early breast cancer patients in the Netherlands, in 2.3% of such patients in Germany, but has been noted to be rare in these patients in Spain or Australia. In the U.S., this mutation is much less common than BRCA mutations and BRCA rearrangements. For example, in the study by Walsh et al., cited above, 14 (4.7%) of the 300 patients with a positive family history of breast cancer (4 affected relatives) who were negative by standard BRCA testing, were positive for CHECK2 mutations (Walsh, 2006). The low frequency makes evaluation of risk and treatment implications less precise. In general, the risk of breast cancer associated with this mutation is less that that associated with either BRCA1 or BRCA2.
A meta-analysis by Weischer et al. concluded that for familial breast cancer, the cumulative risk at age 70 years for CHEK2*1100delC mutation was 37% (95% CI: 26% to 56%) (Weischer, 2008). This risk is lower than cumulative risk at age 70 of 57% for BRCA1 and 49% for BRCA2. In an accompanying editorial, Offit and Garber raise a number of questions about potential use of this assay (Offit, 2008). In particular, they raise questions about the breast cancer risk estimates presented in the Weischer study; a number of the questions relate to the variable methods of ascertainment used in the studies in this meta-analysis. They also note that other mutations, such as CHEK2*S428F, are observed in other populations. The varying frequency is mentioned, with the mutation noted in 0.5–1.0% of the population in northern and eastern Europe compared with 0.2–0.3% in the U.S. Finally, they raise concerns about the implications of the low penetrance of this mutation. They concluded that on the basis of data available at this time, there is not compelling evidence to justify routine clinical testing for CHEK2 to guide the management of families affected with breast cancer. Thus, based on a number of concerns, testing for CHEK2 mutations is considered investigational because the impact on net health outcome is uncertain.
Since the meta-analysis by Weischer, there have been additional studies looking at the risk of breast cancer associated with the CHEK2 mutation. Myszka et al. examined 284 breast cancer patients, 113 ovarian cancer patients, and 287 healthy women from a cohort of Polish individuals (Myszka, 2011). The CHEK2 mutation rate was not higher among patients with breast or ovarian cancer compared to healthy women.
Zhang et al. performed a systematic review of candidate-gene association studies, identifying more than 1,000 published articles (Zhang, 2011). Meta-analysis was performed for a total of 279 genetic variants in 128 genes that were identified by at least 3 different researchers. Significant associations with the risk of breast cancer were found for 29 variants in 20 genes. The association was strong for 10 variants in 6 genes, 4 of which were located in the CHEK2 gene. There was also a strong association found for two variants of the ATM gene and an additional 4 genes that had a single variant with a strong association (CASP8, CTLA4, NBN, and TP53).
Peng et al. performed an overview of systematic reviews and pooled analyses on the association of genetic variants with breast cancer (Peng, 2011). A total of 87 analyses were identified, which examined 145 candidate gene variants and found that 46 variants were significantly associated with breast cancer. The odds ratios for these associations ranged from 0.66 to 3.13. Using the method of false-positive report probability, there were 10 associations in 7 genes that were noteworthy. These genes were CASP8, CHEK2, CTLA4, FGFR2, ILIB, LSP1, and MAP3K1.
A recent publication described the high rate of occult fallopian tube cancers in at-risk women having prophylactic bilateral salpingo-oophorectomy (Hirst, 2009). In this prospective series of 45 women, 4 (9%) were found to have fallopian tube malignancies. The authors noted that this supports other studies that have demonstrated the fimbrial end of the fallopian tube as an important site of cancer in those with BRCA1 or BRCA2 mutations. Similarly, the current NCCN guidelines for assessing high risk in breast and ovarian cancer include both fallopian tube and primary peritoneal cancer as other malignancies that should be asked about when assessing family history to make a decision regarding testing for BRCA1 and BRCA2. Thus, these 2 conditions are added to the policy statements and policy guidelines.
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
A literature search conducted using the MEDLINE database through February 2018 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In a systematic review for the USPSTF, Nelson et al assessed the efficacy of risk-reducing surgery in BRCA-positive women (Li, 2019). The literature search was conducted through March 2019. A total of 13 observational studies (n=9938) provided consistent and moderate-strength evidence of the benefits of risk-reducing surgery. For high-risk women and variant carriers, bilateral mastectomy reduced breast cancer incidence by 90% to 100% and breast cancer mortality by 81% to 100%; oophorectomy or salpingo-oophorectomy reduced breast cancer incidence by 37% to 83%, ovarian cancer incidence by 69% to 100%. Some women experienced reduced anxiety. Limitations of the studies of benefits included lack of comparison groups, variations in methodology and enrollment criteria, and heterogeneous outcome measures. Additionally, a total of 14 observational studies (n=3073) provided low-strength evidence of the harms of risk-reducing surgery. Adverse events included physical complications of the surgery, postsurgical symptoms, and changes in body image. Studies of harms shared the same limitations as the studies of benefits as noted above, with the addition that their findings were inconsistent and the sample sizes were smaller. As reviewers observed, it is still currently unknown whether BRCA variant testing reduces cause-specific or all-cause mortality, or if it improves the QOL. Harms associated with false-negative results or variants of uncertain significance also are unknown.
