Medical Policy

Policy Num:      11.003.137
Policy Name:    Germline Genetic Testing for Hereditary Diffuse Gastric Cancer (CDH1, CTNNA1)
Policy ID:          [11.003.137]  [Ac / B / M+ / P+]  [2.04.154]

Last Review:       September 20, 2024
Next Review:       September 20, 2025
 

Related Policies:

11.003.030 - Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)
11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

Germline Genetic Testing for Hereditary Diffuse Gastric Cancer (CDH1, CTNNA1)

Summary

Description

Hereditary Diffuse Gastric Cancer (HDGC, sometimes called signet ring gastric cancer) is an autosomal dominant syndrome characterized by the development of diffuse gastric cancers. CDH1 is a tumor suppressing gene that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing HDGC and lobular breast cancer. Testing for CTNNA1 variants has also been proposed for individuals with or at risk for HDGC. Knowledge of variant status in individuals at potentially increased risk may impact health care decisions to reduce risk.

Summary of Evidence

For individuals without suspected hereditary diffuse gastric cancer (HDGC) who are at risk for HDGC who receive germline genetic testing for CDH1 variants, the evidence includes retrospective observational studies. Relevant outcomes are overall survival (OS), disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There is no direct evidence of the clinical utility of CDH1 testing in asymptomatic individuals. Penetrance estimates for gastric cancer range from 42% to 70% in men and 33% to 56% in women. Penetrance is higher in individuals from families with more gastric cancer cases and is lower in individuals identified by methods such as multigene panel testing. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of prophylactic total gastrectomy (PTG) to reduce risk of gastric cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with suspected HDGC who receive germline genetic testing for CDH1 variants, the evidence includes retrospective observational studies. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There are no targeted treatments for HDGC based on CDH1 variant status. The benefit of genetic testing to affected individuals would be to inform healthcare decisions to reduce risk of other cancers, and to inform decisions about genetic testing for at-risk family members. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of PTG to reduce risk of gastric cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with suspected HDGC, or without suspected HDGC who are at risk for HDGC who receive germline genetic testing for CTNNA1 variants, the evidence includes a small number of case reports of CTNNA1 variants identified in individuals from families with HDGC. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There is no direct evidence of the clinical utility of testing for CTNNA1 variants in individuals with suspected HDGC or at risk for HDGC. The evidence is insufficient to demonstrate clinical validity and therefore a chain of evidence cannot be established. 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 germline genetic testing of individuals with or at high-risk of HDGC and to determine if its use improves the net health outcome.

Policy Statements

Germline genetic testing for CDH1 variants to identify individuals with or at risk for hereditary diffuse gastric cancer (HDGC) may be considered medically necessary for individuals meeting the following criteria (see Policy Guidelines):

• A diagnosis of diffuse gastric cancer (DGC) before age 50 years; OR
   
• A diagnosis of DGC at any age in individuals of Maori ethnicity, or with a personal or family history of cleft/lip palate; OR
   
• A diagnosis of bilateral lobular breast cancer before age 70 years; OR
   
• Personal or family history of both DGC and lobular breast cancer, one diagnosed before age 70 years; OR
   
• Two 1st- or 2nd-degree relatives (see Policy Guidelines) with a diagnosis of gastric cancer at any age, one DGC; OR
   
• Two 1st- or 2nd-degree relatives (see Policy Guidelines) with a diagnosis of lobular breast cancer before 50 years of age.

Germline genetic testing for CDH1 variants in individuals not meeting the above criteria is considered investigational.

Germline genetic testing for CTNNA1 variants to identify individuals with or at risk for HDGC is considered investigational (see Policy Guidelines).

Policy Guidelines

Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing. The National Comprehensive Cancer Network (NCCN) guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic v3.2023 recommend testing for high-penetrant breast cancer susceptibility genes including CDH1 for individuals diagnosed at any age with lobular breast cancer with personal or family history of diffuse gastric cancer and state, "See NCCN Guidelines for Gastric Cancer". Thus, these two NCCN guidelines' criteria conflict as to the age of lobular breast cancer. Plans with legislative mandated coverage of biomarkers might need to use the broader criteria for coverage determination.

