Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53)

POLICY NUMBER

A.2.04.148

DESCRIPTION

Pancreatic cancer is the fourth leading cause of cancer death in the United States, accounting for 8.3% of all cancer deaths in 2023. Multiple genetic syndromes are associated with an increased risk for pancreatic cancer, and approximately 10% to 15% of patients with pancreatic cancer are thought to have a hereditary susceptibility to the disease. Germline genetic testing for pancreatic cancer susceptibility genes is proposed to guide treatment decisions in patients with pancreatic cancer, and to inform decisions about surveillance in asymptomatic patients at high risk of pancreatic cancer.

Pancreatic Cancer Epidemiology

Pancreatic cancer is the fourth leading cause of cancer death in the U.S., accounting for 8.5% of all cancer deaths in 2024. The disease has a poor prognosis, with only 12.8% of patients surviving to 5 years. Five-year survival for localized pancreatic cancer is 44.0%, but most symptomatic patients have advanced, incurable disease at diagnosis.

Genetics and Pancreatic Cancer

Approximately 10% to 15% of patients with pancreatic cancer are thought to have a hereditary susceptibility to the disease. Multiple genetic syndromes, including hereditary breast and ovarian cancer syndrome, are associated with an increased risk for pancreatic cancer. Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline BRCA or PALB2 variant, with higher rates observed in those with a family or personal history of pancreatic cancer or other BRCA-related malignancies. The incidence of germline PALB2 variants in persons with PDAC is estimated to be between 0.6% and 2.1%.

Having a first-degree relative with pancreatic cancer increases an individual's risk of developing pancreatic cancer, and the degree of risk increases depending on the number of affected relatives. Individuals are considered at high-risk for hereditary pancreatic cancer if they have 2 relatives with pancreatic cancer where 1 is a first-degree relative, have 3 or more relatives with pancreatic cancer or have a history of hereditary pancreatitis. In 80% of pancreatic cancer patients with a family history of pancreatic cancer, the genetic basis of the inherited predisposition is unknown.

Family History and Pancreatic Cancer Risk https://seer.cancer.gov/statfacts/html/pancreas.html

Germline genetic testing for pancreatic cancer susceptibility genes has several proposed purposes. In patients with pancreatic cancer, the purpose of genetic testing would be to guide treatment decisions (e.g., selection of platinum-based chemotherapy for first-line treatment, targeted treatment with a poly ADP ribose polymerase [PARP] inhibitor). In asymptomatic patients at high risk of pancreatic cancer (e.g., due to family history or other clinical factors), the purpose of genetic testing would be to inform decisions about surveillance for early detection of pancreatic cancer. Because the incidence of pancreatic cancer in the general population is low, with a lifetime risk of approximately 1.6%, screening is not recommended for patients who are not at high-risk, but patients with a family history of pancreatic cancer or a syndrome associated with increased risk of pancreatic cancer are potential targets for surveillance.

Testing for variants associated with pancreatic cancer is typically done by direct sequence analysis or next-generation sequencing. A number of laboratories offer to test for the relevant genes, either individually or as panels.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

In December 2019, the FDA approved olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Also in 2019, BRACAnalysis CDx received expanded FDA approval for use as a companion diagnostic for Lynparza (olaparib) in pancreatic cancer patients.

Related medical policies –

• Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA1, PALB2)

• Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

• Genetic Testing for Li-Fraumeni Syndrome

• Germline Genetic Testing for Gene Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1)

• Germline Genetic Testing for Familial Cutaneous Malignant Melanoma (CDKN2A, CDK4)

• Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

POLICY

Genetic testing for BRCA1,BRCA2, and PALB2 variants to guide selection for treatment with platinum-based chemotherapy in previously untreated individuals with locally advanced or metastatic pancreatic cancer may be considered medically necessary.

Genetic testing for BRCA1 and BRCA2 variants to guide selection for treatment with olaparib (Lynparza) in individuals with pancreatic cancer may be considered medically necessary.