OlympiAD is a phase 3 RCT in which patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and a germline BRCA variant were randomized to olaparib (n=205) or standard therapy (n=97) (Robson, 2017). In its initial publication, Robson et al reported that after a median follow-up of 14.5 months, patients receiving olaparib experienced significantly longer progression-free survival compared with patients receiving standard therapy (HR, 0.6; 95% CI, 0.4 to 0.8). The rate of grade 3 or higher adverse events was lower in the group receiving olaparib (37%) compared with the group receiving standard therapy (51%). However, regarding OS, in their subsequent publication, Robson et al further reported that although improvement with olaparib was not significant overall (19.3 vs 17.1 months; HR, 0.90; 95% CI, 0.66 to 1.23) there may be a benefit in the subgroup of patients who had not received chemotherapy for metastatic disease (HR, 0.51; 95% CI 0.29-0.90) (Robson, 2019)
Practice Guidelines and Position Statements
The current NCCN guidelines for prostate cancer are (v.4.2019) (Mitra, 2011). For initial risk stratification and staging workup for clinically localized disease, footnote c states: "Family history for known germline variants and genetic testing for germline variants should include MLH1, MSH2, MSH6, and PMS2 (for Lynch Syndrome)and homologous recombination genes BRCA1, BRCA2, ATM, PALB2, and CHEK2. Consider cancer predisposition NGS panel testing, which includes BRCA1, BRCA2, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2."
Also, in the "Genetic and Molecular Biomarker Analysis" section, germline testing is recommended and footnote ee states“Consider evaluating tumor for alterations in homologous recombination DNA repair such as: BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, and CHEK2.”“At present, this information may be used for genetic counseling, early use of platinum chemotherapy, or eligibility for clinical trials (e.g., PARP inhibitors). If mutations in BRCA2, BRCA1, ATM, CHEK2, or PALB2 are found and/or there is a strong family history of cancer, refer to genetic counseling to assess for the possibility of hereditary breast and ovarian cancer (HBOC) (NCCN, 2019).”
U.S. Preventive Services Task Force
Current USPSTF recommendations for genetic testing of BRCA1 and BRCA2variants in women state (Elmi, 2018):
"The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutation with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing (B recommendation). The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations. (D recommendation)"
Recommended screening tools included the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool,7-Question Family History Screening Tool, International Breast Cancer Intervention Study instrument (Tyrer-Cuziak), and brief versions of the BRCAPRO.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Moore et al published results from the phase 3, international, multi-center, double-blind, placebo-controlled trial of maintenance olaparib 300 mg twice daily in 391 patients with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, and/or fallopian-tube cancer with a BRCA1/2 mutation following a complete or partial clinical response following platinum-based chemotherapy (SOLO-1) (Moore, 2018). A total of 177 sites participated across 15 countries (United States, Australia, Brazil, Canada, China, France, Israel, Italy, Japan, Korea, Netherlands, Poland, New Zealand, Russian Federation, Spain, United Kingdom). Participants were enrolled between September 2013 and March 2015. The primary tumor location was the ovary in 85% of participants. The primary end point was progression-free survival, which was assessed by investigators and defined as the time from randomization to objective disease progression on imaging (according to modified Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) or death from any cause. Median follow-up was 41 months. Median progression-free survival was 13.8 months in the placebo group and not reported for the olaparib group. At 3 years, the proportions of patients free from disease progression and from death was 60% for olaparib and 27% for placebo, resulting in a 70% lower risk of disease progression or death for olaparib (HR 0.30; 95% CI, 0.23 to 0.41). Grade 3 or higher adverse events occurred in 39% of the olaparib group and 18% of the placebo group, with the most common events being anemia (22%) and neutropenia (9%).