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

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

Testing Strategy

• In individuals with a known familial CDH1 variant, targeted testing for the specific variant is recommended.

• In individuals with unknown familial CDH1 variant:

  • To identify clinically significant variants, NCCN advises testing a close relative (see above) who has cancer related to hereditary diffuse gastric cancer (HDGC) syndrome, because that individual has the highest likelihood of obtaining a positive test result. Testing family members without a related cancer diagnosis could be considered if family members with a related cancer are unwilling or unavailable for testing.

• The International Gastric Linkage Consortium recommends germline genetic testing for CTNNA1 variants to identify individuals with or at risk for HDGC who meet criteria for CDH1 testing and have had CDH1 testing with no CDH1 variant identified. Consideration could be given to targeted testing at-risk family members when a CTNNA1 variant has been previously identified in a close family member. However, the evidence on follow-up of asymptomatic CTNNA1 mutation carriers who had small diffuse gastric cancer foci found on prophylactic gastrectomy is based on very limited sample size and it is not known if those findings would have led to invasive cancer (Benusiglio et al, 2019). Without additional study of long-term follow-up with endoscopic surveillance and large cohort studies there is risk of unneeded prophylactic gastrectomy.

Testing Unaffected Individuals

• In unaffected family members of potential CDH1 variant families, most test results will be negative and uninformative. Therefore, it is strongly recommended that an affected family member be tested first whenever possible to adequately interpret the test. Should a CDH1 variant be found in an affected family member(s), DNA from an unaffected family member can be tested specifically for the same variant of the affected family member without having to sequence the entire gene. Interpreting test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result for an established disease-associated variant but leads to difficulties in interpreting negative test results (uninformative negative) or variants of uncertain significance because the possibility of a causative CDH1 variant is not ruled out.

Testing Minors

• The use of genetic testing for CDH1 variants for identifying hereditary diffuse gastric cancer syndrome has limited or no clinical utility in minors, because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious variant. In addition, there are potential harms related to stigmatization and discrimination. Exceptions to this might be based on family history and/or high risk ethnicity.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG-AMP: American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

Benefit Application

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.

BlueCard/National Account Issues

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

Under the Patient Protection and Affordable Care Act, preventive services with a U.S. Preventive Services Task Force recommendation grade of A or B will be covered with no cost-sharing requirements. Plans that have been grandfathered are exceptions to this rule and are not subject to this coverage mandate.

Background

Hereditary Diffuse Gastric Cancer

Hereditary Diffuse Gastric Cancer (HDGC, sometimes called signet ring gastric cancer) is an autosomal dominant syndrome primarily characterized by an increased lifetime risk of diffuse gastric cancer (DGC). The condition is rare. In the general U.S. population, the lifetime risk of developing gastric cancer is 0.8%. Approximately 20% of all gastric cancers are DGCs, and 1% to 3% of these are due to HDGC (approximately 5 to 10 per 100,000 births). The incidence of HDGC is estimated at 5 to 10 per 100,000 births. The diffuse type of gastric cancer is difficult to diagnose on upper endoscopy and as a result, most cases of DGC are diagnosed at late stages. The average age at diagnosis is 37 years. The 5-year relative survival is 5.9% for gastric cancer that has metastasized, compared to 28% for localized gastric cancer.^1,

CDH1

CDH1 is a tumor suppressing gene located on chromosome 16q22.1 that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing HDGC and lobular breast cancer.^2,3, A diagnosis of HDGC can be confirmed by genetic testing, although 20% to 40% of families with suspected HDGC do not have a CDH1 variant on genetic testing. Pathogenic CDH1 variants have been described in Māori families in New Zealand, and individuals of Maori ethnicity have a higher prevalence of diffuse-type gastric cancer than non-Maori New Zealanders. Therefore, guidelines include Maori ethnicity as a risk factor for HDGC. Cleft lip/palate has been described in some HDGC families and is also included in CDH1 genetic testing guidelines.

