Medical Policy

Policy Num:       11.003.107
Policy Name:     Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53)
Policy ID:           [11.003.107]  [Ac / B / M +/ P+]  [2.04.148]

Last Review:        March 03, 2025
Next Review:        March 20, 2026

Related Policies:

11.003.030- Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers
11.003.028- Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.003.022- Genetic Testing for Li-Fraumeni Syndrome
11.003.027- Moderate Penetrance Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk
11.003.036- Genetic Testing for Familial Cutaneous Malignant Melanoma
11.003.019- Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
11.003.059- Genetic Testing for Hereditary Pancreatitis

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

Summary

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.

Summary of Evidence

For individuals who have pancreatic cancer who receive testing for a BRCA1, BRCA2, or PALB2 variant to guide selection for first-line treatment, the evidence includes observational studies. Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1, BRCA2, and PALB2 variants, including among those who do not have a family history of pancreatic cancer. Observational studies have reported a survival advantage when patients with a BRCA or PALB2 variant were treated with platinum-based chemotherapy regimens compared to non-platinum-based regimens. Although these studies are limited by their small sample sizes and retrospective designs, the consistency and magnitude of benefit across studies suggests that genetic testing for these variants to aid in treatments decisions is a reasonable approach. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have pancreatic cancer who receive testing for a BRCA1 or BRCA2 variant to guide selection for targeted treatment, the evidence includes observational studies and 1 randomized controlled trial. Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1 or BRCA2 variants, including among those who do not have a family history of pancreatic cancer. A placebo-controlled trial of olaparib as maintenance therapy in patients with germline BRCA1 or BRCA2 variants and metastatic pancreatic cancer found longer progression-free survival with olaparib (7.4 months vs. 3.8 months; hazard ratio, 0.53; 95% confidence interval 0.35 to 0.82; p=.04 ). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with pancreatic cancer who receive genetic testing for ATM, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 to guide treatment, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with disease-associated variants, including among those who do not have a family history of the disease. However, there is no direct evidence comparing health outcomes in patients tested or not tested for a variant. Additionally, there are no targeted treatments for pancreatic cancer based on these genes, and management changes that would result from testing these genes are unclear. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic and at high risk for hereditary pancreatic cancer who receive testing for genes associated with hereditary pancreatic cancer, the evidence includes observational studies. There is no direct evidence comparing health outcomes in patients tested or not tested for a variant. There is indirect evidence from 2 comparative observational studies of high-risk individuals under surveillance that the risk of progression to pancreatic cancer is higher among individuals with a known pathogenic variant than in individuals identified as at-risk based on family history alone. There is also evidence from prospective observational studies that surveillance of high-risk individuals can identify pancreatic cancer and precursor lesions. In 1 analysis of 76 high-risk individuals under surveillance, survival was better in those who had surgery due to detection of either low- or high-risk neoplastic precursor lesions (n=71) compared to those who had advanced to unresectable disease (n=5). Although observational studies have demonstrated that surveillance can identify pancreatic cancer and precursor lesions in asymptomatic individuals, it is not possible to conclude from this body of evidence that surveillance improves survival. Longer survival time observed in individuals undergoing surveillance could be due to earlier identification of the disease (downstaging) and not the effects of early intervention and treatment. Additionally, evidence is too limited to determine if selecting patients for surveillance based on genetic testing leads to better outcomes than using criteria such as family history alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable

Objective

The objective of this evidence review is to evaluate the clinical validity and clinical utility of genetic testing of individuals with or at high-risk for hereditary pancreatic cancer and to determine if its use improves the net health outcome.

Policy Statements

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 Guidelines

Related Policies on Hereditary Cancer Syndromes

• Genetic testing for BRCA1 and BRCA2 variants

  • 2.04.02 Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers

• Genetic testing for ATM and PALB2 gene variants

  • Policy 2.04.126 Moderate Penetrance Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk

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

  • Policy 2.04.08 Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

• Genetic testing for CDKN2A gene variants

  • Policy 2.04.044 Genetic Testing for Familial Cutaneous Malignant Melanoma

• Genetic testing for TP53 gene variants

  • 2.04.101 Genetic Testing for Li-Fraumeni Syndrome

• Genetic cancer susceptibility panel testing

  • Policy 2.04.93 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 1 is a first-degree relative, OR

• have 3 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 individuals ; 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.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Pancreatic Cancer Epidemiology

Pancreatic cancer is the fourth leading cause of cancer death in the U.S., accounting for 8.3%8.5% of all cancer deaths in 20232024.^1, The disease has a poor prognosis, with only 12.5%12.8% of patients surviving to 5 years. Five-year survival for localized pancreatic cancer is 41.6%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.^2, 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.^3, The incidence of germline PALB2 variants in persons with PDAC is estimated to be between 0.6% and 2.1%.^4,

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 (Table 1).^5, 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.^6,

Table 1. Family History and Pancreatic Cancer Risk

 Sources: American Society of Clinical Oncology; 2, American College of Gastroenterology 7, FDR: first-degree relative.

