CDH1 – risk management

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition characterised by a strong susceptibility to diffuse gastric cancer (DGC) and lobular breast cancer in females.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

Caution 

The advanced^* gastric cancer risk is based on testing having occurred in a family with a strong gastric cancer family history. While signet ring cell carcinomas have been reported in prophylactic total gastrectomy specimens from CDH1 pathogenic variant carriers with no family history of DGC, the magnitude of the risk of developing advanced DGC in these individuals is uncertain.^r

^* Advanced DGC predominantly presents with linitis plastica and invasion of the gastric wall. 

• Unaffected CDH1 pathogenic variant carrier from a family with a history of DGC

Exclusion criteria^**

• Individuals with a family history of DGC, where pathogenic variant testing has not been done or is uninformative
• Unaffected CDH1 pathogenic variant carrier from a family where there is no history of gastric cancer
• Individual with a variant of uncertain significance

** Risk management per the IGCLC 2020 Guidelines^r can be considered.

Management of patients with HDGC requires a multidisciplinary approach and should be managed by a centre experienced in the care of these patients. Specialist dietitian input is required for post-gastrectomy patients to manage dumping syndrome and to avoid nutritional deficiencies. There is usually a 15-20% decrease in body weight.^r

Decision making where there is a family history of very early onset gastric cancer is more complex, as early gastrectomy and associated nutritional problems could impact on normal growth and pubertal development for adolescents.

Pregnancy can be carried to full term following prophylactic gastrectomy, although an interval of at least 6-12 months after surgery is recommended to allow for weight stabilisation and nutritional recovery.

Hereditary diffuse gastric cancer is a rare disorder and guidelines are based on expert opinion of the International Gastric Cancer Linkage Consortium. Updated clinical guidelines were published in 2020^r based on information gathered since the original recommendations were published in 1999. The guidelines are based on observation and the outcome of research protocols.

The published diffuse gastric and lobular breast cancer risks are derived from CDH1 families ascertained because of a history of DGC. In the absence of a family history of DGC, the risk of diffuse gastric or lobular breast cancer is unclear.^r

Gastric

Surgical

Expert consensus supports gastrectomy in asymptomatic individuals with a germline CDH1 pathogenic variant.^r This is because of the high risk of death from gastric cancer, the elimination of risk of gastric cancer after gastrectomy and lack of evidence that surveillance is effective in preventing advanced gastric cancer. Endoscopy is recommended in CDH1 patients prior to total gastrectomy for staging.^r

Families with a history of very early onset gastric cancer have been described,^r and gastrectomy may be considered earlier than usual in these families. The impact of early gastrectomy and associated nutritional problems on normal growth and pubertal development in adolescents must be taken into account when considering the timing of surgery.

Surveillance

The limitations of endoscopy and nature of DGC should be explained to all patients.

For those declining or postponing gastrectomy, endoscopic surveillance should be offered. An Endoscopy Surveillance Protocol for HDGC has been developed by expert consensus^r (see Supplementary Appendix Supplementary Text 1: Endoscopy Surveillance Protocol to Blair et al. 2020). Whenever possible, surveillance should occur in expert centres familiar with HDGC. Signet ring lesions are detected in gastric biopsies for 40-61% of CDH1 carriers, and a positive biopsy is most likely during the first endoscopy.^rr 

Surveillance should only be offered to asymptomatic individuals who would be surgical candidates for gastrectomy if gastric cancer were to be identified.

Breast

Surveillance

There is currently insufficient data on the role and outcome of breast cancer screening in carriers of a CDH1 pathogenic variant, so recommendations are based on the high lifetime risk of breast cancer, particularly the lobular subtype, and the precedents established in other hereditary breast cancer syndromes. MRI may be more sensitive than mammogram for detection of lobular cancer.^r The addition of ultrasound to mammogram can be considered if MRI is not available or contraindicated.^r

Risk-reducing medication

Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer in high-risk women. There have been no studies to date to determine if it is specifically effective for the primary prevention of lobular breast cancer. In view of the potential side effects associated with tamoxifen/raloxifene, risk-reducing medications should be discussed with an experienced medical professional to determine the relevant risks and benefits in an individual pathogenic variant carrier. See COSA medication to lower the risk of breast cancer: clinician guide.

Therapeutic levels of chemopreventative agents could be compromised after total gastrectomy.

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Version 10

Date	Summary of changes
15/09/2023	New eviQ cancer genetics risk management template changes applied - PDF of changes. Version number changed to V.10.

Version 9

Date

Summary of changes

13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template: Summary: Template sentence updated. Target group: Added to exclusion criteria "Individual with a variant of uncertain significance". Cancer/tumour risk management guidelines: Template sentence updated Lifestyle factors sentence moved above the table.  Management of associated health problems: Accordion title changed to "Management of associated health issues". Version number increased to V.9.

