Download Genetic Testing for PALB2 Mutations

MEDICAL POLICY
POLICY TITLE
GENETIC TESTING FOR PALB2 MUTATIONS
POLICY NUMBER
MP-2.279
Original Issue Date (Created):
10/1/2015
Most Recent Review Date (Revised):
5/31/2016
Effective Date:
11/22/2016
POLICY
RATIONALE
DISCLAIMER
POLICY HISTORY
PRODUCT VARIATIONS
DEFINITIONS
CODING INFORMATION
DESCRIPTION/BACKGROUND
BENEFIT VARIATIONS
REFERENCES
I. POLICY
Genetic testing for PALB2 mutations in patients with breast or pancreatic cancer or for cancer
risk assessment in patients with or without a family history of breast or pancreatic cancer is
considered investigational. There is insufficient evidence to support a conclusion concerning the
health outcomes or benefits associated with this procedure.
Policy Guidelines
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.
Cross-references:
MP 2.211 - Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (BRCA1BRCA2)
MP 2.325 - Genetic Cancer Susceptibility Panels Using Next Generation
Sequencing
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II. PRODUCT VARIATIONS
TOP
This policy is applicable to all programs and products administered by Capital BlueCross unless
otherwise indicated below.
FEP PPO*
*The FEP program dictates that all drugs, devices or biological products approved by the U.S.
Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDAapproved drugs, devices or biological products may be assessed on the basis of medical
necessity.
III. DESCRIPTION/BACKGROUND
TOP
PALB2 (partner and localizer of BRCA2) mutations are rare in the general population, however,
studies have estimated the prevalence of a PALB2 mutation in 1% to 3% of patients with
hereditary breast cancer. PALB2 mutations are considered to be of intermediate penetrance, and
carriers have an approximately 2- to 4-fold increased risk of developing breast cancer, when
compared with the general population; these risk estimates may be higher in patients with a
family history of breast cancer.
Cancer predisposing genes can be categorized by the relative risk (RR) of developing a particular
type of cancer if there is a mutation identified in one of these genes. Genes that are considered
highly penetrant are associated with a RR for cancer (compared with the general population) of
greater than 5, intermediate penetrant genes confer RRs from 2 to 4, and low-penetrant genes
with a RR of about 1.5.1 Cancer syndromes that are associated with highly penetrant genes have
established clinical management guidelines for patients who have been identified as having a
pathogenic mutation in one of these genes (eg, BRCA), and it has been established that increased
surveillance and risk-reducing interventions lead to improved patient outcomes. However, for
gene mutations that confer an intermediate or low risk of developing cancer, clinical
management guidelines are lacking, and it is unknown whether identifying mutations in these
non-highly-penetrant genes will lead to improved patient outcomes.
Hereditary Breast Cancer
Breast cancer can be classified as sporadic, familial, or hereditary. Sporadic breast cancer
accounts for 70% to 75% of cases and is thought to be due to nonhereditary causes. Familial
breast cancer, of which there are more cases within a family than statistically expected, but with
no specific pattern of inheritance, accounts for 15% to 25% of cases. Hereditary breast cancer
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accounts for 5% to 10% of cases and is characterized by well-known susceptibility genes with
apparently autosomal dominant transmission.
The “classic” inherited breast cancer syndrome is the hereditary breast and ovarian cancer
syndrome, most of which are due to mutations in the BRCA1 and BRCA2 genes. Other hereditary
cancer syndromes such as Li-Fraumeni syndrome (associated with TP53 mutations), Cowden
syndrome (associated with PTEN mutations), Peutz-Jeghers syndrome (associated with STK11
mutations), hereditary diffuse gastric cancer, and, possibly, Lynch syndrome, also predispose
patients to varying degrees of risk for breast cancer.
Highly penetrant mutations in the BRCA1, BRCA2, TP53, and PTEN genes may be associated
with a lifetime breast cancer risk ranging from 40% to 85%. Only about 5% to 10% of all cases
of breast cancer are attributable to a highly penetrant cancer predisposition gene. In addition to
breast cancer, mutations in these genes may also confer a higher risk for other cancers.2 Clinical
management guidelines for these syndromes associated with highly penetrant mutations address
cancer surveillance strategies and risk-reducing interventions (eg, bilateral prophylactic
mastectomy).