CTNNA1

CTNNA1, which encodes the protein Catenin Alpha-1, is a suspected tumor suppressor and susceptibility gene for HDGC.

Regulatory Status

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). Germline genetic testing for CDH1 variants is available under the auspices of the 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 has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in August 2022 with a search of the PubMed database. The most recent literature update was performed through July 5, 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 CDH1 Variants in Individuals Without Suspected Hereditary Diffuse Gastric Cancer Who are at Risk for Hereditary Diffuse Gastric Cancer

Clinical Context and Test Purpose

The purpose of CDH1 variant testing in individuals without suspected hereditary diffuse gastric cancer (HDGC) who are at risk for HDGC is to inform a decision about initiating surveillance and, if appropriate, treatment with prophylactic total gastrectomy (PTG; complete removal of the stomach) and/or prophylactic mastectomy.

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

Populations

The relevant population of interest is individuals without cancer or without cancer that is related to HDGC, but who are at risk for HDGC. Criteria have been established to identify individuals at risk and include the following:^4,

• Two gastric cancer cases in a family, one confirmed diffuse gastric cancer (DGC) regardless of age; or

• DGC diagnosed before age 50 years without a family history; or

• Personal or family history of DGC and lobular breast cancer, one diagnosed before age 70 years; or

• Two cases of lobular breast cancer in family members before 50 years of age; or

• DGC at any age in individuals of Māori ethnicity, or with a personal or family history of cleft lip/cleft palate; or

• Bilateral lobular breast cancer before age 70 years.

Interventions

The test being considered is genetic testing for CDH1 variants.

Knowledge of variant status in individuals at potentially increased risk of a CDH1 variant may impact healthcare decisions to reduce risk.

Comparators

The comparator of interest is risk assessment without genetic testing (e.g., based on family history alone).

Outcomes

The specific outcomes of interest are development of HDGC or lobular breast cancer, overall survival (OS), disease-specific survival, and harms of treatment including prophylactic gastrectomy and mastectomy.

Study Selection Criteria

Head-to-head studies comparing health outcomes with and without the test provide direct evidence. Randomized controlled trials (RCTs) are preferred but are unlikely to be conducted due to the rarity of the condition.

To establish a chain of evidence for clinical utility of a genetic test, evidence is needed to demonstrate:

1. An established association between the marker and future disorder AND

2. There is a pre-symptomatic phase for the disorder and interventions or surveillance are available AND

3. Interventions in the pre-symptomatic phase are likely to improve outcomes (i.e., prevent or delay onset of disease, or detect disease at an earlier stage during which treatment is more effective, or discontinuation of ineffective or unnecessary interventions).

Review of Evidence

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.

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 of the clinical utility of CDH1 genetic testing to improve the net health outcome.

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.

Association between CDH1 Variants and Risk of Cancer

Penetrance estimates derived from studies of families with pathogenic CDH1 variants are shown in Table 1. Estimates from families with CDH1 variants selected based on strict clinical criteria have been higher than those derived from multigene panel testing in individuals not meeting these criteria.

Hansford et al (2015) conducted a penetrance analysis on 75 families with identified CDH1 pathogenic variants (N=3858 relatives).^5, In this cohort, the cumulative incidence of gastric cancer by age 80 years was 70% (95% confidence interval [CI], 59% to 80%) for male participants and 56% (95% CI, 44% to 69%) for female participants. The risk of breast cancer for female participants was 42% (95% CI, 23% to 68%) by age 80 years. As indicated by results of multigene panel testing, these penetrance estimates are likely overestimates for individuals who harbor a variant but do not have a family history.