Version 8

Date

Summary of changes

28/04/2021

Protocol reviewed at October 2020 reference committee meeting. Discussions continued via email and MS Teams. New 2020 eviQ template changes applied. Approved for publication with the following changes made: Summary: 'Hereditary diffuse gastric cancer is a heterogeneous dominantly inherited disorder with 25-50% of cases being due to a pathogenic variant in the CDH1 (E-cadherin) gene. The disorder is' changed to 'Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition' Template sentence inserted: 'The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.' Caution: 'The risk of gastric cancer in a CDH1 pathogenic variant carrier in the absence of a family history of gastric cancer is uncertain.' changed to 'While signet ring cell carcinomas have been reported in prophylactic total gastrectomy specimens from CDH1 pathogenic variant carriers with no family history of DGC, the magnitude of the risk of developing advanced DGC in these individuals is uncertain.' Note added Target group: Exclusion criteria bullet 1: 'cannot be' changed to 'has not been'; Note added Lifetime risk of cancer/tumour: Accordion and table column 1 heading changed to 'cancer/tumour' Column 3: heading changed from 'age 85 years' to 'age 80 years' Column 2 and 3: figures updated New note to table inserted Cancer/tumour risk management guidelines: Accordion and table column 1 heading changed to 'cancer/tumour' New sentence inserted before table: 'The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.' Table: Gastric Surgical and Surveillance recommendations completely redrafted Breast Surgical and Surveillance recommendations redrafted Breast Risk-reducing medication inserted Notes to table amended Management of associated health problems: 'There is usually a 10-15% decrease in body weight, principally body fat. For individuals with a family history of very early onset gastric cancer, gastrectomy may be considered earlier than usual. Decision making may be even more complex for adolescents, where early gastrectomy and associated nutritional problems could impact on normal growth and pubertal development.' changed to read: 'There is usually a 15-20% decrease in body weight. Decision making where there is a family history of very early onset gastric cancer is more complex, as early gastrectomy and associated nutritional problems could impact on normal growth and pubertal development for adolescents.' final sentence: ', although an interval of at least 6-12 months after surgery is recommended to allow for weight stabilisation and nutritional recovery' inserted at end Evidence for risk management guidelines: second sentence '2015' changed to '2020' final sentence 'unknown' changed to 'unclear' Gastric Surgical: paragraph 1 major changes; inserted new paragraph 2 Gastric Surveillance: completely redrafted Breast Surveillance: 'MRI may be superior' changed to ' MRI may be more sensitive than mammogram' and new sentence inserted: 'The addition of ultrasound to mammography can be considered if MRI is not available or contraindicated.' Breast Risk-reducing medication inserted Support and information: Template change to: 'First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.' Website resources: extra resources added Version number increased to V.8. Review in 2 years.

Version 7

Date	Summary of changes
27/11/2019	"Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.7.

Version 6

Date	Summary of changes
25/10/2012	Discussed at August 2012 reference committee meeting.
08/11/2012	Approved and published.
25/03/2013	Cancer risk management guidelines table, colorectal surveillance discussed at March 6 2013 reference committee meeting and this section changed from: 'recommended for mutation carriers where there is a close relative with bowel cancer from aged 40 yrs (or 10 yrs younger than affected cases) and repeated at intervals of 3-5 years' to 'consider colonoscopy where there is a close relative with bowel cancer from aged 40 yrs (or 10 yrs younger than affected cases) and repeated at intervals of 5 years unless polyps are found'.
02/12/2013	For review second yearly.
18/09/2015	Discussed at May 2015 reference committee meeting and approved for publishing, with the following changes: Title - updated. Lifetime risk of cancer table - updated. Cancer risk management guidelines table: Gastric - surveillance - changed to no evidence of long term benefit. Breast - surveillance - added to consider continuing MRI as may be superior for detection of lobular cancer. Colorectal cancer deleted. Management of associated problems and side effects - sentence reworded. Evidence for risk management guidelines - updated. Reference list - updated.
07/01/2016	Sentence added to Risk Management template: the impact of lifestyle on cancer risk should be discussed.
14/04/2016	Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".
28/09/2016	'Unaffected' removed from title.
19/10/2016	Protocol reviewed during cancer genetic chair/co-chair teleconference 12 Oct 2016: no changes required, protocol is to be reviewed with ID 1080 Genetic testing for heritable mutations in the CHD1 gene (Oct 2017).
31/05/2017	Transferred to new eviQ website. Version number changed to V.4.
2/05/2018	Protocol reviewed and presented at November 2017 reference committee meeting. Discussion continued over email and document approved for publication with the following changes:  Mode of breast cancer screening for women > 50 removed to align with international guidelines. Surveilance of breast cancer screening updated to include no upper age limit.  Version change to V.5.
28/08/2019	Protocol title changed from 'Risk management for individuals with a heritable CDH1 mutation' to 'CDH1 – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.6.