Medical Policy

 

Subject: Combined PALB2 and BRCA2 Mutation Testing for Oncologic Indications
Document #: GENE.00027 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description/Scope

This document addresses combined PALB2 and BRCA mutation testing for assessing an individual’s risk of developing cancer.

Note: For information on genetic testing for BRCA 2 mutations, see:

Position Statement

Investigational and Not Medically Necessary:

Combined PALB2 and BRCA2  mutation testing is considered investigational and not medically necessary for oncologic indications, including familial pancreatic cancer.

Rationale

Pancreatic cancer has a high mortality rate because the majority of cases are not diagnosed until the cancer has metastasized to distal areas of the body. Approximately 95% of pancreatic cancers occur sporadically. Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer. Several genes have been implicated in hereditary pancreatic cancer, including the familial breast-ovarian cancer gene BRCA2 and, more recently, its partner gene PALB2. The most commonly mutated gene is BRCA2, whose protein product is a binding partner for another tumor suppressor gene product, the PALB2 (partner and localizer of BRCA2) gene. The PALB2 protein stabilizes the BRCA2 protein and anchors it to structures within the nucleus allowing the BRCA2 protein to repair DNA breaks which may occur prior to cell division or be induced by radiation and other environmental exposures.

The Panexia™ test involves genetic sequence analysis of the coding regions and portions of the non-coding regions of the BRCA2 and PALB2 genes. The Panexia™ test is performed by Myriad Genetic Laboratories which is certified under the federal Clinical Laboratory Improvement Amendments (CLIA) of 1988. According to information on the Myriad Genetic Laboratories’ web site, the technical specifications for the Panexia™ test indicate that both the analytical specificity and sensitivity are greater than 99%. However, there were no published studies identified which provided verification of this data. Also, there was no information regarding the clinical specificity or sensitivity found in the published literature. For this reason, it is unclear which individuals with suspected FPC will have a positive test result (a mutation in both BRCA2 and PALB2 genes). In addition, studies could not be found which demonstrated the clinical utility (for example, the survival outcome benefit) of combined BRCA2 and PALB2 gene testing.

Although published studies of the Panexia™ test were not found, recent studies have reported on the prevalence of BRCA2 and PALB2 genetic mutations in select at-risk populations. To gain more insight into the role of BRCA2 mutations in FPC, Hahn and colleagues (2003) analyzed the frequency of BRCA2 germline mutations in 26 European families in which at least two first-degree relatives were diagnosed with histologically confirmed pancreatic ductal adenocarcinoma. The researchers used two sources to identify families with FPC: the German National Case Collection for Familial Pancreatic Carcinoma of the German Cancer Foundation and the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. A total of 5 (19%) of the families in the study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in the study met the criteria for familial breast or ovarian cancer. The researchers concluded that BRCA2 germ line mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least 2 first-degree relatives affected with ductal adenocarcinoma of the pancreas.

Ferrone and colleagues (2009) evaluated the prevalence of BRCA1 and BRCA2 mutations in an unselected group of Jewish participants and compared subjects with resected BRCA mutation-associated pancreatic adenocarcinoma to pancreatic adenocarcinoma participants without mutations. Of the 187 Jewish subjects who underwent resection for pancreatic adenocarcinoma, tissue was available for 145 of the participants. Founder mutations for BRCA1 and BRCA2 were identified in 5.5% of subjects (2 with BRCA1 [1.3%] and 6 with BRCA2 [4.1%]). A previous cancer was reported in 24% (35 of 145) of the participants with the most common sites being breast and prostate cancer (9 of 35; 74% and 8 of 35; 23%, respectively). The authors concluded that BRCA2 mutations are associated with an increased risk of pancreatic adenocarcinoma.

Jones and colleagues (2009) conducted an analysis of 96 individuals with FPC. Three (3.1%) distinct truncating mutations in the PALB2 gene were identified by exomic sequencing. Some, but not all, of the participants with the PALB2 mutation had an associated history of breast cancer. The authors concluded that complete sequencing of protein-coding genes may lead to the identification of a gene responsible for a hereditary disease.

In another study, Slater and colleagues (2010) used the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) and the German National Case Collection for Familial Pancreatic Cancer to evaluate whether truncating PALB2 mutations could also be detected in European families with a history of FPC. The researchers directly sequenced the 13 exons of the PALB2 gene in affected index cases of 81 families with a history of FPC. An index case was defined as the first medically identified individual, stimulating investigation of other members of the family to discover a possible genetic factor. None of these subjects carried a BRCA2 mutation, but the researchers did identify three (3.7%) truncating PALB2 mutations which were associated with three families with a positive history of breast cancer. The authors concluded that PALB2 mutations might be the cause of FPC in a small subset of European families, especially those with an additional occurrence of breast cancer.