Roberts et al (2019) conducted a retrospective cohort study of 75 families (N=1679 individuals, 238 with an identified CDH1 pathogenic variant).^6, This cohort was not exclusively ascertained based on strict HDGC genetic testing criteria. Penetrance estimates were calculated using data from 41 of the 75 families with complete pedigrees available (54.7%). The cumulative incidence was significantly elevated relative to Surveillance, Epidemiology, and End Results (SEER) program incidence for gastric cancer in men and women, and for breast cancer in women. The cumulative incidence was not significantly elevated for colorectal cancer for men or women. This study indicated that gastric cancer risk in individuals with CDH1 pathogenic variants identified by multigene panel testing who do not meet established clinical testing criteria is significantly lower than CDH1 pathogenic variant risk estimates generated by studies with more biased ascertainment strategies.

Table 1. Penetrance Estimates for CDH1 Variants

CI: confidence interval; HDGC: hereditary diffuse gastric cancer; IGCLC: International Gastric Cancer Linkage Consortium.

Cancer Risk Reduction Strategies in Individuals with CDH1 Variants

Prophylactic Total Gastrectomy

The effectiveness of PTG to reduce gastric cancer risk in asymptomatic individuals with CDH1 variants has been described in case reports and case series, with occult cancer frequently observed on pathological examination.^7,8,9,

Although it carries surgical risks and can impact quality of life, current guidelines recommend offering the procedure to CDH1 variant carriers between ages 20 and 30 because it is the only method to eliminate the risk of gastric cancer in such individuals.^10,

Endoscopic Surveillance

For individuals who decline or are unable to undergo PTG, endoscopic surveillance is an option but it is less effective than PTG. Benesch et al (2021) conducted a systematic review of endoscopic surveillance using 2 different strategies: the Cambridge Protocol, which employs a systematic examination of the stomach with 30 biopsies, and random biopsies.^11, The reviewers identified 34 cases reports and case series, representing a total of 266 individuals. The test sensitivity and negative predictive value of random biopsies were 20.9% and 15.2%, respectively, and for the Cambridge Protocol, 27.1% and 22.1%, respectively. The authors concluded that the Cambridge Protocol has not been shown to improve test performance over random biopsies. Given the poor test performance of endoscopic surveillance, the authors recommended that individuals choosing surveillance over PTG should be fully informed of its poor performance.

Benesch et al (2021) also conducted a retrospective cohort study of 97 consecutive asymptomatic individuals in Newfoundland and Labrador with a CDH1 variant.^11, All had been identified using genetic testing criteria at the time of presentation from 2002 to 2017. From 2002 to 2020, 67 individuals had undergone PTG, and 17 of 53 females had undergone prophylactic mastectomy. The sensitivity of endoscopic biopsies was 28.0% with a negative predictive value of 18.2%.

Asif et al (2023) conducted a prospective cohort study as part of a natural history study of hereditary gastric cancers to evaluate the effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma ^12,. Patients age 2 years and older (N=270) who were asymptomatic carriers of pathogenic or likely pathogenic CDH1 variants were enrolled. At data cutoff, a total of 467 endoscopies had been performed, with a median of 1 procedure (interquartile range [IQR], 1 to 3) per patient. A total of 38,803 total gastric biopsy samples were collected, of which 1163 (3%) were positive for signet ring cell carcinoma. Overall, 101 of 270 (37%) patients had signet ring cell carcinoma cancer foci detected during the initial screening endoscopy; positive cancer foci were detected in 382 anatomic regions in all 270 patients. For patients with 2 or more surveillance endoscopies, signet ring cell carcinoma was detected in 76 of 120 patients (63%). There were 98 of 270 patients (36%) that went on to have PTG. Only two (less than 1%) of the 467 endoscopies had non-targeted biopsy samples that were negative for signet ring cell carcinoma while having a positive targeted biopsy. Authors concluded that repeated endoscopic surveillance is a plausible alternative to PTG when used with thorough clinical and pathological gastric assessment.