Genetic testing for ATM, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 in individuals with pancreatic cancer is considered investigational unless the individual meets criteria for testing as specified in another policy (see Policy Guidelines).

Genetic testing for ATM, BRCA1, BRCA2, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), PALB2, STK11, and TP53 in asymptomatic individuals at high risk for hereditary pancreatic cancer is considered investigational unless the individual meets criteria for testing as specified in another policy (see Policy Guidelines).

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Related Policies on Hereditary Cancer Syndromes

• Genetic testing for BRCA1 and BRCA2 variants

  • Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)

• Genetic testing for ATM and PALB2 gene variants

  • Germline Genetic Testing for Gene Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1)

• Genetic testing for EPCAM, MMR (MLH1, MSH2, MSH6, PMS2), and STK11 gene variants

  • Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

• Genetic testing for CDKN2A gene variants

  • Germline Genetic Testing for Familial Cutaneous Malignant Melanoma (CDKN2A, CDK4)

• Genetic testing for TP53 gene variants

  • Genetic Testing for Li-Fraumeni Syndrome

• Genetic cancer susceptibility panel testing

  • Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

Testing At-Risk Relatives

Individuals are considered at high risk for hereditary pancreatic cancer if they have:

• 2 close relatives with pancreatic adenocarcinoma where one is a first-degree relative, OR

• have three or more close relatives with pancreatic cancer, OR

• have a history of hereditary pancreatitis.

For familial assessment, 1st-, 2nd-, and 3rd-degree relatives are blood relatives on the same side of the family (maternal or paternal).

• 1st-degree relatives are parents, siblings, and children.

• 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.

• 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins.

At-risk relatives primarily refer to first-degree relatives. However, some judgment must be permitted, e.g., in the case of a small family pedigree, when extended family members may need to be included in the testing strategy.

Targeted Variant Testing

It is recommended that, when possible, initial genetic testing for variants associated with hereditary pancreatic cancer be performed in an affected family member so that testing in unaffected family members can focus on the pathogenic variant found in the affected family member. In unaffected family members of potential hereditary pancreatic cancer 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 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.

Genetic Counseling

Experts recommend formal genetic counseling for individuals who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

1. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

2. appropriate with regard to standards of good medical practice; and

3. not solely for the convenience of the Member, his or her Provider; and

4. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

01/01/2021: New policy added. Approved by Medical Policy Advisory Committee (MPAC).

05/01/2022: Policy title changed from "Genetic Testing for Hereditary Pancreatic Cancer" to "Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes." Policy description updated regarding genetics and pancreatic cancer. Genetic testing for PALB2 removed from first investigational statement regarding testing for patients with pancreatic cancer. First medically necessary statement revised to state: Genetic testing for BRCA1, BRCA2, and PALB2 variants to guide selection for treatment with platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic pancreatic cancer may be considered medically necessary. Added statement that genetic testing for BRCA1 and BRCA2 variants to guide selection for treatment with olaparib (Lynparza) in patients with pancreatic cancer may be considered medically necessary. Code Reference section updated to add CPT codes 81307 and 81308 to the medically necessary codes table.

12/21/2022: Code Reference section updated to revise the description for CPT codes 81445 and 81455, effective 01/01/2023.

03/14/2023: Policy title changed from "Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes" to "Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53)." Policy reviewed. Policy statements and Policy Guidelines updated with minor wording changes.

07/26/2023: Policy description and Policy Guidelines revised to update related medical policies.

12/21/2023: Code Reference section updated to revise the code descriptions for CPT codes 81445 and 81455, effective 01/01/2024.

03/18/2024: Policy description updated regarding new data for pancreatic cancer. Policy statements unchanged. Policy Guidelines updated.

12/31/2024: Code Reference section updated to revise description for CPT codes 81432 and 81435 effective 01/01/2025.

04/09/2025: Policy description updated regarding new data for pancreatic cancer. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.148

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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