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.

Regulatory Status

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.^8,

Rationale

This evidence review was created in February 2020 and was updated with a search of the PubMed database. The most recent literature update was performed through December 23, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition. The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Genetic Testing for a BRCA1, BRCA2, or PALB2 Variant to Select First-Line Treatment

Clinical Context and Test Purpose

The purpose of genetic testing for a BRCA1, BRCA2, or PALB2 variant in individuals with pancreatic cancer is to identify individuals who might benefit from a platinum-containing chemotherapy regimen.

The following PICO was used to select literature to inform this review.

Population

The relevant population of interest is individuals with previously untreated, locally advanced or metastatic pancreatic cancer.

Interventions

The test being considered is genetic testing for a BRCA1, BRCA2, or PALB2 variant.

Comparators

Alternatives to genetic testing would be treatment as usual without genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be improvements in overall survival (OS) and disease-specific survival in individuals with pancreatic cancer.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary clinical management changes or unnecessary cascade testing for other cancers. False-negative test results can lead to the absence of clinical management changes.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that reported on the sensitivity and specificity and/or diagnostic yield of the test were considered, including curated sources of information on genes associated with increased risk of pancreatic cancer (eg, summaries from professional societies).

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1, BRCA2, and PALB2 variants.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Several retrospective observational studies and an uncontrolled subgroup analysis from a randomized controlled trial of veliparib have reported a survival advantage for pancreatic cancer patients with BRCA or PALB2 pathogenic variants who received platinum-containing chemotherapy (Tables 2 and 3).

Golan et al (2014) analyzed survival data and clinical characteristics from databases of pancreatic cancer patients treated at 3 institutions between 1994 and 2012, including 71 patients with BRCA1 or BRCA2 variants.^9, Longer median overall survival was observed in patients with BRCA variants who received platinum-based chemotherapy compared to those who received non-platinum-based chemotherapies (22 months [range, 6 to 27] vs. 9 months [range, 4 to 12]; p=.039 ).

Three retrospective cohort studies used similar methods to compare survival outcomes in patients with or without BRCA or PALB2 variants who were treated with platinum-based chemotherapy.^10,11,4, In these studies, patients with a pathogenic variant were matched to control patients on prognostic factors such as age at diagnosis, sex, and stage of disease. All of these studies reported a survival advantage when variant-positive patients were treated with platinum versus non-platinum-based regimens, while there was no advantage for platinum-based therapy in patients who did not harbor a BRCA or PALB2 variant (See Table 3).

Limitations of these studies are summarized in Tables 4 and 5. Major limitations include the studies' small sample sizes and retrospective designs. The timing of genetic testing varied within the patient cohorts (e.g. some patients were tested before and others after their pancreatic cancer diagnosis). It is possible that patients who survived their pancreatic ductal adenocarcinoma (PDAC) diagnosis longer were more likely to undergo genetic testing. Because many control patients were not tested, some may have been variant-positive. However, this is less of a concern because this would have biased results toward the null. There was also heterogeneity in the timing and type of chemotherapy regimens patients received. Although the studies attempted to control for confounding by matching patients on important prognostic factors or using statistical analysis methods, the potential for unmeasured confounding decreases confidence in the results. Despite these limitations, consistency in the magnitude and direction of results across studies suggest that a strategy of testing for these variants to aid in decision-making about first-line treatment is a reasonable approach.

O'Reilly et al (2020) conducted a randomized controlled trial (RCT) of platinum-based chemotherapy with or without the poly ADP ribose polymerase (PARP) inhibitor veliparib in patients with previously untreated, locally advanced or metastatic pancreatic cancer and a BRCA or PALB2 germline variant. Two-year OS rate for the entire cohort was 30.6% (95% confidence interval [CI], 17.8% to 44.4%), and 3-year OS rate for the entire cohort was 17.8% (95% CI, 8.1% to 30.7%).Overall survival did not differ significantly when veliparib was added to the platinum-based regimen. The trial was not designed to compare platinum-based versus standard chemotherapy, but it does provide uncontrolled evidence of the effectiveness of platinum-containing chemotherapy in patients with germline pathogenic BRCA or PALB2 variants. The major limitation of this analysis was the lack of a control group of patients who did not receive platinum-based chemotherapy.