Breast Surveillance and Risk-Reducing Mastectomy

Estimates of the risk of breast cancer in individuals with a CDH1 variant range from 42% to 55% (Table 1), and case series have reported lobular carcinoma in situ in individuals from families with CDH1 variants who have undergone prophylactic bilateral mastectomy.^13, There is a lack of prospective data on imaging for lobular breast cancer, and surveillance guidelines rely heavily on the evidence base from individuals with germline BRCA1/2 pathogenic variants. For individuals at risk for HDGC, guidelines recommend annual breast surveillance starting at age 30 years and consideration of bilateral risk-reducing mastectomy.^14,

Section Summary: Genetic Testing for CDH1 Variants in Individuals Without Suspected Hereditary Diffuse Gastric Cancer Who are at Risk for Hereditary Diffuse Gastric Cancer

There is no direct evidence of the clinical utility of CDH1 testing in asymptomatic individuals. Penetrance estimates for gastric cancer range from 42% to 70% in men and 33% to 56% in women. Penetrance is higher in individuals from families with more gastric cancer cases and is lower in individuals identified by methods such as multigene panel testing. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of PTG to reduce risk of gastric cancer.

Summary of Evidence

For individuals without suspected hereditary diffuse gastric cancer (HDGC) who are at risk for HDGC who receive germline genetic testing for CDH1 variants, the evidence includes retrospective observational studies. Relevant outcomes are overall survival (OS), disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There is no direct evidence of the clinical utility of CDH1 testing in asymptomatic individuals. Penetrance estimates for gastric cancer range from 42% to 70% in men and 33% to 56% in women. Penetrance is higher in individuals from families with more gastric cancer cases and is lower in individuals identified by methods such as multigene panel testing. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of prophylactic total gastrectomy (PTG) to reduce risk of gastric cancer. 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 CDH1 Variants in Individuals With Suspected Hereditary Diffuse Gastric Cancer

Clinical Context and Test Purpose

The purposes of germline genetic testing for CDH1 variants in individuals with suspected HDGC are:

1) to confirm a diagnosis of HDGC

2) to inform decisions about initiating surveillance and, if appropriate, treatment with prophylactic gastrectomy or mastectomy

3) to guide decisions about genetic testing for at-risk family members

Populations

The relevant population of interest is individuals with diffuse gastric or lobular breast cancer who are suspected of having HDGC. In individuals with such cancer, criteria have been established to identify individuals at risk and include the following:

• DGC diagnosed before age 50 years without a family history; or

• Personal or family history of DGC and lobular breast cancer, 1 diagnosed before age 70 years; or

• DGC at any age in individuals of Maori ethnicity, or with a personal or family history of cleft lip/cleft palate; or

• Bilateral lobular breast cancer before age 70 years.

Interventions

The test being considered is germline genetic testing for CDH1 variants.

Comparators

The comparator of interest is standard care without genetic testing for CDH1 variants.

Outcomes

The specific outcomes of interest are development of HDGC or lobular breast cancer, OS, disease-specific survival, and harms of treatment including prophylactic gastrectomy and mastectomy.

Study Selection Criteria

Head-to-head studies comparing health outcomes with and without the test provide direct evidence of clinical utility. Randomized controlled trials are preferred but are unlikely to be conducted due to the rarity of the condition.

In the absence of direct evidence, a chain of evidence is needed.

To establish a chain of evidence of the clinical utility of a genetic test to benefit an individual with a condition, evidence is needed from studies demonstrating:

• The clinical validity of testing AND
• A definitive diagnosis cannot be made based on history, physical examination, pedigree analysis, and standard diagnostic studies/tests alone; AND

A definitive diagnosis:

• Leads to changes in clinical management of the condition that improve outcomes; or

• Eliminates the need for further clinical workup or invasive testing; or

• Leads to discontinuation of interventions that are unnecessary and/or ineffective.