Pujade-Lauraine et al published results from the phase 3, international, multi-center, double-blind, placebo-controlled trial of maintenance olaparib 300 mg twice daily in 295 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer, with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy (SOLO-2) (Pujade-Lauraine, 2017). A total of 123 sites participated across 16 countries (United States, Australia, Belgium, Brazil, Canada, France, Germany, Israel, Italy, Japan, Korea, Netherlands, Poland, Russian Federation, Spain, United Kingdom). Participants were enrolled between September 2013 and November 2014. The primary tumor location was the ovary in 85% of participants. The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomization until objective radiological disease progression or death using modified RECIST version 1.1. Median follow-up was 22.1 months in the olaparib group and 22.2 months in the placebo group. Olaparib resulted in a significantly longer progression-free survival (19.1 vs 5.5 months; HR 0.30, 95% CI, 0.22 to 0.41). Grades 3 and 4 adverse events occurred in 32% and 4% of olaparib patients, respectively and 15% and 3% of the placebo group. The most common grade 3 or higher adverse event in the olaparib group was anemia (19%).
Mirza et al published results from the phase 3, international, multi-center, double-blind, placebo-controlled trial of 553 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that evaluated maintenance treatment with niraparib 300 mg once daily (NOVA) (Mirza, 2016). This trial was conducted by the European Network for Gynecological Oncological Trial groups and investigators across 107 sites in the United States, Canada, and Hungary. Two independent cohorts were separately evaluated on the basis of the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort), as determined on BRACAnalysis testing. Participants were enrolled between August 2013 and June 2016 and the majority had stage III or IV ovarian cancer. The gBRCA cohort consisted of 201 individuals (36.3%). The primary endpoint was progression-free survival. Overall median follow-up duration was 16.9 months. Progression-free survival was significantly longer in the niraparib group, regardless of the presence or absence of gBRCA mutations (gBRCA cohort: 21.0 vs 5.5 months; HR 0.27, 95% CI, 0.17 to 0.41; non-gBRCA cohort: 9.3 vs 3.9 months; HR 0.45, 95% CI, 0.34 to 0.61). Thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%) were the most common grade 3 or higher adverse events in the niraparib group.
Moore et al published results from the phase 2, multi-center, single-arm clinical trial of niraparib monotherapy 300 mg once daily in individuals with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens (QUADRA) (Moore, 2019). Between April 2015 and November 2017, this trial enrolled 463 patients across 56 sites in the United States and Canada. All participants underwent tumor homologous recombination deficiency (HRD) testing and blood germline BRCA-mutated status testing and were stratified into 4 cohorts: BRCA-mutated, HRD-positive/non-BRCA-mutated, HRD-negative, and HRD unknown. The majority of participants had ovarian cancer (79%). The BRCA-mutated cohort consisted of 87 (19%) participants. In the BRCA-mutated cohort, the primary endpoint of investigator-assessed confirmed overall response was met by 30% (95% CI, 17% to 64%) and 36% of patients with stable disease at 24 weeks had a progression-free survival ratio greater than 1.3 (9/25). In the overall population, anemia (24%) and thrombocytopenia (21%) were the most frequent grade 3 or higher adverse events. A key limitation of this trial is its lack of a control group.
Coleman et al published results from the phase 3, international, multi-center, double-blind trial of 564 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that compared rucaparib maintenance treatment to placebo following response to second-line or later platinum-based chemotherapy (ARIEL3) (Coleman, 2017). A total of 87 sites participated across 11 countries (United States, Australia, Belgium, Canada, France, Germany, Israel, Italy, New Zealand, Spain, United Kingdom). Germline mutations were identified using the BRACAnalysis CDx test. Tumor tissue samples were tested using a clinical trial assay and the FoundationFocus CDx test. Three nested cohorts were evaluated: patients with BRCA mutations, patient with homologous recombination deficiencies, and the intention-to-treat populations. Participants were enrolled between April 2014 and July 2016 and the majority had epithelial ovarian cancer (84%). A total of 196 (34.8%) had BRCA1/2 mutations. The primary endpoint was progression-free survival, which was significantly longer in the rucaparib group in the BRCA-mutant cohort (16.6 months vs 5.4 months; HR 0.23, 95% CI, 0.16 to 0.34), the homologous recombination deficient carcinoma cohort (13.6 months vs 5.4 months; HR 0.32, 95% CI, 0.24 to 0.42), and in the intention-to-treat cohort (10.8 months vs 5.4 months; HR 0.36, 95% CI, 0.30 to 0.45). Grade 3 or higher adverse events were reported in 56% of patients in the rucaparib group compared with 15% in the placebo group. The most common of these were anemia or decreased hemoglobin concentration.
Kristeleit et al published integrated results from 2 multi-center, single-arm, open-label trials of rucaparib 600 mg twice daily (Study 10 and ARIEL2) in patients with high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and a deleterious BRCA1 or BRCA2 mutation who had progressed after receiving two or more prior chemotherapies (including two or more platinum-based therapies) (Kristeleit, 2019). The majority of patients had epithelial ovarian cancer (87.3%). The efficacy population consisted of 79 patients who took at least one dose of rucaparib. Median treatment and follow-up durations were not reported. The primary end point was investigator-assessed, confirmed objective response rate, which was 64.6% (95% CI, 53.0% to 75.0%). Median progression-free survival was 332 days (95% CI, 255 to 391). Grade 3 or greater adverse events occurred in 63.2% of patients, which were most frequently decreased hemoglobin (24.2%), asthenia/fatigue (11.3%) and alanine/aspartate aminotransferase increased (10.8%).