Table 2. Platinum-based Chemotherapy for Pancreatic Cancer Treatment in Patients with a BRCA1, BRCA2, or PALB2 Variant: Study Characteristics

 FOLFIRINOX: folinic acid, fluorouracil, irinotecan and oxaliplatin; FOLFOX: folinic acid, fluorouracil and oxaliplatin, or cisplatin/gemcitabine; PDAC: pancreatic ductal adenocarcinoma; RCT: randomized controlled trial. 

Table 3. Platinum-based Chemotherapy for Pancreatic Cancer Treatment in Patients with a BRCA1, BRCA2, or PALB2 Variant: Study Results

 CI: confidence interval; HR: hazard ratio; OS: overall survival.

Table 4. Study Relevance Limitations

 The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations

 The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There is no direct evidence from RCTs of the clinical utility of germline testing for BRCA or PALB2 variants in patients with pancreatic cancer.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The consistency and magnitude of benefit across studies suggests that genetic testing for these variants to aid in treatments decisions is a reasonable approach.

Section Summary: Genetic Testing for a BRCA1, BRCA2, or PALB2 Variant to Select First-Line Treatment

Retrospective cohort studies and an uncontrolled analysis from a randomized controlled trial have reported a survival advantage when patients with a BRCA or PALB2 variant were treated with platinum-based chemotherapy regimens compared to non-platinum-based regimens. Although these studies are limited by their small sample sizes and retrospective designs, the consistency and magnitude of benefit across studies suggests that genetic testing for these variants to aid in treatments decisions is a reasonable approach.

For individuals who have pancreatic cancer who receive testing for a BRCA1, BRCA2, or PALB2 variant to guide selection for first-line treatment, the evidence includes observational studies. Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1, BRCA2, and PALB2 variants, including among those who do not have a family history of pancreatic cancer. Observational studies have reported a survival advantage when patients with a BRCA or PALB2 variant were treated with platinum-based chemotherapy regimens compared to non-platinum-based regimens. Although these studies are limited by their small sample sizes and retrospective designs, the consistency and magnitude of benefit across studies suggests that genetic testing for these variants to aid in treatments decisions is a reasonable approach. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Genetic Testing for a BRCA1 or BRCA2 Variant to Select Targeted Treatment

Clinical Context and Test Purpose

The purpose of genetic testing for a BRCA1 or BRCA2 variant in individuals with pancreatic cancer is to guide selection of targeted treatment for pancreatic cancer.

The following PICO was used to select literature to inform this review.

Population

The relevant population of interest is individuals with metastatic or recurrent pancreatic cancer.

Interventions

The test being considered is genetic testing for a BRCA1 or BRCA2 variant to select targeted treatment with PARP inhibitors such as olaparib.

Comparators

Alternatives to genetic testing would be treatment as usual without genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be improvements in OS and disease-specific survival in individuals with pancreatic cancer.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary clinical management changes or unnecessary cascade testing for other cancers. False-negative test results can lead to the absence of clinical management changes.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that reported on the sensitivity and specificity and/or diagnostic yield of the test were considered, including curated sources of information on genes associated with increased risk of pancreatic cancer (eg, summaries from professional societies).

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1 and BRCA2 variants.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence

Golan et al (2019) conducted a placebo-controlled RCT of olaparib as maintenance therapy in patients with germline BRCA1 or BRCA2 variants and metastatic pancreatic cancer (Tables 6 and 7).^12, Of 3315 patients screened, 247 (7.5%) had a germline BRCA variant. Median progression-free survival was longer in the olaparib group, but there was no difference in OS.

Table 6. RCT of Targeted Treatment in Patients With Pancreatic Cancer: Study Characteristics

  NCT: National Clinical Trial 02184195, Multicentre Study of Maintenance Olaparib Monotherapy in Patients With gBRCA Mutated Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy; RCT: randomized controlled trial.

Table 7. RCT of Targeted Treatment in Patients With Pancreatic Cancer: Results

  CI: confidence interval; HR: hazard ratio; RCT: randomized controlled trial.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are no direct outcome data on the clinical usefulness of testing for confirmation of a BRCA1 or BRCA2 variant in patients with pancreatic cancer (ie, no studies have reported outcomes data for patients tested and not tested for a variant).

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of indirect evidence would demonstrate that genetic testing can identify individuals with pathogenic variants associated with pancreatic cancer who would not otherwise be identified, that treatments are available for these patients that would not otherwise be given to patients with pancreatic cancer, and that these treatments improve health outcomes.