To establish a chain of evidence of the clinical utility of an affected individual's germline to benefit family members, evidence is needed from studies demonstrating:

• An association between the genetic variant and clinical disease has been established; and

• Family members are available who may be at risk for the disorder; and

• The individual tested has a clinical diagnosis of the condition (or represents the family member who is most likely to harbor the pathogenic variant), but genetic testing has not been performed; and

• There is a pre-symptomatic phase for the disorder in which interventions are available; and

• Interventions in the pre-symptomatic phase are likely to improve outcomes.

Review of Evidence

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.

There are no targeted treatments for HDGC based on CDH1 variant status. The benefit of genetic testing to affected individuals would be to inform healthcare decisions to reduce risk of other cancers. That is, in individuals diagnosed with lobular breast cancer, a confirmed diagnosis of HDGC could inform decisions about undergoing total gastrectomy to prevent gastric cancer. In individuals diagnosed with DGC, a confirmed diagnosis of HDGC could inform decisions about increased surveillance or prophylactic mastectomy to prevent breast cancer. Additionally, testing would inform decisions about genetic testing for at-risk family members.

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 of the clinical utility of germline genetic testing for CDH1 variants in individuals with suspected HDGC.

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 evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of prophylactic total gastrectomy to reduce risk of gastric cancer.

Section Summary: Genetic Testing for CDH1 Variants in Individuals With Suspected Hereditary Diffuse Gastric Cancer

There are no targeted treatments for HDGC based on CDH1 variant status. The benefit of genetic testing to affected individuals would be to inform healthcare decisions to reduce risk of other cancers, and to inform decisions about genetic testing for at-risk family members. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of PTG to reduce risk of gastric cancer.

Summary of Evidence

For individuals with suspected HDGC who receive germline genetic testing for CDH1 variants, the evidence includes retrospective observational studies. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There are no targeted treatments for HDGC based on CDH1 variant status. The benefit of genetic testing to affected individuals would be to inform healthcare decisions to reduce risk of other cancers, and to inform decisions about genetic testing for at-risk family members. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of PTG to reduce risk of gastric cancer. 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 CTNNA1 Variants to Identify Individuals With or at Risk for Hereditary Diffuse Gastric Cancer

Clinical Context and Test Purpose

The purposes of CTNNA1 variant testing to identify individuals with or at risk for HDGC are:

1) to inform decisions about initiating surveillance and, if appropriate, treatment with PTG and/or prophylactic mastectomy, and

2) to inform decisions about testing family members.

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

Populations

The relevant populations of interest are individuals with suspected HDGC, or who are at risk for HDGC based on family history or clinical factors.

Interventions

The test being considered is genetic testing for CTNNA1 variants.

Knowledge of variant status in individuals at potentially increased risk of a CTNNA1 variant may impact healthcare decisions to reduce risk.

Comparators

The comparators of interest are risk assessment without CTNNA1 genetic testing (e.g., based on family history or CDH1 testing alone).

Outcomes

The specific outcomes of interest are development of HDGC or lobular breast cancer, OS, disease-specific survival, and harms of treatment including prophylactic gastrectomy and mastectomy.

Study Selection Criteria

Head-to-head studies comparing health outcomes with and without the test provide direct evidence of clinical utility. Randomized controlled trials are preferred but are unlikely to be conducted due to the rarity of the condition.

In the absence of direct evidence, a chain of evidence is needed.

To establish a chain of evidence of the clinical utility of a genetic test to benefit an individual with a condition, evidence is needed from studies demonstrating

• The clinical validity of testing AND
• A definitive diagnosis cannot be made based on history, physical examination, pedigree analysis, and standard diagnostic studies/tests alone; AND

A definitive diagnosis:

• Leads to changes in clinical management of the condition that improve outcomes; or

• Eliminates the need for further clinical workup or invasive testing; or

• Leads to discontinuation of interventions that are unnecessary and/or ineffective.