Other mutations may be associated with intermediate penetrance and a lifetime breast cancer risk
of 20% to 40% (eg, some PALB2 mutations, CHEK2). Low-penetrance mutations discovered in
genome-wide association studies (eg, single-nucleotide polymorphisms), are generally common
and confer a modest increase in risk, although penetrance can vary based on environmental and
lifestyle factors.
Hereditary Pancreatic Cancer
Pancreatic cancer may have a familial component in approximately 10% of cases, and some are
associated with familial cancer syndromes such as Peutz-Jeghers syndrome, familial malignant
melanoma syndrome, Lynch syndrome, and hereditary breast-ovarian cancer syndrome. PALB2
has also been identified as increasing pancreatic cancer risk.
Pancreatic Cancer Screening
Patients with a family history of pancreatic cancer are advised on risk-reducing strategies
including smoking cessation and weight loss. The possibility of screening for pancreatic cancer
may be discussed, however, there are no generally accepted guidelines as to the modality of
screening that should be used or the time interval at which screening should be performed, nor is
the impact of screening on survival clear.
PALB2 Gene
BRCA1, BRCA2, and PALB2 are 3 breast cancer susceptibility genes that function together in the
same DNA-damage response pathway.
PALB2 (partner and localizer of BRCA2) is a tumor suppressor gene, that encodes for the PALB2
protein interacting with the protein produced by the BRCA2 gene. The PALB2 protein stabilizes
the BRCA2 protein, allowing the BRCA2 protein to repair DNA double-strand breaks by a
process known as homologous recombination. Monoallelic germline loss-of-function mutations
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in PALB2 are associated with an increased risk of breast and pancreatic cancer and biallelic
mutations lead to a Fanconi anemia complementation group, designated subtype N (FANCN).
Most pathogenic PALB2 mutations detected are truncating frameshift or stop codons and are
scattered throughout the gene. However, not all PALB2 variants examined and reported in the
literature are pathogenic. For example, a 2013 meta-analysis by Zhang et al of “common
variants” included associations with variants not likely pathogenic and reported pooled odds
ratios between 1.36 and 1.64 (depending on the mode of inheritance).3
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory
service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the
Clinical Laboratory Improvement Act (CLIA). PALB2 testing is available under the auspices of
CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To
date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of
this test.
Many commercial laboratories currently offer a wide variety of diagnostic procedures for PALB2
testing often included as part of panel (a listing can be obtained www.genetests.org).
Myriad offers the Panexia® test (BRCA2 and PALB2), either comprehensive (with full
sequencing determination by polymerase chain reaction and large rearrangement analysis for
deletions and duplications by chromosome microarray analysis or single-site analysis (performed
for a targeted gene region).
Ambry Genetics BRCAplus™ includes comprehensive PALB2 mutation analysis together with
BRCA and 4 other susceptibility genes.
Customized next-generation sequencing panels provide simultaneous analysis of multiple cancer
predisposition genes, and typically include both intermediate- and high-penetrant genes. See MP2.325 Genetic Cancer Susceptibility Panels Using Next Generation Sequencing which addresses
the inclusion of PALB2 in these types of panels.
IV. RATIONALE
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A literature review was completed through October 27, 2015 (see Appendix Table 1 for genetic
testing categories). Literature that describes the analytic validity, clinical validity, and clinical
utility of genetic testing for PALB2 mutations was sought.
Analytic Validity
Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in
excluding a mutation that is absent.
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According to a large reference laboratory, analytic validity of testing detects 99% of described
PALB2 gene sequence mutations.4 Judkins et al (2015) reported analytic sensitivity exceeding
99.9% (Sanger sequencing referent) for all genes in a 25-gene panel that includes PALB2.5
Clinical Validity
For genetic susceptibility to cancer, clinical validity can be considered, in part, on the following
levels:
1. Does a positive test identify a person as having an increased risk of developing cancer?
2. If so, how high is the risk of cancer associated with a positive test and how certain is the
estimated risk?