Section Summary: Genetic Testing for a BRCA1 or BRCA2 Variant to Select Targeted Treatment

Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1 or BRCA2 variants, including among those who do not have a family history of pancreatic cancer. A placebo-controlled trial of olaparib as maintenance therapy in patients with germline BRCA1 or BRCA2 variants and metastatic pancreatic cancer found longer progression-free survival with olaparib (7.4 months vs. 3.8 months; hazard ratio [HR], 0.53; 95% CI 0.35 to 0.82; P=.04).

For individuals who have pancreatic cancer who receive testing for a BRCA1 or BRCA2 variant to guide selection for targeted treatment, the evidence includes observational studies and 1 randomized controlled trial. Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with BRCA1 or BRCA2 variants, including among those who do not have a family history of pancreatic cancer. A placebo-controlled trial of olaparib as maintenance therapy in patients with germline BRCA1 or BRCA2 variants and metastatic pancreatic cancer found longer progression-free survival with olaparib (7.4 months vs. 3.8 months; hazard ratio, 0.53; 95% confidence interval 0.35 to 0.82; p=.04 ). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Genetic Testing for ATM, CDKN2A , EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, and TP53 to Guide Treatment in Individuals with Pancreatic Cancer

Clinical Context and Test Purpose

The purpose of genetic testing for genes associated with pancreatic cancer in individuals with pancreatic cancer is to guide treatment for pancreatic cancer.

The following PICO was used to select literature to inform this review.

Population

The relevant population of interest is individuals with pancreatic cancer.

Interventions

The test being considered is genetic testing for ATM, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, and TP53.

Comparators

Alternatives to genetic testing would be treatment as usual without genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be improvements in OS and disease-specific survival in individuals with pancreatic cancer.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary clinical management changes or unnecessary cascade testing for other cancers. False-negative test results can lead to the absence of clinical management changes.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that reported on the sensitivity and specificity and/or diagnostic yield of the test were considered, including curated sources of information on genes associated with increased risk of pancreatic cancer (eg, summaries from professional societies).

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence

Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with disease-associated variants; some recent studies are summarized in Table 8. A case-control analysis conducted by Hu et al (2018) compared the association of germline pathogenic variations in 3030 patients with pancreatic cancer to 176,241 controls from 2 public genome databases.^13, There were significant associations between pancreatic cancer and pathogenic variations in 6 genes associated with pancreatic cancer (ATM, BRCA1, BRCA2, CDKN2A, MLH1, and TP53). Overall, pathogenic variants were identified in 5.5% of patients with pancreatic cancer.

Observational studies have reported that pathogenic variants are found in patients with pancreatic cancer who do not have a family history of the disease. In Hu et al (2018), pancreatic cancer associated variants were found in 7.9% of patients with a family history of pancreatic cancer and 5.2% of those without a family history of pancreatic cancer.^13, Shindo et al (2017) reported that pathogenic variants were identified in 3.9% of a cohort of 854 patients with pancreatic adenocarcinoma.^14, Of those with an identified pathogenic variant, only 3 (9.0%) reported a family history of pancreatic cancer.

Table 8. Study Characteristics: Clinical Validity of Genetic Tests in Patients with Pancreatic Cancer

 CI: confidence interval.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

There are currently no targeted treatments for pancreatic cancer based on germline testing for ATM, CDKN2A , EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, or TP53. It is unclear what management changes would be implemented based on results of such testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There are no direct outcome data on the clinical usefulness of genetic testing for ATM, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PMS2, PALB, STK11, and TP53 (ie, no studies have reported outcomes data for patients tested and not tested).

Indirect Evidence

A chain of indirect evidence would demonstrate that genetic testing can identify individuals with pathogenic variants associated with pancreatic cancer who would not otherwise be identified, that treatments are available for these patients that would not otherwise be given to patients with pancreatic cancer, and that these treatments improve health outcomes.

Section Summary: Genetic Testing for ATM, CDKN2A , EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, and TP53 in Individuals with Pancreatic Cancer

Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with disease-associated variants, including among those who do not have a family history of the disease. However, there is no direct evidence comparing health outcomes in patients tested or not tested for these variants. There are no targeted treatments for pancreatic cancer based on these variants.

For individuals with pancreatic cancer who receive genetic testing for ATM, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 to guide treatment, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with disease-associated variants, including among those who do not have a family history of the disease. However, there is no direct evidence comparing health outcomes in patients tested or not tested for a variant. Additionally, there are no targeted treatments for pancreatic cancer based on these genes, and management changes that would result from testing these genes are unclear. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Genetic Testing in Asymptomatic Individuals who are at Risk for Hereditary Pancreatic Cancer

Clinical Context and Test Purpose

The purpose of genetic testing of asymptomatic individuals who are at high-risk for hereditary pancreatic cancer is to inform decisions about surveillance for early detection of pancreatic cancer. Given that most symptomatic pancreatic cancer is detected at an advanced stage and has a poor prognosis, targeted surveillance of high-risk individuals has the potential to identify tumors at an earlier stage that are more amenable to treatment.