To establish a chain of evidence of the clinical utility of an affected individual's germline to benefit family members, evidence is needed from studies demonstrating:

• An association between the genetic variant and clinical disease has been established; and

• Family members are available who may be at risk for the disorder; and

• The individual tested has a clinical diagnosis of the condition (or represents the family member who is most likely to harbor the pathogenic variant), but genetic testing has not been performed; and

• There is a pre-symptomatic phase for the disorder in which interventions are available; and

• Interventions in the pre-symptomatic phase are likely to improve outcomes.

Review of Evidence

Clinical Validity

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).

Information on penetrance of CTNNA1 variants is limited to case reports.^15, For example, Benusiglio et al (2019) identified 1 family with a CTNN1 variant and diffuse gastric cancer foci in resected tissue from a patient undergoing prophylactic gastrectomy.^16, Hansford et al (2019) identified CTNNA1 variants in 2 HDGC families that were CDH1 negative.^5,

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 of the clinical utility of testing for CTNNA1 variants in individuals with suspected or at risk for HDGC. The evidence is insufficient to demonstrate clinical validity and therefore a chain of evidence cannot be established.

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.

Section Summary: Genetic Testing for CTNNA1 Variants to Identify Individuals With or at Risk for Hereditary Diffuse Gastric Cancer

There is no direct evidence of the clinical utility of testing for CTNNA1 variants to identify individuals with or at risk for HDGC. Evidence of clinical validity is limited to a small number of case reports and is insufficient to establish clinical validity. Therefore, a chain of evidence for clinical utility cannot be constructed.

Summary of Evidence

For individuals with suspected HDGC, or without suspected HDGC who are at risk for HDGC who receive germline genetic testing for CTNNA1 variants, the evidence includes a small number of case reports of CTNNA1 variants identified in individuals from families with HDGC. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There is no direct evidence of the clinical utility of testing for CTNNA1 variants in individuals with suspected HDGC or at risk for HDGC. The evidence is insufficient to demonstrate clinical validity and therefore a chain of evidence cannot be established. 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

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.

International Gastric Cancer Linkage Consortium

In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) updated their guidelines on hereditary diffuse gastric cancer (HDGC), including genetic testing criteria.^14, The guideline authors noted that, because of the relatively low incidence of HDGC, randomized controlled trial data are lacking and the recommendations relied on consensus expert opinion, expert evidence, and observational studies. Therefore, the evidence level for their recommendations was categorized as "low" to "moderate" according to GRADE definitions (i.e., further research is likely to very likely to have an important impact on confidence in the estimate of the effect addressed by the recommendation).

The Guidelines recommended the following criteria for genetic testing:

Family Criteria (family members must be first or second degree blood relatives of each other)

• Two or more cases of gastric cancer in family regardless of age, with at least one diffuse gastric cancer (DGC); or

• One or more case of DGC at any age and 1 or more case of lobular breast cancer before age 70 years in different family members; or

• Two or more cases of lobular breast cancer in family members before age 50 years.

Individual Criteria

• DGC before age 50 years; or

• DGC at any age in individuals of Maori ethnicity; or

• DGC at any age in individuals with a personal or family history (1st degree) of cleft lip/cleft palate; or

• History of DGC and lobular breast cancer, both diagnosed before age 70 years; or

• Bilateral lobular breast cancer, diagnosed before age 70 years; or

• Gastric in situ signet ring cells and/or pagetoid spread of signet ring cells in individuals before age 50 years.

The guidelines also note:

Histologically-confirmed intestinal-type gastric and non-lobular breast cancer cases should not be used to fulfil testing criteria as these are not part of HDGC.

Individuals who fulfill criteria for HDGC genetic testing should first have CDH1 analyzed and, if no variant identified, be considered for CTNNA1 analysis.