Schneider and colleagues (2011) reported the 10-year experience of a national FPC registry (FaPaCa) in Germany. Since 1999, the FaPaCa has collected data on families with at least 2 first-degree relatives with confirmed pancreatic cancer, who did not fulfill the criteria of other hereditary tumor syndromes. Histopathological verification of tumor diagnoses and genetic counseling were prerequisites for enrollment in the study. Ninety-four of the 452 families evaluated fulfilled the criteria for participation in the study. Pancreatic cancer represented the sole tumor entity in 38 (40%) families. Additional tumor types occurred in 56 families, including breast cancer (n=28), colon cancer (n=20) and lung cancer (n=11). In 70 (74%) families, the pattern of inheritance was consistent with an autosomal dominant trait. Mutation analyses of BRCA2, PALB2, CDKN2a, RNASEL, STK11, NOD2, CHEK2 and PALLD, revealed deleterious causative germline mutations of BRCA2 and PALB2 in 2 of 70 (3%) and 2 of 41 (4.9%) German FPC families, respectively. Prospective pancreatic cancer screening with endoscopic ultrasound (EUS), MRI and MRCP detected precancerous lesions in 5.5%-12.5% of individuals at risk, depending on histological verification.

Harinck and colleagues (2012) studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 FPC families and in non-BRCA1/2 familial breast cancer families with at least one pancreatic cancer case. Mutation analysis was carried out using direct sequencing and multiplex ligation-dependent probe amplification and was performed on a total of 64 participants from 56 distinct families (28 FPC families, 28 familial breast cancer families). In total, 31 subjects (48%) originated from FPC families; 24 were FPC participants (77%), 6 had a personal history of breast cancer (19%) and 1 was a suspected carrier (3.2%). The remaining 33 participants (52%) were all females with breast cancer of whom 31 (94%) had a family history of pancreatic cancer and 2 (6.1%) had a personal history of pancreatic cancer. The PALB2 mutation was not found in any of the 64 subjects. The authors concluded that PALB2 does not have a major causal role in familial clustering of pancreatic cancer and breast cancer in non-BRCA1/2 families in the Dutch population.

While  National Cancer Institute has concluded that additional data are needed to define the best candidates for PALB2 gene mutation testing and the National Comprehensive Cancer Network® (NCCN) has recommended that MRI breast screening be carried out in women with PALB2 mutation, neither organization has recommended that both the PALB2 and BRCA2 genes be assessed in order to determine an individual’s risk of developing cancer (NCCN, 2016; NCI, 2016).

In summary, there is insufficient evidence in the published literature to draw conclusions regarding the clinical utility of combined BRCA2 and PALB2 gene testing.

Background/Overview

According to the American Cancer Society, there will be approximately 53,670 new cases of pancreatic cancer in the United States in 2016. An estimated 43,090 deaths are expected to occur as a result of pancreatic cancer. Pancreatic cancer is more common in men than in women. Pancreatic cancer accounts for approximately 3% of all cancers in the United States (ACS, 2017).

Pancreatic cancer often develops without early symptoms. Fewer than 20% of individuals diagnosed with pancreatic cancer are candidates for surgery because pancreatic cancer is usually detected after the disease has metastasized beyond the pancreas. For all stages combined, the 1- and 5-year survival rates for pancreatic cancer are 26% and 6%, respectively. Individuals diagnosed with local disease have a 5-year survival rate of 22%. More than half of individuals are diagnosed at a distant stage, for which 5-year survival rate is 2%.

Most pancreatic cancers (approximately 95%) are considered sporadic. Familial (genetic) pancreatic cancer accounts for approximately 3% of all pancreatic cancer (Langer et al, 2009). The PALB2 gene provides instructions for making a partner protein for the BRCA2 gene product. PALB2 interacts with the protein produced from the BRCA2 gene to repair broken strands of DNA, which prevents cells from accumulating genetic damage that can trigger them to divide uncontrollably. By helping repair mistakes in DNA, the PALB2 and BRCA2 proteins play a critical role in maintaining cellular stability. Mutations in the tumor suppressor genes, PALB2 and BRCA2, are autosomal dominant traits. A mutation in either of these genes may increase the risk of malignant transformation and cancer.