The following PICO was used to select literature to inform this review.

Population

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.

Interventions

The test being considered is testing for variants in genes associated with pancreatic cancer, including ATM, BRCA1, BRCA2, CDKN2A , EPCAM, MLH1, MSH2, MSH6, PALB2, STK11, and TP53.

For individuals without cancer who are at high-risk for hereditary pancreatic cancer, surveillance may be performed by endoscopic ultrasonography, magnetic resonance imaging (MRI), and/or computed tomography.

Comparators

Alternatives to genetic testing include risk assessment using criteria other than genetic testing (eg, family history).

Outcomes

The potential beneficial outcomes of primary interest would be improvements in OS and disease-specific survival.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary clinical management changes or unnecessary cascade testing for asymptomatic family members. False-negative test results can lead to the absence of clinical management changes or a lack of testing for asymptomatic family members.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that reported on the sensitivity and specificity and/or diagnostic yield of the test were considered, including curated sources of information on genes associated with increased risk of pancreatic cancer (eg, summaries from professional societies).

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Multiple genetic syndromes, including hereditary breast and ovarian cancer syndrome, are associated with an increased risk for pancreatic cancer (Table 9). Most of these are also associated with increased risk of other cancers. However, individual genes associated with the syndromes have been identified as increasing risk of pancreatic cancer, even in the absence of 1 of these syndromes.

Table 9. Pancreatic Cancer Susceptibility Genes and Associated Syndromes

 Sources: American Society of Clinical Oncology;2, American College of Gastroenterology7, NA: not available.

A prospective observational study of individuals under surveillance for pancreatic cancer on the basis of a family history of pancreatic cancer identified a known pathogenic variant in a pancreatic cancer susceptibility gene in 4.3% (15/345) (Table 10).^18, In addition, 66 variants of unclear significance were identified. The cumulative incidence of pancreatic cancer in the germline variant group was higher than in the familial risk group, adjusted for age and sex and accounting for death as a competing event (HR, 2.85; 95% CI, 1.0 to 8.18; p=.05).

Table 10. Clinical Validity of Genetic Testing in Asymptomatic Individuals at High Risk for Hereditary Pancreatic Cancer

  CI: confidence interval; HGD: high-grade dysplasia; HR: hazard ratio; PDAC: pancreatic ductal adenocarcinoma.

Surveillance in Asymptomatic Individuals at High Risk for Hereditary Pancreatic Cancer

Recent prospective observational studies have reported the yield of screening and outcomes in high-risk individuals enrolled in pancreatic cancer surveillance programs (Table 11). Surveillance protocols varied somewhat and evolved over time, but typically included annual MRI and/or endoscopic ultrasound, with more frequent follow-up when a suspicious lesion was identified.

A 16-year follow-up study of surveillance in individuals at high-risk of pancreatic cancer due to family history or genetic factors was reported by Canto et al (2018).^19, The overall detection rate over 16 years was 7%, including incident and prevalent neoplasms. Of 354 individuals under surveillance, 10 pancreatic cancers were detected, and 9 of 10 were resectable. Among these, 85% survived for 3 years.

Vasen et al (2016) found that surveillance of CDKN2A variant carriers detected most pancreatic adenocarcinomas at a resectable stage.^20, In patients at risk for familial pancreatic cancer (those from families with 2 or 3 first-degree relatives with pancreatic cancer), however, the yield of screening was low.

Konings et al (2019) published a report of outcomes on 76 high-risk individuals from the International Cancer of the Pancreas Screening (CAPS) surveillance programs in 4 countries (U.S., the Netherlands, Israel, and Italy) who had either undergone pancreatic surgery because of the detection of a suspicious pancreatic lesion (n=71) or progressed to advanced unresectable malignant disease (n=5).^21, Survival rate was significantly poorer for individuals with advanced pancreatic cancer compared with those who had surgery (40% vs. 83% respectively, p=.050; mean survival 9.5 vs. 54.3 months, p<.001).

Dbouk et al (2022) published results of the CAPS5 cohort, consisting of 1461 individuals who were determined to be at high risk for PDAC based either on presence of a germline pathogenic variant (48.5%) or family history without a known germline pathogenic variant (51.5%).^22, A total of 9 individuals were diagnosed with a screen-detected pancreatic adenocarcinoma. The study authors concluded that their results "support current CAPS surveillance recommendations and argue against the notion of limiting pancreatic surveillance to those high-risk individuals with known pathogenic mutations."