Abida et al published results from the phase 2, multi-center, single-arm clinical trial of rucaparib in patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC) that supported its accelerated FDA-approval in 2020 (TRITON2) (Abida, 2020). This trial enrolled 115 patients who were treated with rucaparib 600 mg twice daily. For the efficacy population, median treatment duration was 8.1 months and median follow-up was 17.1 months. The primary endpoint of objective response rate, which was rated by blinded, independent radiology review, was 43.5% (95% CI, 31.0% to 56.7%). Median radiographic progression-free survival duration was 9.0 months (95% CI, 8.3 to 13.5). Anemia was the most frequent grade 3 or higher adverse event (25.2%). A key limitation of this trial is its lack of a control group. Continued approval for this indication for rucaparib may be contingent upon verification of progression-free survival in the ongoing confirmatory TRITON3 trial (NCT02975934), which is a randomized, controlled phase 3 trial evaluating rucaparib 600 mg twice daily versus physician’s choice treatment in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation.
Litton et al published results from a phase 3, randomized, open-label trial of 431 patients with advanced breast cancer and a germline BRCA1/2 mutation that compared talazoparib 1 mg once daily to standard single-agent therapy (EMBRACA) (Litton, 2018). BRCA1/2 mutation was detected by BRACAnalysis testing. The primary endpoint was progression-free survival. Median duration of follow-up for that endpoint was 11.2 months. Progression-free survival was significantly longer in the talazoparib group (8.6 months vs 5.6 months; HR 0.54, 95% CI, 0.41 to 0.71). The rate of overall grade 3 or higher adverse events was similar for talazoparib compared with the standard care (25.5% vs 25.4%), but hematologic grade 3-4 adverse events (primarily anemia) were more frequent for talazoparib (55% vs 38%) compared with nonhematologic grade 3-4 adverse events (32% vs 38%). Based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), compared to baseline, there was a significant improvement in the talazoparib group (+3.0; 95% CI, 1.2 to 4.8) and a significant decline in the standard therapy group (-5.4; 95% CI, -8.8 to -2.0). Although the trial was open-label, assessment of the primary outcome was based on blinded independent central review.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In the OlympiA trial, patients with HER2-negative early-stage breast cancer (Clinical Stage I-III) and germline BRCA1/2 mutations treated with (neo)adjuvant chemotherapy were considered at high risk of recurrent disease when the following eligibility criteria were met for treatment with olaparib (Tutt, 2021):
Tutt et al published results from the phase 3 multicenter, multinational, and double-blind OlympiA RCT, which evaluated the safety and efficacy of olaparib in patients with germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants and high-risk, human epidermal growth factor receptor 2 (HER2)-negative primary early-stage breast cancer after definitive local treatment and neoadjuvant or adjuvant chemotherapy (Tutt, 2021). Patients with triple-negative breast cancer who were treated with adjuvant chemotherapy were required to have axillary node-positive disease or an invasive primary tumor measuring at least 2 cm on pathological analysis. Patients treated with neoadjuvant chemotherapy were required to have not achieved pathological complete response. Patients treated with adjuvant chemotherapy for hormone receptor (HR)-positive, HER2-negative breast cancer were required to have at least 4 pathologically confirmed positive lymph nodes. Those treated with neoadjuvant chemotherapy were required to have not achieved a pathological complete response with a CPS+EG score of 3 or higher. This scoring system estimates relapse probability on the basis of clinical and pathological stage (CPS) and estrogen-receptor status and histologic grade (EG). Scores range from 0 to 6, with higher scores reflecting a worse prognosis. Approximately half of patients received adjuvant chemotherapy and half neoadjuvant chemotherapy, with the majority (93.7%) receiving a combination of an anthracycline and a taxane in their regimen. Patients with triple-negative disease comprised 82.2% of the trial population. Patients were randomized 1:1 to treatment with twice daily 300 mg olaparib (n = 921) or placebo (n=915) for 52 weeks. At the prespecified interim analysis, 86% of the primary analysis target of 330 events of invasive disease or death in the intention-to-treat population were observed, with a median follow-up duration of 2.5 years (IQR, 1.5 to 3.5 y). The 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8%; 95% CI, 4.5% to 13.0%). Invasive disease-free survival was significantly longer among patients receiving olaparib (HR, 0.58; 99.5% CI, 0.41 to 0.82; p<.001). While fewer deaths were reported in the olaparib group (59 versus 86) with a HR of 0.68 (99% CI, 0.44 to 1.05; p =.02), the between-group difference did not cross the prespecified multiple-testing procedure boundary for significance of p<.01. Subgroup analysis of invasive disease-free survival revealed treatment effects for olaparib over placebo that were consistent with those in the overall analysis population across all stratification groups and prespecified subgroups. Serious adverse events occurred in 8.7% and 8.4% of patients treated with olaparib and placebo, respectively. Adverse events leading to trial regimen discontinuation occurred in 9.9% and 4.2% of patients treated with olaparib and placebo, respectively.