The likelihood that someone with a positive test result will develop cancer is affected not only by
the presence of the gene mutation, but also by other modifying factors that can affect the
penetrance of the mutation (eg, environmental exposures, personal behaviors) or by the presence
or absence of mutations in other genes.
Prevalence of PALB2 Mutations in Patients With Hereditary Breast or Pancreatic Cancer
Fernandes et al (2014) sought to determine the prevalence of PALB2 mutations in patients with
hereditary breast cancer.6 They performed comprehensive sequencing of PALB2 from 1479
patients who were referred, nonconsecutively, to a large, reference laboratory for genetic testing
for hereditary breast and ovarian cancer syndrome (caused by a germline mutation in BRCA1 or
BRCA2). All patients tested negative for BRCA mutations, both by Sanger sequencing and for
large genomic rearrangements. The samples tested were stratified into 2 groups, based on the
clinical history provided on the test requisition form. The “high-risk” group (n=955) consisted of
samples from patients with breast cancer before age 50 years or male breast cancer at any age,
and a family history of 2 or more diagnoses of breast cancer before age 50 or ovarian cancer at
any age. The “lower-risk” group (n=524) consisted of samples from patients diagnosed with
breast cancer whose personal and family history information did not meet criteria for inclusion
into the high-risk group. Mutations identified by sequencing were classified as deleterious
(disease causing), variant of unknown significance, or a polymorphism. Deleterious mutations
were identified in 12 (0.81%) of 1479 patients. In the high-risk group, deleterious mutations
were identified in 10 patients (1.05%; 95% confidence interval [CI], 0.5% to 1.92%) and 2 in the
lower risk group (0.38%; 95% CI, 0.05% to 1.37%). The difference in prevalence between the 2
risk groups was not statistically significant (p=0.14). Fifty-seven (3.9%) PALB2 mutations of
uncertain significance were identified among the 1479 patients.
Casadei et al (2011) determined the prevalence of PALB2 mutations in 1144 familial breast
cancer patients with negative BRCA mutation testing.7 Thirty-three (2.9%) patients were found to
have PALB2 mutations. Compared with their female relatives without PALB2 mutations (not
population-base controls), the risk of breast cancer was increased 2.3-fold (95% CI, 1.5 to 4.2)
by age 55 and 3.4-fold (95% CI, 2.4 to 5.9) by age 85.
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Ding et al (2011) determined the frequency of pathogenic BRCA2 mutations, followed by
sequencing of the PALB2 gene in BRCA2-negative male breast cancer patients.8 BRCA2
mutations were identified in 18 of 115 patients; the difference in BRCA2 mutation frequencies
between cases with and without a family history of breast cancer was not statistically significant.
Of the 97 BRCA2-negative cases, 1 PALB2 mutation with confirmed pathogenicity and 1
mutation predicted to be pathogenic was identified, for a prevalence of pathogenic PALB2
mutations of 1% to 2%.
Stadler et al (2011) investigated the prevalence of PALB2 mutations in breast-pancreas cancer
families.9 Testing was performed in patients with either a personal history of both breast and
pancreatic cancer or a personal history of breast cancer and a family history of a first-degree
relative with pancreatic cancer. No PALB2 mutations were identified in 77 breast and pancreatic
cancer families, including 22 probands with a personal history of both breast and pancreatic
cancer.
Hofstatter et al (2011) studied whether PALB2 mutations were more prevalent in families with
both breast and pancreatic cancers.10 Eligible subjects were required to have a personal history of
breast cancer and negative testing for BRCA1 and BRCA2 mutations. Other eligibility criteria
included a family history of pancreatic cancer in first- or second-degree relatives or a personal
history of pancreatic cancer. Of the 94 patients tested, 2 deleterious mutations were identified,
for a prevalence of 2.1%.