In a cohort of 366 Dutch individuals at high risk of PDAC followed for 63 months (standard deviation, 43.2 months), Overbeek et al (2022) reported a 9.3% incidence of PDAC in the subset of individuals with a germline pathogenic variant and no PDAC in those with family history but no pathogenic variant.^23, Three out of 10 (30%) individuals with PDAC were detected at an early stage. The resectability rate was 60% (6/10) overall and 50% (4/8) for incident cases.

Although these observational studies have demonstrated that surveillance can identify pancreatic cancer and precursor lesions in asymptomatic individuals, it is not possible to conclude from this body of evidence that surveillance improves survival. Longer survival time observed in individuals undergoing surveillance could be due to earlier identification of the disease (lead-time bias) and not the effects of early intervention and treatment.

Table 11. Studies of Surveillance in Individuals at High Risk of Pancreatic Cancer

 CAPS: Cancer of the Pancreas Screening; CT: computed tomography; EUS: endoscopic ultrasound; FAMMM: familial atypical multiple mole melanoma; FDR: first-degree relative; FPC: familial pancreatic cancer; MRCP, magnetic resonance cholangiopancreatography; MRI: magnetic resonance imaging; PDAC: pancreatic ductal adenocarcinoma.

Screening and Surveillance for Other Cancers in Asymptomatic Patients at High-Risk for Hereditary Pancreatic Cancer

Genes that are associated with pancreatic cancer are also associated with increased risk of other cancers and genetic cancer syndromes (see Table 9). For this reason, genetic testing in patients with pancreatic cancer has been proposed to identify patients who are candidates for surveillance, early treatment, and prevention of cancers such as breast, ovarian, colon, and melanoma. A review of the evidence in other cancers is beyond the scope of this review, and is addressed in the following policies:

• 2.04.02 - Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome (BRCA1 or BRCA2)

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

• 2.04.44 - Genetic Testing for Familial Cutaneous Malignant Melanoma

• 2.04.93 - Genetic Cancer Susceptibility Panels Using Next-Generation Sequencing

• 2.04.101 - Genetic Testing for Li-Fraumeni Syndrome

• 2.04.126 - Moderate Penetrance Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

There is no direct evidence comparing health outcomes in asymptomatic patients tested or not tested for genes associated with hereditary pancreatic cancer.

Chain of Evidence

A chain of indirect evidence would demonstrate that genetic testing can identify individuals with pathogenic variants associated with hereditary pancreatic cancer who would not otherwise be identified, that treatments or increased surveillance are available for these patients that would not otherwise be given to patients with hereditary pancreatic cancer, and that these interventions improve health outcomes.

Section Summary: Genetic Testing in Asymptomatic Individuals who are at Risk for Hereditary Pancreatic Cancer

There is no direct evidence comparing health outcomes in patients tested or not tested for a variant. There is indirect evidence from 2 comparative observational studies of high-risk individuals under surveillance that the risk of progression to pancreatic cancer is higher among individuals with a known pathogenic variant than in individuals identified as at-risk based on family history alone. There is also evidence from prospective observational studies that surveillance of high-risk individuals can identify pancreatic cancer and precursor lesions. In 1 analysis of 76 high-risk individuals under surveillance, survival was better in those who had surgery due to detection of either low- or high-risk neoplastic precursor lesions (n=71) compared to those who had advanced to unresectable disease (n=5). Although observational studies have demonstrated that surveillance can identify pancreatic cancer and precursor lesions in asymptomatic individuals, it is not possible to conclude from this body of evidence that surveillance improves survival. Longer survival time observed in individuals undergoing surveillance could be due to earlier identification of the disease (lead-time bias) and not the effects of early intervention and treatment. Additionally, evidence is too limited to determine if selecting patients for surveillance based on genetic testing leads to better outcomes than using criteria such as family history alone.

For individuals who are asymptomatic and at high risk for hereditary pancreatic cancer who receive testing for genes associated with hereditary pancreatic cancer, the evidence includes observational studies. There is no direct evidence comparing health outcomes in patients tested or not tested for a variant. There is indirect evidence from 2 comparative observational studies of high-risk individuals under surveillance that the risk of progression to pancreatic cancer is higher among individuals with a known pathogenic variant than in individuals identified as at-risk based on family history alone. There is also evidence from prospective observational studies that surveillance of high-risk individuals can identify pancreatic cancer and precursor lesions. In 1 analysis of 76 high-risk individuals under surveillance, survival was better in those who had surgery due to detection of either low- or high-risk neoplastic precursor lesions (n=71) compared to those who had advanced to unresectable disease (n=5). Although observational studies have demonstrated that surveillance can identify pancreatic cancer and precursor lesions in asymptomatic individuals, it is not possible to conclude from this body of evidence that surveillance improves survival. Longer survival time observed in individuals undergoing surveillance could be due to earlier identification of the disease (downstaging) and not the effects of early intervention and treatment. Additionally, evidence is too limited to determine if selecting patients for surveillance based on genetic testing leads to better outcomes than using criteria such as family history alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Gastroenterology