Hussain et al published results from the open-label, multicenter, phase 3 PROfound trial which randomized patients with metastatic castration-resistant prostate cancer and disease progression following prior treatment with a next-generation hormonal agent to treatment with olaparib 300 mg twice daily (n = 256) or investigator's choice of enzalutamide or abiraterone acetate plus prednisone (n = 131) (Hussain, 2020). Patients were divided into two cohorts based on their homologous recombination repair (HRR) gene mutation status. Specifically, patients with mutations in BRCA1, BRCA2, or ATM were randomized to Cohort A (n = 245) and patients with mutations in 12 other HRR pathway genes were randomized to Cohort B (n = 142). Patients with co-mutations were assigned to Cohort A. The primary efficacy outcome was radiological progression-free survival (rPFS) in Cohort A, which demonstrated a statistically significant improvement for olaparib compared to control with a median rPFS of 7.4 months versus 3.6 months (HR, 0.34; 95% CI, 0.25 to 0.47; p<.0001). Median OS was 19.1 months versus 14.7 months (HR, 0.69; 95%CI: 0.50 to 0.97; p =.0175) for olaparib compared to control. Exploratory gene-level analyses demonstrated HRs for death (olaparib versus control) among patients with an alteration in only BRCA1 and only BRCA2 of 0.42 (95% CI, 0.12 to 1.53) and 0.59 (95% CI, 0.37 to 0.95), respectively.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Suszynska et al reported a systematic review of variants identified in panels of breast and ovarian cancer-related genes (Suszynska, 2019). Results were reported for PALB2, CHEK2, and ATM. CHEK2 and ATM results will be discussed in the following sections. The systematic review included studies published through July 2017 reporting on genetic test results of breast and ovarian cancer patients who were referred for evaluation by a multi-gene panel. Given that the Suszynska et al report included only studies reporting on test results from a panel, it does not substantially overlap with the studies described in the following section including other PALB2 association studies. The studies of panel results were used to calculate mutation frequencies by the gene. As a control, population mutation frequencies were extracted from the Genome Aggregation Database. Forty-three studies included panels in breast cancer patients. In the breast cancer studies, 95,853 patients were included in the analysis of PALB2. PALB2 variants were identified in 0.9% of breast cancer patients. The meta-analytic estimate odds ratio (OR) of the association between PALB2 variants and risk of breast cancer was 4.8 (95% CI, 4.1 to 5.6).
A number of studies reporting relative risks (RR) or ORs for the association between PALB2 and breast cancer were identified (Catucci, 2014; Antoniou, 2014; Casadei, 2011; Cybulski, 2015; Erkko, 2008; Heikkinen, 2009; Rahman, 2007; Thompson, 2015; Southey, 2016; Lu, 2019; Woodward, 2021). Study designs included family segregation (Erkko, 2008; Yang, 2020), kin-cohort (Antoniou, 2014), family-based case-control (Casadei, 2011; Rahman, 2007; Li, 2021), and population-based or multicenter case-control (Catucci, 2014; Cybulski, 2015; Heikkinen, 2009; Thompson, 2015; Southey, 2016; Lu, 2019; Woodward, 2021). The 2 multinational studies included individuals from up to 5 of the single-country studies (Antoniou, 2014; Southey, 2016). The number of pathogenic variants identified varied from 1 (founder mutations examined) to 48. Studies conducted from single-country samples are described first followed by the 2 multinational collaborative efforts.
Woodward et al assessed the contribution of PALB2 gene variants to familial breast and ovarian cancer (Woodward, 2021). A total of 3127 women with a histologically confirmed diagnosis of invasive or in situ breast cancer or an epithelial nonmucinous ovarian cancer who had undergone germline testing of BRCA1, BRCA2, PALB2, and CHEK2_c.1100delC were included. Cases were identified from centers in the U.K.