Jones et al (2009) examined 96 patients with familial pancreatic cancer for germline PALB2
mutations.11 Protein-truncating PALB2 variants were identified in 3 patients (3.1%). Slater et al
(2010) evaluated probands from 81 European familial pancreatic cancer families and identified 3
protein-truncating PALB2 variants (3.7%).12
In patients with familial breast cancer, others have reported mutation prevalence within a similar
range.13 In addition, founder mutations have been identified (eg, among women of Finnish,14
French-Canadian,15 Polish,16 and Australian17 descent).
Assessing the Risk of Developing Breast Cancer in an Individual With a PALB2 Mutation
A number of studies have examined relative and absolute risks of breast cancer in women with
PALB2 mutations. All but 2 (Antoniou et al,18 Cybulski et al19) were limited by small numbers of
affected cases. Estimated risks varied according to specific mutations, age, and family histories.
A 2015 meta-analysis included 13 studies of protein-truncating variants where odds ratios (ORs)
were either reported or calculable.20 Relevant studies not included in that analysis are
summarized separately.
Erkko et al (2008) studied PALB2 mutations in 1918 Finnish women with breast cancer.14
Seventeen PALB2 c.1592delT probands were examined; 10 (mean age onset, 54.3 years) had a
family history of breast cancer and 7 did not (mean age onset, 59.3 years). The relative risk (RR)
of breast cancer conferred by the mutation was 14.3 (95% CI, 6.6% to 31.2%) but decreased with
increasing age. The estimated cumulative risk of breast cancer at age 70 years was 40% (95% CI,
17% to 77%). Although the small number of women with c.1592delT mutations resulted in
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substantial uncertainty in the point estimates, the results are consistent with at least moderate
penetrance.
Southey et al (2010) evaluated 1403 Australasian women with invasive breast cancer not
selected based on family history.17 From a model assuming Hardy-Weinberg equilibrium, a
dominant action of PALB2 c.3113 G > A, and other influences on breast cancer risk, 5
population-based mutation carrier families had a hazard ratio of 30.1 (95% CI, 7.5 to 120) for
developing breast cancer. The cumulative risk to age 50 was estimated at 49% (95% CI, 15% to
93%), and 91% (95% CI, 44% to 100%) by age 70. Although the estimates consistent increased
breast cancer risk, implications are limited by the large uncertainty as reflected in the confidence
intervals.
Antoniou et al (2014) studied the risk of breast cancer associated with inherited PALB2
mutations.18 The risk was analyzed among 362 members of 154 families who had deleterious
mutations in PALB2; those with nondeleterious variants or variants of uncertain pathogenicity
were excluded from the study. Families were identified through 14 research centers. Some
families were ascertained through clinics for patients at high risk for breast cancer and others
through screening of patients with breast cancer who were not selected on the basis of a positive
family history.
Pedigree likelihoods were constructed with pedigree-analysis software. The 154 families
included 311 women with PALB2 mutations, 229 of whom had breast cancer, and 51 men with
PALB2 mutations, 7 of whom had breast cancer. Among the 154 families, 48 different loss-offunction PALB2 mutations were identified—only 2 mutations were commonly identified
(c.1592del in 44 families, c.3113del in 25 families), with the remainder found in between 1 and 8
families. Carriers of a PALB2 mutation had a 9.47 relative risk of breast cancer (95% CI, 7.16 to
12.57) compared with the U.K. population under a single-gene model with age-constant constant
relative risk. The cumulative risk of breast cancer for female PALB2 mutation carriers by age 50
years was 14% (95% CI, 9% to 20%) and by 70 years, 35% (95% CI, 26% to 46%). The absolute
breast cancer risk for PALB2 female mutation carriers by age 70 years ranged from 33% (95%
CI, % to 44%) for those without a family history of breast cancer, to 58% (95% CI, 50% to 66%)
for those with a family history of breast cancer (defined as those with 2 first-degree relatives
with breast cancer at 50 years of age). The RR of ovarian cancer among PALB2 mutation carriers
was 2.3 (95% CI, 0.77 to 6.97; p=0.18). The RR of breast cancer for males with PALB2
mutations, compared with the male breast cancer incidence in the general population, was
estimated to be 8.3 (95% CI, 0.77 to 88.5; p=0.08).