In 2015, the American College of Gastroenterology Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes includes the following recommendations on genetic testing for pancreatic cancer:^7,

• Individuals should be considered to be at risk for familial pancreatic adenocarcinoma if they (i) have a known genetic syndrome associated with pancreatic cancer, including hereditary breast-ovarian cancer syndrome, familial atypical multiple melanoma, and mole syndrome, PJS [Peutz-Jeghers syndrome], LS [Lynch syndrome], or other gene mutations associated with an increased risk of pancreatic adenocarcinoma; or (ii) have 2 relatives with pancreatic adenocarcinoma, where 1 is a first-degree relative; (iii) have 3 or more relatives with pancreatic cancer; or (iv) have a history of hereditary pancreatitis.

• Genetic testing of patients with suspected familial pancreatic cancer should include analysis of BRCA1/2, CDKN2A, PALB2, and ATM. Evaluation for PJS, LS, and hereditary pancreatitis-associated genes should be considered if other component personal and/or family history criteria are met for the syndrome.

American Society of Clinical Oncology

In 2019, an American Society of Clinical Oncology (ASCO) opinion statement addressed the identification and management of patients and family members with a possible predisposition to pancreatic adenocarcinoma and made the following recommendations:^2,

• PCO [provisional clinical opinion] 1.2 Individuals with a family history of pancreatic cancer affecting 2 first-degree relatives meet the criteria for familial pancreatic cancer. Individuals whose family history meets criteria for familial pancreatic cancer, those with 3e or more diagnoses of pancreatic cancer in the same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing (Type: informal consensus; benefits outweigh harms; Strength of statement: strong).

• PCO 1.3 Genetic risk evaluation should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer syndromes to determine the most appropriate testing strategy and discuss implications of the findings for family members. Germline genetic testing for patients with pancreatic cancer should be offered in the context of shared decision making. (Type: informal consensus; benefits outweigh harms; Strength of statement: strong).

• PCO 2.1 All patients diagnosed with pancreatic adenocarcinoma should undergo an assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk includes obtaining a personal cancer history and family history of cancers in first- and second-degree relatives. However, recent data demonstrate that many individuals who develop pancreatic cancer in the setting of genetic predisposition lack clinical features or family cancer history typically associated with the corresponding hereditary syndrome. Therefore, germline genetic testing may be discussed with patients with a personal history of pancreatic cancer, even if family history is unremarkable (Type: informal consensus; benefits outweigh harms; Strength of statement: strong).

In 2020, ASCO published a guideline update on recommendations for second-line therapy options for metastatic pancreatic cancer.^24, In patients who have a germline BRCA1 or BRCA2 mutation and who have received first-line platinum based chemotherapy without disease progression for at least 16 weeks, options for continued treatment include chemotherapy or the poly ADP ribose polymerase (PARP) inhibitor olaparib.

International Cancer of the Pancreas Screening Consortium

In 2020, the International Cancer of the Pancreas Screening Consortium published an updated consensus document on the management of patients with increased risk for familial pancreatic cancer.^25, The panel recommended pancreatic cancer surveillance performed in a research setting for the following individuals:

• All patients with Peutz-Jeghers syndrome (carriers of a germline LKB1/STK11 gene mutation)

• All carriers of a germline CDKN2A mutation

• Carriers of a germline BRCA2, BRCA1, PALB2, ATM, MLH1, MSH2, or MSH6 gene mutation with at least 1 affected first-degree blood relative

• Individuals who have at least 1 first-degree relative with pancreatic cancer who in turn also has a first-degree relative with pancreatic cancer (familial pancreatic cancer kindred)

The preferred surveillance tests are endoscopic ultrasound and magnetic resonance imaging (MRI). The recommended age to initiate surveillance depends on an individual's gene mutation status and family history, but no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer. There was no consensus on the age to end surveillance.