Li et al assessed the association between 14 known genes associated with HBOC in a sample of 1990 BRCA 1/2-negative family members with breast cancer and/or ovarian cancer and 1902 older women (>40 years of age) who were cancer free at the time of the study (Li, 2021). The initial assessment in 3892 women was conducted with targeted gene panel sequencing, followed by assessment of 145 candidate genes and 14 known HBOC genes in a sample of 3780 BRCA1 and BRCA2-negative families and 3839 controls. Index cases were identified from Familial Cancer Centers and a Pathology center in Australia, and controls were identified from the LifePool mammography screening study.
Lu et al included an analysis of 11,416 patients with breast cancer and/or ovarian cancer who were referred for genetic testing from 1200 U.S. hospitals and clinics and of 3988 controls referred for genetic testing for noncancer conditions between 2014 and 2015 (Lu, 2019). Whole-exome sequencing was used and suspected pathogenic variants in the breast or ovarian cancer-associated genes were confirmed by Sanger sequencing.
Kurian et al reported the association between pathogenic variants and breast or ovarian cancer using a commercial laboratory database of 95,561 women tested clinically for hereditary cancer risk using a multi-gene panel that included PALB2, CHEK2, and ATM (Kurian, 2017). Although the country is not stated, the patients underwent testing between 2013 and 2015 performed at a Clinical Laboratory Improvement Amendments (CLIA) laboratory and, thus, will be assumed to include patients from the U.S. Cases were women with a single diagnosis of breast or ovarian cancer. Controls were women from the same database (i.e., being tested for hereditary cancer) with no cancer history at the time of genetic testing. The multivariable models for breast cancer risk are reported here. Among the breast cancer patients, 244 (0.92%) had a PALB2 variant. The association between PALB2 and breast cancer adjusting for age, ancestry, personal and family cancer histories, and Lynch and adenomatous polyposis colon cancer syndromes had an OR of 3.39 (95% CI, 2.79 to 4.12).
Thompson et al evaluated Australian women with breast cancer (n=1996) referred for genetic evaluation from 1997 to 2014 (Thompson, 2015). A control group was accrued from participants in the LifePool study (n=1998) who were recruited for a mammography screening program. All PALB2 coding exons were sequenced by next-generation sequencing and novel variants verified by Sanger sequencing. Large deletions or rearrangements were not evaluated. Nineteen distinct pathogenic variants were identified, including 6 not previously described in 26 (1.3%) cases and in 4 (0.2%) controls with an odds for breast cancer of 6.58 (95% CI, 2.3 to 18.9). Moreover, 54 missense variants identified were slightly more common in cases (OR, 1.15; 95% CI, 1.02 to 1.32).
Cybulski et al examined 2 loss-of-function PALB2 variants (c.509_510delGA, c.172_175delTTGT) in women with invasive breast cancer diagnosed between 1996 and 2012 in Poland (Cybulski, 2015). From 12,529 genotyped women, a PALB2 variant was identified in 116 (0.93%) cases (95% CI, 0.76% to 1.09%) versus 10 (0.21%, 95% CI, 0.08% to 0.34%) of 4702 controls (OR, 4.39; 95% CI, 2.30 to 8.37). A BRCA1 variant was identified in 3.47% of women with breast cancer and in 0.47% of controls (OR, 7.65; 95% CI, 4.98 to 11.75). Authors estimated that a PALB2 sequence variant conferred a 24% cumulative risk of breast cancer by age 75 years (in the setting of age-adjusted breast cancer rates slightly more than half that in the U.K. or the U.S.) (Antoniou, 2015; NCI SEER Program, 2022). A PALB2 variant was also associated with poorer prognosis: 10-year survival of 48.0% versus 74.7% when the variant was absent (HR adjusted for prognostic factors, 2.27; 95% CI, 1.64 to 3.15).
Catucci et al performed population-based case-control studies in Italy (Milan or Bergamo) among women at risk for hereditary breast cancer and no BRCA1 or BRCA2 variant (Catucci, 2014). In Milan, 9 different pathogenic PALB2 variants were detected in 12 of 575 cases and none in 784 controls (blood donor); in Bergamo, PALB2 c.1027C>T variants were detected in 6 of 113 cases and in 2 of 477 controls (OR, 13.4; 95% CI, 2.7 to 67.4). Performed in 2 distinct populations, the combined sample size was small, and uncertainty existed as indicated by the large effect estimate.