National Comprehensive Cancer Network

National Comprehensive Cancer Network (NCCN) Guidelines on Gastric Cancer (v.1.2023v.2.2024) include the following recommendations:^4,

Genetic testing for CDH1 mutations should be considered when any of the following criteria are met:

• Two gastric cancer cases in a family, 1 confirmed DGC regardless of age; or

• DGC diagnosed before age 50 years without a family history; or

• Personal or family history of DGC and lobular breast cancer, one diagnosed before age 70 years; or

• Two cases of lobular breast cancer in family members before 50 years of age; or

• DGC at any age in individuals of Māori ethnicity, or with a personal or family history of cleft lip/cleft palate; or

• Bilateral lobular breast cancer before age 70 years.

Prophylactic total gastrectomy is recommended between ages 18 and 40 for individuals with a CDH1 variant. Prophylactic gastrectomy prior to 18 years of age is not recommended, but may be considered for certain patients, especially those with family members diagnosed with gastric cancer before 25 years of age.

CDH1 variant carriers who elect not to undergo prophylactic gastrectomy should be offered screening every 6 to 12 months by upper endoscopy with multiple random biopsies.

Individuals with CDH1 variants should be followed using high-risk guidelines as outlined in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.

For those patients without a strong family history of DGC, genetics counseling with multidisciplinary review is indicated.

The Guidelines do not address CTNNA1 testing.

U.S. Preventive Services Task Force Recommendations

Not applicable.

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

An ongoingunpublished trial that might influence this review is listed in Table 2.

Table 2. Summary of Key Trials

NCT: national clinical trial.

References

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Stomach Cancer. https://seer.cancer.gov/statfacts/html/stomach.html. Accessed July 8, 2024.
2. Lee K, Krempely K, Roberts ME, et al. Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants. Hum Mutat. Nov 2018; 39(11): 1553-1568. PMID 30311375
3. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. Mar 26 1998; 392(6674): 402-5. PMID 9537325
4. National Comprehensive Cancer Network. Gastric Cancer. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed July 8, 2024.
5. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. Apr 2015; 1(1): 23-32. PMID 26182300
6. Roberts ME, Ranola JMO, Marshall ML, et al. Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers. JAMA Oncol. Sep 01 2019; 5(9): 1325-1331. PMID 31246251
7. DiBrito SR, Blair AB, Prasath V, et al. Total Gastrectomy for CDH-1 Mutation Carriers: An Institutional Experience. J Surg Res. Mar 2020; 247: 438-444. PMID 31685251
8. Ithurralde-Argerich J, Rosner L, Rizzolo M, et al. Laparoscopic Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer in CDH1 Mutation Carriers. J Laparoendosc Adv Surg Tech A. Jul 2021; 31(7): 729-737. PMID 34097461
9. Mastoraki A, Danias N, Arkadopoulos N, et al. Prophylactic total gastrectomy for hereditary diffuse gastric cancer. Review of the literature. Surg Oncol. Dec 2011; 20(4): e223-6. PMID 21872467
10. van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. Jun 2015; 52(6): 361-74. PMID 25979631
11. Benesch MGK, Bursey SR, O'Connell AC, et al. CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation. Cancers (Basel). May 26 2021; 13(11). PMID 34073553
12. Asif B, Sarvestani AL, Gamble LA, et al. Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study. Lancet Oncol. Apr 2023; 24(4): 383-391. PMID 36990610
13. Kluijt I, Siemerink EJ, Ausems MG, et al. CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int J Cancer. Jul 15 2012; 131(2): 367-76. PMID 22020549
14. Blair VR, McLeod M, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. Aug 2020; 21(8): e386-e397. PMID 32758476
15. Lobo S, Benusiglio PR, Coulet F, et al. Cancer predisposition and germline CTNNA1 variants. Eur J Med Genet. Oct 2021; 64(10): 104316. PMID 34425242
16. Benusiglio PR, Colas C, Guillerm E, et al. Clinical implications of CTNNA1 germline mutations in asymptomatic carriers. Gastric Cancer. Jul 2019; 22(4): 899-903. PMID 30515673
17. Guerra J, Pinto C, Pinto P, et al. Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer. Cancers (Basel). Aug 29 2023; 15(17). PMID 37686589

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