National Comprehensive Cancer Network

Two National Comprehensive Cancer Network (NCCN) guidelines address germline genetic testing in individuals with or at high risk for pancreatic cancer.^26,6,

The Guidelines on Genetic/Familial High-risk Assessment: Breast, Ovarian, and Pancreatic ( v.2.2024v.2.2025) recommend germline testing for all individuals with exocrine pancreatic cancer, and specify that testing of first-degree relatives should only be done only if it is impossible to test the individual who has pancreatic cancer.^26,

The Guideline on Treatment of Pancreatic Adenocarcinoma ( v.1.2024v.1.2025) recommends germline testing for any patient with confirmed pancreatic cancer using comprehensive gene panels for hereditary cancer syndromes.^6, The guideline specifies the following genes as those typically tested for pancreatic cancer risk: ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, ), PALB2, PMS2, STK11, and TP53.

For patients with locally advanced disease, preferred first-line therapy regimens include gemcitabine + cisplatin for patients with BRCA1/2 or PALB2 variants For patients with metastatic disease who have received previous platinum-based chemotherapy, olaparib is preferred only for patients with germline BRCA1/2 variants.

Genetic counseling is recommended for patients who test positive for a pathogenic variant, or for patients with a positive family history of pancreatic cancer, regardless of test results. The guidelines also recommend genetic counseling for patients who test positive for a pathogenic variant or for patients with a positive family history of pancreatic cancer, regardless of variant status.

U.S. Preventive Services Task Force Recommendation

The 2019 U.S. Preventive Services Task Force recommendation on screening for pancreatic cancer applies to asymptomatic adults not known to be at high-risk of pancreatic cancer.^5, The recommendation does not apply to persons at high-risk of pancreatic cancer due to an inherited genetic syndrome or due to a history of hereditary pancreatic cancer.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

 NCT: national clinical trial.

References

1. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Pancreatic Cancer. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed January 8, 2025.
2. Stoffel EM, McKernin SE, Khorana AA. Evaluating Susceptibility to Pancreatic Cancer: ASCO Clinical Practice Provisional Clinical Opinion Summary. J Oncol Pract. Feb 2019; 15(2): 108-111. PMID 30589608
3. O'Reilly EM, Lee JW, Zalupski M, et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. May 01 2020; 38(13): 1378-1388. PMID 31976786
4. Reiss KA, Yu S, Judy R, et al. Retrospective Survival Analysis of Patients With Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations. JCO Precision Oncology. Published online January 19, 2018. DOI: 10.1200/PO.17.00152.
5. Owens DK, Davidson KW, Krist AH, et al. Screening for Pancreatic Cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. Aug 06 2019; 322(5): 438-444. PMID 31386141
6. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed December 21, 2024.
7. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. Feb 2015; 110(2): 223-62; quiz 263. PMID 25645574
8. Food & Drug Administration. Premarket Approval: BRACAnalysis CDx. 2019. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P140020S019. Accessed January 8, 2025.
9. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. Sep 09 2014; 111(6): 1132-8. PMID 25072261
10. Wattenberg MM, Asch D, Yu S, et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer. Feb 2020; 122(3): 333-339. PMID 31787751
11. Yu S, Agarwal P, Mamtani R, et al. Retrospective survival analysis of patients with resected pancreatic ductal adenocarcinoma and a Germline BRCA or PALB2 mutation. JCO Precision Oncol. Published online March 28, 2019. DOI: 10.1200/PO.18.00271
12. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer. N Engl J Med. Jul 25 2019; 381(4): 317-327. PMID 31157963
13. Hu C, Hart SN, Polley EC, et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. Jun 19 2018; 319(23): 2401-2409. PMID 29922827
14. Shindo K, Yu J, Suenaga M, et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. Oct 20 2017; 35(30): 3382-3390. PMID 28767289
15. Brand R, Borazanci E, Speare V, et al. Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer. Sep 01 2018; 124(17): 3520-3527. PMID 30067863
16. Mandelker D, Zhang L, Kemel Y, et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. Sep 05 2017; 318(9): 825-835. PMID 28873162
17. Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. Mar 2015; 148(3): 556-64. PMID 25479140
18. Abe T, Blackford AL, Tamura K, et al. Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. J Clin Oncol. May 01 2019; 37(13): 1070-1080. PMID 30883245
19. Canto MI, Almario JA, Schulick RD, et al. Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance. Gastroenterology. Sep 2018; 155(3): 740-751.e2. PMID 29803839
20. Vasen H, Ibrahim I, Ponce CG, et al. Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers. J Clin Oncol. Jun 10 2016; 34(17): 2010-9. PMID 27114589
21. Konings ICAW, Canto MI, Almario JA, et al. Surveillance for pancreatic cancer in high-risk individuals. BJS Open. Oct 2019; 3(5): 656-665. PMID 31592073
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26. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed December 22, 2024.

Codes

Applicable Modifiers

N/A

Policy History