Casadei et al studied 959 U.S. women (non-Ashkenazi Jewish descent) with a family history of BRCA1- or BRCA2-negative breast cancer and 83 female relatives using a family-based case-control design (Casadei, 2011)). Using conventional sequencing, pathogenic PALB2 variants were detected in 31 (3.2%) women with breast cancer and none in controls. Compared with their female relatives without PALB2 variants, the risk of breast cancer increased 2.3-fold (95% CI, 1.5 to 4.2) by age 55 years and 3.4-fold (95% CI, 2.4 to 5.9) by age 85 years. Mean age at diagnosis was not associated with the presence of a variant (50.0 years with vs. 50.2 years without). Casadei et al provided few details of their analyses. Additionally, participants reported over 30 ancestries and, given intermarriage in the U.S. population, stratification may have had an impact on results. Generalizability of the risk estimate is therefore unclear.
Heikkinen et al conducted a population-based case-control study at a Finnish university hospital employing 2 case groups (947 familial and 1274 sporadic breast cancers) and 1079 controls (Heikkinen, 2009). The study sample was obtained from 542 patients with familial breast cancer, a series of 884 oncology patients (79% of consecutive new cases), and 986 surgical patients (87% of consecutive new cases); 1706 were genotyped for the PALB2 c.1592delT variant. All familial cases were BRCA1- and BRCA2-negative, but among controls, there were 183 BRCA carriers. PALB2 variant prevalence varied with family history: 2.6% when 3 or more family members were affected and 0.7% in all breast cancer patients. Variant prevalence was 0.2% among controls. In women with hereditary disease, a PALB2 c.1592delT variant was associated with an increased risk of breast cancer (OR, 11.0; 95% CI, 2.65 to 97.78), and was higher in women with the strongest family histories (women with sporadic cancers; OR, 4.19; 95% CI, 1.52 to 12.09). Although data were limited, survival was lower among PALB2-associated cases (10-year survival, 66.5%; 95% CI, 44.0% to 89.0% vs. 84.2%; 95% CI, 83.1% to 87.1% in women without a variant; p=.041; HR, 2.94; p=.047). A PALB2 variant was also associated with triple-negative tumors: 54.5% versus 12.2% with familial disease and 9.4% in sporadic cancers.
Yang et al performed a complex segregation analysis to estimate relative and absolute risks of breast cancer from data on 524 families with PALB2 pathogenic variants from 21 countries, the most frequent being c.3113G>A (Yang, 2020). Female breast cancer relative risk (RR) was 7.18 (95% CI, 5.82 to 8.85; p=6.5x10-75) when assumed to be constant with age. The age-trend model provided the best fit (p=2x10-3) and demonstrated a pattern of decreasing RR with each increased decade in age. The RR was 4.69 (95% CI, 3.28 to 6.70) in those 75 years of age per the age-trend model.
Southey et al examined the association of 3 PALB2 variants (2 protein-truncating: c.1592delT and c.3113G>A; 1 missense c.2816T>G) with breast, prostate, and ovarian cancers (Southey, 2016). The association with breast cancer was examined among participants in the Breast Cancer Association Consortium (BCAC; 42,671 cases and 42,164 controls). The BCAC (part of the larger Collaborative Oncological Gene-environment Study) included 48 separate studies with participants of multiple ethnicities, but mainly European, Asian, and African American. Most studies were population- or hospital-based case-controls with some oversampling cases with family histories or bilateral disease. A custom array was used for genotyping at 4 centers, with 2% duplicate samples. The ORs were estimated adjusting for study among all participants, and excluding those studies selecting patients based on family history or bilateral disease (37,039 cases, 38,260 controls). The c.1592delT variant was identified in 35 cases and 6 controls (from 4 studies in the U.K., Australia, U.S., Canada; OR, 4.52; 95% CI, 1.90 to 10.8; p<.001); in those with no family history or bilateral disease (OR, 3.44; 95% CI, 1.39 to 8.52; p=.003). The c3113G>A variant was identified in 44 cases and 8 controls (9 studies from Finland and Sweden; OR, 5.93; 95% CI, 2.77 to 12.7; p<.001) and in those with no family history or bilateral disease (OR, 4.21; 95% CI, 1.84 to 9.60; p<.001). There was no association between the c2816T>G missense variant and breast cancer (found in 150 cases and 145 controls). These results, derived from a large sample, used a different analytic approach than Antoniou et al, described next, and examined only 2 pathogenic variants. The magnitude of the estimated RR approaches that of a high penetrance gene but is accompanied by wide CIs owing to the study design and low carrier prevalence. The lower estimates obtained following exclusion of those selected based on family history or bilateral disease are consistent with the importance of carefully considering the risk of hereditary disease prior to genetic testing.
