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Genetic Test: Hereditary Diffuse Gastric Cancer (CDH1, CTNNA1) | |
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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.
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 (NCI SEER Program, 2022).
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 (Lee, 2018; Guilford, 1998). 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.
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Policy/ Coverage: |
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Germline genetic testing for CDH1 variants to identify individuals with or at risk for hereditary diffuse gastric cancer (HDGC) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals meeting the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Germline genetic testing for CDH1 variants in all other situations not addressed in this or any other policy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, germline genetic testing for CDH1 variants in all other situations not addressed in this or any other policy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Germline genetic testing for CTNNA1 variants to identify individuals with or at risk for HDGC does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, germline genetic testing for CTNNA1 variants to identify individuals with or at risk for HDGC is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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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 11, 2022.
Genetic Testing for CDH1 Variants in Individuals Without Suspected Hereditary Diffuse Gastric Cancer Who are at Risk for Hereditary Diffuse Gastric Cancer
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.
Criteria have been established to identify individuals without cancer or without cancer related to HDGC who are at risk for HDGC (NCCN, 2022):
Penetrance 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 conducted a penetrance analysis on 75 families with identified CDH1 pathogenic variants (N=3858 relatives) (Hansford, 2015). 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 conducted a retrospective cohort study of 75 families (N=1679 individuals, 238 with an identified CDH1 pathogenic variant) (Roberts, 2019). 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.
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 (DiBrito, 2020; Ithurralde-Argerich, 2021; Mastoraki, 2011).
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 (van der Post, 2015).
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 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 (Benesch, 2021). 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 also conducted a retrospective cohort study of 97 consecutive asymptomatic individuals in Newfoundland and Labrador with a CDH1 variant (Benesch, 2021). 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%.
Estimates of the risk of breast cancer in individuals with a CDH1 variant range from 42% to 55%, and case series have reported lobular carcinoma in situ in individuals from families with CDH1 variants who have undergone prophylactic bilateral mastectomy (Kluiit, 2012). 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 (Blair, 2020).
Genetic Testing for CDH1 Variants in Individuals With Suspected Hereditary Diffuse Gastric Cancer
Criteria have been established to identify individuals with diffuse gastric or lobular breast cancer who are at risk of having HDGC:
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.
There is no direct evidence of the clinical utility of germline genetic testing for CDH1 variants in individuals with suspected HDGC.
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.
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.
Information on penetrance of CTNNA1 variants is limited to case reports (Lobo, 2021). For example, Benusiglio et al identified 1 family with a CTNN1 variant and diffuse gastric cancer foci in resected tissue from a patient undergoing prophylactic gastrectomy (Benusiglio, 2019). Hansford et al identified CTNNA1 variants in 2 HDGC families that were CDH1 negative (Hansford, 2015).
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.
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.
National Comprehensive Cancer Network (NCCN) Guidelines on Gastric Cancer (v.2.2022) include the following recommendations (NCCN, 2022):
Genetic testing for CDH1 mutations should be considered when any of the following criteria are met:
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.
In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) updated their guidelines on HDGC, including genetic testing criteria (Blair, 2020). 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)
Individual Criteria
The guidelines also note:
Histologically confirmed intestinal-type gastric and non-LBC 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 haveCDH1 analyzed and, if no variant identified, be considered for CTNNA1 analysis.
Summary of Key Trials
NCT03030404 Hereditary Gastric Cancer Syndromes: An Integrated Genomic and Clinicopathologic Study of the Predisposition to Gastric Cancer has a planned enrollment of 1150 and expected completion date of December 2026
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A prospective cohort study was conducted 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 (Asif, 2023). 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 of38,803 total gastric biopsy samples were collected, of which 1163 (3%) were positive for signet ring cell carcinoma. Overall, 101of 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.
National Comprehensive Cancer Network (NCCN) Guidelines on Gastric Cancer (v. 1.20232.2022) include the following recommendations (NCCN, 2023):
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.
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CPT/HCPCS: | |
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References: |
Asif B, Sarvestani AL, Gamble LA, et al.(2023) 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 Benesch MGK, Bursey SR, O'Connell AC, et al.(2021) 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 Benusiglio PR, Colas C, Guillerm E, et al.(2019) Clinical implications of CTNNA1 germline mutations in asymptomatic carriers. Gastric Cancer. Jul 2019; 22(4): 899-903. PMID 30515673 Blair VR, McLeod M, Carneiro F, et al.(2020) Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. Aug 2020; 21(8): e386-e397. PMID 32758476 DiBrito SR, Blair AB, Prasath V, et al.(2020) Total Gastrectomy for CDH-1 Mutation Carriers: An Institutional Experience. J Surg Res. Mar 2020; 247: 438-444. PMID 31685251 Guilford P, Hopkins J, Harraway J, et al.(1998) E-cadherin germline mutations in familial gastric cancer. Nature. Mar 26 1998; 392(6674): 402-5. PMID 9537325 Hansford S, Kaurah P, Li-Chang H, et al.(2015) Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. Apr 2015; 1(1): 23-32. PMID 26182300 Ithurralde-Argerich J, Rosner L, Rizzolo M, et al.(2021) 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 Kluijt I, Siemerink EJ, Ausems MG, et al.(2012) 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 Lee K, Krempely K, Roberts ME, et al.(2018) 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 Lobo S, Benusiglio PR, Coulet F, et al.(2021) Cancer predisposition and germline CTNNA1 variants. Eur J Med Genet. Oct 2021; 64(10): 104316. PMID 34425242 Mastoraki A, Danias N, Arkadopoulos N, et al.(2011) Prophylactic total gastrectomy for hereditary diffuse gastric cancer. Review of the literature. Surg Oncol. Dec 2011; 20(4): e223-6. PMID 21872467 National Cancer Institute (NCI).(2022) Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Stat Facts: Stomach Cancer. https://seer.cancer.gov/statfacts/html/stomach.html. Accessed August 3, 2022. National Comprehensive Cancer Network (NCCN).(2022) Gastric Cancer. Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed August 3, 2022. National Comprehensive Cancer Network.(2023) Gastric Cancer https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed June 23, 2023. Roberts ME, Ranola JMO, Marshall ML, et al.(2019) 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 van der Post RS, Vogelaar IP, Carneiro F, et al.(2015) 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 |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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