The risk estimates in this study are higher than those reported in other studies, suggesting a
higher risk of breast cancer with a PALB2 mutation in an individual with a family history of
breast cancer. The authors suggested that, in certain populations, the breast cancer risk for
PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
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Additionally, Easton et al (2015) in a review of panel testing pooled RRs from 4 case-control and
family studies including Antoniou et al. Methods were not detailed but they estimated a PALB2
mutation to confer a RR of 5.3 (95% CI, 3.0 to 9.4).21
Thompson et al (2015) evaluated 1996 Australian women with breast cancer referred for genetic
evaluation and 1998 controls.22 Nineteen protein-truncating variants were identified—26 in cases
(1.3%) and 4 in controls (0.2%) with a relative odds for breast cancer of 6.58 (95% CI, 2.3 to
18.9). In addition, many missense variants identified were slightly more common in cases
(OR=1.15; 95% CI, 1.02 to 1.32).
Cybulski et al (2015) examined 2 loss-of-function PALB2 mutations (509_510delGA,
172_175delTTGT) in women with invasive breast cancer diagnosed between 1996 and 2012 in
Poland.19 From 12,529 women genotyped, a PALB2 mutation was identified in 116 (0.93%; 95%
CI, 0.76% to 1.09%) versus 10 of 4702 controls (0.21%; 95% CI, 0.08% to 0.34%) (OR for
breast cancer, 4.39; 95% CI, 2.30 to 8.37). In contrast, a BRCA1 mutation was identified in
3.47% of women with breast cancer and 0.47% of controls (OR=7.65; 95% CI, 4.98 to 11.75).
The authors estimated a PALB2 mutation conferred a 24% cumulative risk of breast cancer by
age 75 (in the a setting of age-adjusted breast cancer rates that are slightly over half that in the
United Kingdom23 or the United States [http://seer.cancer.gov/statfacts/html/breast.html]). A
PALB2 mutation was also associated with poorer prognosis—a 10-year survival of 48.0% versus
74.7% and a hazard ratio adjusted for prognostic factors of 2.27 (95% CI, 1.64 to 3.15) for death.
Finally, Aloraifi et al (2015) conducted a meta-analysis of studies reporting genotyped cases
along with controls in women with protein-truncating variants including those in PALB2.20
Studies of women with early-onset breast cancer (<50 years of age), presence of a family history,
or bilateral breast cancers were identified (PubMed search through June 1, 2014). Studies of
sporadic or male breast cancers were excluded. Thirteen studies of PALB2 protein-truncating
variants were included—5862 cases (91 with PALB2 variants) and 17,453 controls (9 with
PALB2 variants). Studies were conducted in a variety of ethnic groups. The authors reported a
pooled OR for breast cancer of 21.40 (95 CI, 10.10 to 45.32). However, in 9 studies, no controls
were identified with a variant or effectively “0 events” in the control group, contributing the
large magnitude of effect and wide confidence interval. Sensitivity analyses, of particular
relevance given the unstable estimates, were not reported. The estimate reported is also
substantially larger than that reported by either Antoniou18 or Cybulski.19
Section Summary: Clinical Validity
Estimated absolute and relative risk varied across studies, but the magnitudes are consistent with
increased breast cancer risk conferred by protein-truncating PALB2 variants. But given the low
prevalence of mutations, the overall number of women studied with protein-truncating PALB2
variants is not large—approximately 500 with breast cancer and 105 without. Only 2 studies
included over 40 women with breast cancer and PALB2 mutations. Additionally, with few
exceptions (eg, c.1592del, c.3113d) specific variants were uncommon. The magnitude of
increased risk for pancreatic cancer is unclear.
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Clinical Utility
Clinical utility refers to how the results of the diagnostic test will be used to change management
of the patient and whether these changes in management lead to clinically important
improvements in health outcomes.
Identifying a person with a mutation that confers a high risk of developing cancer could lead to
changes in clinical management and improved health outcomes. There are well-defined clinical
guidelines on the management of patients who are identified as having a high-risk hereditary
cancer syndrome. Changes in clinical management could include modifications in cancer
surveillance, specific risk-reducing measures (eg, prophylactic surgery), and treatment guidance
(eg, avoidance of certain exposures). In addition, other at-risk family members could be
identified.