Antoniou et al analyzed data from 362 members of 154 families with deleterious PALB2 variants (Antoniou, 2014). Individuals with benign variants or variants of uncertain significance were excluded. Families were recruited at 14 centers in 8 countries (U.S., U.K., Finland, Greece, Australia, Canada, Belgium, Italy) and had at least 1 member with a BRCA1- or BRCA2-negative PALB2-positive breast cancer. There were 311 women with PALB2 variants: 229 had breast cancer; 51 men also had PALB2 variants (7 had breast cancer). Of the 48 pathogenic (loss-of-function) variants identified, 2 were most common (c.1592delT in 44 families, c.3113G>A in 25 families); 39 of the 48 pathogenic variants were found in just 1 or 2 families. Carriers of PALB2 variants (men and women) had a 9.47-fold increased risk for breast cancer (95% CI, 7.16 to 12.57) compared with the U.K. population under a single-gene model and age-constant RR; 30% of tumors were triple-negative. For a woman aged 50 to 54 years, the estimated RR was 6.55 (95% CI, 4.60 to 9.18). The RR of breast cancer for males with PALB2 variants, compared with the male breast cancer incidence in the general population, was 8.3 (95% CI, 0.77 to 88.5; p=.08). The cumulative risk at age 50 years of breast cancer for female PALB2 carriers without considering family history was 14% (95% CI, 9% to 20%); by age 70 years, it was 35% (95% CI, 26% to 46%). A family history of breast cancer increased the cumulative risk. If a woman with a PALB variant has a sister and mother who had breast cancer at age 50 years, by age 50 years she would have a 27% (95% CI, 21% to 33%) estimated risk of developing breast cancer; and by age 70 years, a 58% (95% CI, 50% to 66%) risk. These results emphasize that family history affects penetrance. Authors noted that the study "includes most of the reported families with PALB2 variant carriers, as well as many not previously reported".
Rosenthal et al reported an analysis of the impact of testing for genes other than BRCA1/2 and by calculating whether carriers of these gene variants would have been identified as candidates for enhanced screening based on family history alone (Rosenthal, 2017). The database included 194,107 women who were tested using a hereditary cancer panel between 2013 and 2016. The women were referred by their health care providers for clinical suspicion of hereditary cancer. It is unclear what proportion of the women met professional society criteria for genetic testing for breast cancer risk; baseline information regarding family history was not reported. Of the women in the database, 893 had PALB2 variants and were eligible for Claus assessment to estimate the risk of breast cancer. Approximately 27% of women with PALB2 variants would have had an estimated risk of breast cancer of 20% or higher based on the Claus model. The report did not include health outcomes and it is unclear whether enhanced screening in women who had a moderate penetrance variant but did not have an estimated risk of breast cancer of 20% or greater based on the Claus model would have improved health outcomes from enhanced surveillance.
Studies of women at high-risk based on family history alone or in those with BRCA1 and BRCA2 variants are relevant to the clinical utility of PALB2 testing given the penetrance estimates for PALB2 and related molecular mechanism ("BRCA-ness"). Interventions to decrease breast cancer risk in asymptomatic high-risk women include screening (e.g., starting at an early age, the addition of magnetic resonance imaging to mammography, and screening annually), chemoprevention, and prophylactic mastectomy (Phi, 2016; Phillips, 2013; Hartmann, 2001)). In women with breast cancer, contralateral prophylactic mastectomy is of interest; other treatment decisions are dictated by clinical, pathologic, and other prognostic factors.
In women at high-risk of hereditary breast cancer, including BRCA1 and BRCA2 carriers, evidence supports a reduction in subsequent breast cancer after bilateral or contralateral prophylactic mastectomy. Decision analyses have also concluded the impact on breast cancer incidence extends life in high, but not average risk, women (Portschy, 2014). For example, Schrag et al modeled the impact of preventive interventions in women with BRCA1 or BRCA2 variants and examined penetrance magnitudes similar to those estimated for a PALB2 variant (Schrag, 1997; Schrag, 2000). Compared with surveillance, a 30-year-old BRCA carrier with an expected 40% risk of breast cancer and 5% risk of ovarian cancer by age 70 years would gain an expected 2.9 years following a prophylactic mastectomy alone and an additional 0.3 years with a prophylactic oophorectomy (Schrag, 1997). A 50-year-old female BRCA carrier with node-negative breast cancer and a 24% risk of contralateral breast cancer at age 70 years would anticipate 0.9 years in improved life expectancy (0.6 years for node-negative disease) following a prophylactic contralateral mastectomy (Schrag, 2000).
A consensus guideline on genetic testing for hereditary breast cancer was updated in February 2019 (ASBrS, 2019). The guideline states that genetic testing should be made available to all patients with a personal history of breast cancer and that such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and patient family history. Furthermore, patients who had previous genetic testing may benefit from updated testing. Finally, genetic testing should be made available to patients without a personal history of breast cancer when they meet National Comprehensive Cancer Network (NCCN) guideline criteria. The guidelines also note that variants of uncertain significance are not clinically actionable.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.
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