Panexia is an example of at least one commercially available test which assesses the combined PALB2 and BRCA mutation status.  Panexia is conducted in the CLIA certified Myriad Genetic Laboratories.

Definitions

Adenocarcinoma: A type of cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties.

Genetic testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes.

Mutation: A change in DNA sequence.

PALB2 (Partner and Localizer gene of the BRCA2 gene): A gene that makes a protein that interacts with BRCA2 protein and is involved in DNA repair.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:

CPT

 

81479

Unlisted molecular pathology procedure [when specified as Panexia test]

ICD-10 Diagnosis

 

 

All diagnoses

When services are also Investigational and Not Medically Necessary:

CPT

 

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer), full gene sequence

ICD-10 Diagnosis

 

 

All malignant neoplasm diagnoses including, but not limited to, the following:

C25.0-C25.9

Malignant neoplasm of pancreas

C50.011-C50.929

Malignant neoplasm of breast

C56.1-C56.9

Malignant neoplasm of ovary

Z80.0

Family history of malignant neoplasm of digestive organs [pancreas]

Z80.3

Family history of malignant neoplasm of breast

Z80.41

Family history of malignant neoplasm of ovary

Z85.07

Personal history of malignant neoplasm of pancreas

Z85.3

Personal history of malignant neoplasm of breast

Z85.43

Personal history of malignant neoplasm of ovary

References

Peer Reviewed Publications:

  1. Antoniou AC, Foulkes WD, Tischkowitz M. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014; 371(17):1651-1652.
  2. Ferrone CR, Levine DA, Tang LH, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol. 2009; 27(3):433-438.
  3. Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003 Feb 5; 95(3):214-221.
  4. Harinck F, Kluijt I, van Mil SE et al. Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated. Eur J Hum Genet. 2012; 20(5):577-579.
  5. Jones S. Hruban RH. Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009; 324(5924):217.
  6. Langer P, Kann PH, Fendrich V, et al. Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer. Gut. 2009; 58(10):1410-1418.
  7. Poley JW, Kluijt I, Gouma DJ, et al. The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer. Am J Gastroenterol. 2009; 104(9):2175-2181.
  8. Schneider R, Slater EP, Sina M, et al. German national case collection for familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer. 2011; 10(2):323-330.
  9. Slater EP, Langer P, Niemczyk E, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010; 78(5):490-494.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. National Cancer Institute: Genetics of Breast and Gynecologic Cancers (PDQ®) – Health Professional Version. Bethesda, MD: National Cancer Institute. Updated August 24, 2016. Available at: https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq/. Accessed on September 12, 2017.
  2. NCCN Clinical Practice Guidelines in Oncology™ (NCCN). © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on August 31, 2016.
  1. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol. 2015; 33(31):3660-3667.
Websites for Additional Information
  1. American Cancer Society. Key statistics for pancreatic cancer. Last revised January 6, 2017. Available at: http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics. Accessed on September 12, 2017.
  2. Genetics Home Reference. PALB2. Published September 12, 2017. Available at: http://ghr.nlm.nih.gov/gene/PALB2. Accessed on September 12, 2017.
  3. Panexia™ Technical Specifications. Myriad Genetic Laboratories, Inc. Updated August 2012. Available at: http://d1izdzz43r5o67.cloudfront.net/technical-specifications/Tech+Specs+Panexia+August_2012_FINAL.pdf. Accessed on September 12, 2017.
Index

BRCA2
PALB2
Pancreatic cancer
Panexia™ test

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Background/Overview, References, Websites for Additional Information and History sections.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Title changed to “Combined PALB2 and BRCA2 Mutation Testing for Oncologic Indications”. Position Statement revised to indicate “Combined PALB2 and BRCA2 mutation testing is considered investigational and not medically necessary for oncologic indications, including familial pancreatic cancer”. Updated Description, Background/Overview, Rationale, References, Websites for Additional Information and History sections.

Reviewed

11/05/2015

MPTAC review.

Reviewed

11/04/2015

Hematology/Oncology Subcommittee review. Updated Description, Background/Overview, Rationale, References, and History sections. Removed ICD-9 codes from Coding section.

Reviewed

11/13/2014

MPTAC review.

Reviewed

11/12/2014

Hematology/Oncology Subcommittee review. Updated References, Background/Overview and History sections.

Reviewed

11/14/2013

MPTAC review.

Reviewed

11/13/2013

Hematology/Oncology Subcommittee review. Updated Background/Overview, References and History sections.

New

11/08/2012

MPTAC review.

New

11/07/2012

Hematology/Oncology Subcommittee review. Initial document development.