Study: Lifetime cancer risks in people with an inherited mutation in CDH1

Relevance: Medium-High

Strength of Science: High

Research Timeline: Post Approval

Relevance Rating Details

What is this study about?

This study looked at the lifetime risk of stomach and breast cancer in families with a known CDH1 mutation. Mutations in CDH1 cause hereditary diffuse gastric cancer syndrome, which is associated with an increased risk for both an aggressive form of stomach cancer that is hard to detect and a type of breast cancer known as lobular breast cancer.  This syndrome is more recently being referred to as diffuse gastric and lobular breast cancer syndrome.

Over time, estimates of the lifetime risks of cancers among people with a CDH1 gene mutation have changed. These changes are due to increased numbers of people having genetic testing. More information is available for researchers when the number of people completing genetic testing increases. This helps improve the overall understanding of the lifetime risks of cancers in people with inherited mutations.

Why is this study important?

Mutations in the CDH1 gene are uncommon. People with CDH1 mutations face difficult decisions to manage their risk for cancer. People with CDH1 mutations may be recommended to have risk-reducing gastrectomy (removal of the stomach) to prevent gastric cancer. Hereditary diffuse gastric cancer is a very aggressive type of cancer that is difficult to detect early. You can read more about the risk-management guidelines for people with CDH1 mutations here.

Reliable lifetime risk information for stomach and breast cancers is important because it influences decisions to have risk-reducing surgeries, such as removal of the stomach or breasts.

Previous estimates of the lifetime cancer risks for people with a CDH1 mutation were determined with studies of a small number of people. Risks for stomach cancer were estimated to be very high—up to 70 percent for men and up to 84 percent for women. In these prior studies, the lifetime risk of lobular breast cancer in women ranged from 39 to 52 percent.

More recent data from people having genetic testing in commercial labs suggested a lifetime cancer risk from 25 to 42 percent for stomach cancer. The lifetime risk for lobular breast cancer in women was 42 to 55 percent. Small numbers of people also limited these studies.

Based on the latest research of CDH1 lifetime cancer risks, the National Comprehensive Cancer Network (NCCN) updated their risk estimates for people with a CDH1 mutation. The NCCN now estimates based on all available studies a lifetime stomach cancer risk that ranges from 14 to 33 percent in women and 21 to 42 percent in men. NCCN guidelines also state that the risk of lobular breast cancer in women ranges from 37 to 55 percent.

Study findings

Researchers looked at families with at least one person who was known to have a CDH1 mutation. Family histories of stomach and breast cancer were self-reported and then confirmed by medical records. Participants included 213 CDH1 families (7,323 individuals) from North America. Among the participants, 883 had a CDH1 mutation. (For this study, a common feature in people with inherited CDH1 mutations, early T1a signet ring cells carcinomas, were not counted as true invasive cancers when estimating cancer risk as these are not thought to be life-threatening. Counting these as cancers doubled the risk estimates).

In this study, when researchers looked at people with a CDH1, and not taking into account their family history, results showed that:

• The lifetime risk of stomach cancer for men was just over 10%.
• The lifetime risk of stomach cancer for women was almost 7%.
• The lifetime risk of breast cancer for women was 37%.
  • This is similar to previous estimates.

When researchers looked at people with a CDH1 mutation who had family members with stomach cancer, the lifetime risk estimate of stomach cancer increased:

• The lifetime risk for people with 1 close relative with stomach cancer was just under 20%.
• The lifetime risk for people with 2 close relatives with stomach cancer was just under 30%.
• The lifetime risk for people with 3 close relatives with stomach cancer was 38%.

What does this mean for me?

In this study, the lifetime risk of stomach cancer among families with a CDH1 mutation was between 10-38%, with higher risk seen in families with a strong family history of invasive gastric cancer. The lower end of this risk estimate is substantially lower than earlier estimates.  However, the lifetime risk of breast cancer was similar to earlier estimates. The NCCN now estimates based on all available studies a lifetime stomach cancer risk that ranges from 14 to 33 percent in women and 21 to 42 percent in men. NCCN guidelines also state that the risk of lobular breast cancer in women ranges from 37 to 55 percent.  These new findings may help people make individualized decisions about their cancer risk management.

If you have an inherited mutation in CDH1 it is important to have a healthcare team with expertise in providing care to people with CDH1 mutations. Be sure to know your family’s cancer history and share it with your healthcare team. It is also important to update your healthcare providers on any changes in your family’s cancer history that have happened between your last and current appointment.

For more information on CDH1 visit our website here.

Reference

Ryan CE, Fasaye G, Gallanis AF, et al. Germline CDH1 Variants and Lifetime Cancer Risk. JAMA. 2024;332(9):722–729.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 12/10/24