HDGC FAMILIES: WHAT’S NEXT?

There are basically four possible CDH1 genetic test results.

· Pathogenic variant: a variant known to cause or capable of causing cancer.
· Negative: no variant found.
· Benign: a variant with no impact on health.
· Variant of Uncertain Significance (VUS): a variation was found, but it is unknown if the change is associated with a greater risk of causing cancer.

Follow your path.

Several paths have been laid out to guide the management of those at risk for HDGC. They are based upon updated HDGC genetic testing criteria, individual test results, and family cancer history. One size does not fit all, even for those headed down similar paths. Test results must be interpreted in the context of particular gene variant, family cancer history, individualized assessment, and other health and personal circumstances.There are three primary paths:

• Pathogenic CDH1 or CTNNA1 carriers
  • DGC in family (categorized as HDGC)
  • Only LBC, no DGC (categorized as HLBC)
  • No DGC or LBC
• Variant of Uncertain Significance (VUS)
• ‘HDGC-like’ Families (Negative for (CDH1 or CTNNA1)

Refer to  HDGC Fact Sheet for overview.
Refer to HDGC Clinical Guidelines for details.

WHERE DO YOU FIT? WHAT’S NEXT?

Pathogenic CDH1 or CTNNA1 carriers

A pathogenic variant in the CDH1 gene interferes with the normal function of the gene, directly contributing to the development of disease.

Recommended management for those who have a pathogenic CDH1 variant are clearly outlined in the IGCLC HDGC Clinical Guideline. Generally speaking, for those categorized ad HDGC families, endoscopic surveillance is recommended until such time that one is prepared to undergo prophylactic total gastrectomy (PGT), which is the recommended course of treatment. Annual gastric surveillance is recommended in HLBC families, with TG on positive biopsy and consideration for TG. Women should undergo annual breast surveillance or BRRM +/- reconstruction. It is recommended to seek care by a multidisciplinary medical team with expertise in HDGC, including a high risk breast center.

Next steps:
– Become familiar with the IGCLC HDGC Clinical Guidelines.
– Inform family members who may be at risk for HDGC syndrome. Your genetic counselor can help you with this process.
– Share information about HDGC with others, including a downloadable HDGC Fact Sheet.
– Seek a multidisciplinary medical team with expertise in HDGC. This may require travel to an HDGC expert center.
– HLBC families are eligible to join PROMPT; Prospective Registry Of MultiPlex Testing registry to advance research and understanding of CDH1 variants in HLBC families.

Talk about Surveillance:
The purpose of surveillance is to diagnose cancer at as early a stage as possible. Surveillance for diffuse gastric has not been particularly effective, hence the strong recommendation for risk-reducing surgery.  Ongoing research seeks more reliable methods to surveil for diffuse gastric cancer.
– Although risk reducing gastric surgery is the recommended approach to managing diffuse gastric cancer risk, talk to a gastroenterologist about a strategy for endoscopic surveillance while considering options.
– Decide if and when you want to proceed with prophylactic (preventive) total gastrectomy (PGT).
– For women, breast awareness beginning at age 18. Begin high risk breast cancer surveillance at age 30, to include clinical breast exam twice a year, and mammogram and breast MRI.
– Based upon personal and family history, consider colonoscopy every 3-5 years, beginning at age 40.

Talk about Surgery:
– The HDGC Clinical Guideline recommends risk-reducing surgery (also called prophylactic surgery) for diffuse gastric cancer, to reduce the risk of cancer by removing the stomach entirely before cancer can develop. This is a significant operation. It is important to thoroughly discuss the risks and benefits with specially trained medical providers at an HDGC center of excellence.

Talk about Medications:
Sometimes tamoxifen or other drugs are used to help prevent breast cancer in women. There remains much to be learned about these preventive drugs in some with CDH1 mutations. Talk to your medical team about this option as it relates to your situation.

Research is in progress in New Zealand to develop preventive drugs as an alternative to risk reducing surgery. Clinical trials may begin in the next 4-5 years. You can support this research through the HDGC Research Endowment Fund established specifically for this purpose.

– Consider enrollment in studies, surveys, clinical trials, and gastric cancer and genetic registries.

‘HDGC-like’ Families (Negative for CDH1 or CTNNA1)

If you have been tested for a CDH1 or CTNNA1 gene variant because you have clinical features suggestive of HDGC (meeting the established for criteria for testing for HDGC) and no variant is found, it could be that another gene variant is in play that has not yet been discovered. Researchers continue to work on identifying other gene variants that may contribute to HDGC. Gastric surveillance in an HDGC expert center should be considered. PTG is not advised. Breast management based upon individualized assessment is recommended.

Family members falling into this category who have a diffuse gastric cancer (DGC) diagnosis or lobular breast cancer (LBC) diagnosis should consider DNA banking (Prevention Genetics) to be used for future testing and discovery of other variants associated with gastric cancer in the future.

Variant of Uncertain Significance (VUS)

Unlike variants classified as pathogenic (causing or capable of causing disease) it is unclear whether or not this alteration in the DNA actually increases the risk of disease, or is a benign variation that has no impact on gene function.

Next steps:
– Discuss IGCLC HDGC Guidelines with your medical provider.
– Consideration should be given to gastric surveillance and breast management based upon individual assessment.
– If you have received a genetic test result of a VUS alteration in the CDH1 gene, please consider joining the PROMPT: Prospective Registry Of MultiPlex Testing registry to advance research and to follow the status of your variant.
– Talk to your genetic counselor about further knowledge and study of your particular variant. A lab in Portugal performs analysis of many CDH1 VUS alterations in order to advance research and inform patients and clinicians about the severity of the variant. If you are diagnosed with a CDH1 VUS, please have your genetic counselor contact us for more information on how to obtain services for functional evaluation at Raquel Seruca’s lab (IPATIMUP/i3S, Porto). There is no fee for these services.
– Read more about the work in Portugal related to CDH1 VUS.

Resources: Genetics

Publications: CDH1|Genetics