The body of evidence is consistent with protein-truncating PALB2 variants conferring increased
absolute and relative risks for breast cancer. In some studies, the magnitudes of estimated risk
exceed those that could change management—eg, screening asymptomatic carriers (eg, with
lifetime risk >20%) with magnetic resonance imaging and clinical exam. However, the number
of additional women recommended to undergo screening based on PALB2 testing, over and
above based on family history alone, is unclear. Furthermore, PALB2 results have not been
incorporated into standard risk models. Whether the increased risk warrants considering risk
reduction mastectomy requires a high level of certainty; the existing body of evidence does not
yet provide that level of certainty. Furthermore, given that many mutations are rare, the basis for
determining pathogenicity (ie, whether the variant is protein-truncating) may be limited requiring
considerable genetic expertise.
Protein-truncation PALB2 variants appear to be responsible for some cases of familial pancreatic
cancers, but the proportion is uncertain. Whether screening asymptomatic high-risk patients can
improve health outcomes is unclear,24-26 a consensus recommendation from International Cancer
of the Pancreas Screening consortium concluded “PALB2 mutation carriers with one or more
affected FDR [first-degree relative] with PC [pancreatic cancer] should be screened (agree
77.5%, grade very low, ‘probably do it’).”
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in December 2015 did not identify any ongoing or unpublished
trials that would likely influence this review.
Summary of Evidence
The evidence for genetic testing for a protein-truncating PALB2 variant in individuals who have
a personal or family history of cancer and criteria suggesting risk of hereditary breast/ovarian
cancer syndrome includes studies of analytic validity, mutation prevalence, and multiple studies
of breast cancer risk, including 1 meta-analysis. Relevant outcomes are overall survival, diseasespecific survival, as well as test accuracy and validity. Reported accuracy of the test has been
high. Estimated absolute and relative risk for breast cancer varied across studies, but the
magnitudes are consistent with increases conferred by protein-truncating PALB2 variants. But
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given the low prevalence of variants, the overall number of women studied with proteintruncating PALB2 variants is not large. Additionally, with few exceptions, specific variants are
uncommon. Whether PALB2 testing would result in management changes that would not occur
based on family history alone is unclear. Whether the increased risk warrants considering riskreduction mastectomy requires a high level of certainty; the existing body of evidence does not
yet provide that level of certainty. The evidence is insufficient to determine the effects of the
technology on health outcomes.
The evidence for genetic testing for a protein-truncating PALB2 variant in individuals who have
a family history of pancreatic cancer includes studies of prevalence in patients with familial
pancreatic cancer. Relevant outcomes are overall survival, disease-specific survival, as well as
test accuracy and validity. Protein-truncating PALB2 variants appear responsible for some cases
of familial pancreatic cancers, but the proportion is unclear. Whether screening asymptomatic
high-risk patients can improve health outcomes is uncertain. The evidence is insufficient to
determine the effects of the technology on health outcomes.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate
with and make recommendations during this process, through the provision of appropriate
reviewers, input received does not represent an endorsement or position statement by the
physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 2 academic medical centers and 5 specialty
societies, for a total of 7 reviewers in 2014. The review was limited to input about whether
PALB2 testing to estimate risk of developing breast cancer should be medically necessary, and
whether testing results alter patient management. Reviewer input on both questions was mixed.
Practice Guidelines and Position Statements
American Society of Clinical Oncology
In a 2015 policy statement update on genetic and genomic testing for cancer susceptibility,27 the
American Society of Clinical Oncology stated that testing for high-penetrance mutations in
appropriate populations has clinical utility in that mutations inform clinical decision making and
facilitate the prevention or amelioration of adverse health outcomes. The update notes: “Clinical
utility remains the fundamental issue with respect to testing for mutations in moderate
penetrance genes. It is not yet clear whether the management of an individual patient or his or
her family should change based on the presence or absence of a mutation. There is insufficient
evidence at the present time to conclusively demonstrate the clinical utility of testing for
moderate-penetrance mutations, and no guidelines exist to assist oncology providers.”
National Comprehensive Cancer Network
National Comprehensive Cancer Network (NCCN) guideline on genetic/familial high-risk
assessment for breast and ovarian cancer (v.2.2015)28 recommends breast magnetic resonance
imaging screening when a pathogenic PALB2 mutation is detected based on the cumulative
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lifetime breast cancer risk. Evidence was judged insufficient to support risk-reduction
mastectomy or risk-reduction salpingo-oophorectomy in women with identified pathogenic
PALB2 mutations.
NCCN guidelines for pancreatic cancer do not address the use of testing for PALB2 mutations.
International Cancer of the Pancreas Screening Consortium
A multidisciplinary consortium, the International Cancer of the Pancreas Screening Consortium,
met to discuss pancreatic screening and vote on statements. Consensus was considered reached if
75% or more agreed or disagreed. There was excellent agreement that, to be successful, a
screening program should detect and treat T1N0M0 margin-negative pancreatic cancers and
high-grade dysplastic precursor lesions. It was agreed that the following were candidates for
screening: first-degree relatives of patients with pancreatic cancer from a familial pancreatic
cancer kindred with at least 2 affected first-degree relatives; patients with Peutz-Jeghers
syndrome; and p16, BRCA2, PALB2, and hereditary nonpolyposis colorectal cancer mutation
carriers with 1 or more affected first-degree relative.29
U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for PALB2 mutation testing have
been identified.
Medicare National Coverage
There is no national coverage determination (NCD).
V. DEFINITIONS
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NA
VI. BENEFIT VARIATIONS
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The existence of this medical policy does not mean that this service is a covered benefit under
the member's contract. Benefit determinations should be based in all cases on the applicable
contract language. Medical policies do not constitute a description of benefits. A member’s
individual or group customer benefits govern which services are covered, which are excluded,
and which are subject to benefit limits and which require preauthorization. Members and
providers should consult the member’s benefit information or contact Capital for benefit
information.
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VII. DISCLAIMER
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Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute medical
advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of
members. Members should discuss any medical policy related to their coverage or condition with their provider
and consult their benefit information to determine if the service is covered. If there is a discrepancy between this
medical policy and a member’s benefit information, the benefit information will govern. Capital considers the
information contained in this medical policy to be proprietary and it may only be disseminated as permitted by
law.
VIII. CODING INFORMATION
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Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The
identification of a code in this section does not denote coverage as coverage is determined by the
terms of member benefit information. In addition, not all covered services are eligible for separate
reimbursement.
Investigational therefore not covered:
CPT Codes®
81406
Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.
IX. REFERENCES
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1. Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes.
Biomed Res Int. 2013;2013:747318. PMID 23586058
2. Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J. Jul-Aug
2012;18(4):310-319. PMID 22846731
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X. POLICY HISTORY
MP 2.279
TOP
CAC 6-2-15 New policy adopting BCBSA. PALB2 genetic testing is
investigational.
CAC 5/31/16 Consensus review. Policy statement unchanged. Policy
Guidelines and Appendix added. Description/Background, Rationale and
References updated. Coding reviewed.
Administrative Update 11/22/16 -Variation reformatting 10/21/16.
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Appendix
Appendix Table 1. Categories of Genetic Testing Addressed in MP-2.279
Category
1. Testing of an affected individual's germline to benefit the individual
1a. Diagnostic
1b. Prognostic
1c. Therapeutic
2. Testing cancer cells from an affected individual to benefit the individual
2a. Diagnostic
2b. Prognostic
2c. Therapeutic
3. Testing an asymptomatic individual to determine future risk of disease
4. Testing of an affected individual's germline to benefit family members
5. Reproductive testing
5a. Carrier testing: preconception
5b. Carrier testing: prenatal
5c. In utero testing: aneuploidy
5d. In utero testing: mutations
5e. In utero testing: other
5f. Preimplantation testing with in vitro fertilization
Addressed
X
TOP
Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance
Company®, Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the BlueCross
BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider
relations for all companies.
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