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Investigators have known about hereditary diffuse gastric cancer syndrome for decades, but only identified its molecular causes in the 1990s, said gastrointestinal oncologist Bryson Katona, MD, PhD.
Investigators have known about hereditary diffuse gastric cancer syndrome (HDGC) for decades, but only identified its molecular causes in the 1990s, said gastrointestinal oncologist Bryson Katona, MD, PhD. Until that point, he added, medical technology was not sufficiently advanced to identify the genetic etiology of the cancer predisposition syndrome.
“One of the hallmarks of HDGC is diffuse gastric cancer [DGC],” said Katona. He is director of the gastrointestinal cancer genetics program and director of the gastrointestinal cancer risk evaluation program with Abramson Cancer Center at the University of Pennsylvania. “The precursor to diffuse gastric cancer in these patients are these small focuses of signet ring cells, microscopic focuses that can only be seen under the microscope and can’t be detected by any other type of diagnostic modality—we can’t see them on endoscopy, and they can’t be picked up on a CT scan or a PET scan.”
Gastric cancer is the fifth most common neoplasm and the third most deadly cancer, according to GLOBOCAN data from 2018. Stomach cancer, which includes cardia and noncardia gastric cancer, accounted for an estimated 783,000 deaths in 2018.1
Approximately 20% of all stomach cancers are diffuse gastric cancers, also called signet ring cell gastric cancer. HDGC, first identified in an extended Māori family in New Zealand in a paper published in 1998, accounts for just 1% to 3% of gastric cancers.2,3
HDGC is associated with mutations in the CTNNA1 gene or CDH1 gene, which is also associated with increased risk for lobular breast cancer. The lifetime risk for gastric cancer in CDH1- mutation carriers ranges from 67% to 70% for men and 56% to 83% for women, but the risks for CTNNA1 carriers remain poorly defined.4 Katona won a $250,000 grant from the DeGregorio Family Foundation in September 2021 to conduct the CTNNA1 Familial Expansion Study (CAFÉ) study (NCT05126290), which aims to clarify the cancer risks for those carrying a CTNNA1 mutation.
“We’ll be recruiting families with CTNNA1 mutations worldwide to collect information about their personal and family history of cancer so that we can get a better understanding of the cancer risks associated with this gene,” he said. “We hope that by collecting [data on] families with CTNNA1 mutations, we will really be able to get a much better sense of what the cancer risks are and what different types of cancers these individuals may be affected with, which will, ultimately, help with how we manage these patients, what kind of screening we do, and what type of preventative surgeries they may or may not need. It will be really helpful for informing how we manage these families in the future.”
As of 2020, the International Gastric Cancer Linkage Consortium (IGCLC) relaxed its criteria for genetic testing of individuals at elevated risk for HDGC, increasing threshold age for isolated DGC cases to 50 years. The consortium kept the 2015 criteria, which recommended testing in individuals with a personal or family history of cleft lip/cleft palate and DGC, or with HDGC precursor lesions. Physicians should analyze individuals who fulfill criteria for HDGC genetic testing for CDH1 first and, if no variant is identified, consider CTNNA1 analysis (Figure).4
Figure. International Gastric Cancer Linkage Consortium 2020 HDGC Genetic Testing Criteria4
“About 15% of HDGC families will have some family history of cleft lip or cleft palate,” Katona said.
There is no systemic treatment available for cancer prevention in HDGC. The only therapy for prevention is prophylactic total gastrectomy and patients are advised to undergo the surgery by the age of 30. However, surgery is not recommended for patients aged 70 years or older because of increased perioperative risks and prolonged recovery.4
“Prophylactic total gastrectomy is really all we have for these patients. We can do screening on a regular basis with upper endoscopy, but we have not shown that we’ve been able to effectively identify cancer early,” Katona said. “We don’t have any good medications to prevent [this] cancer and there are no specific dietary changes. We don’t want these patients to smoke, but this is an area where we definitely need more research. It seems like in this day and age, we would have something more to offer to these patients other than just prophylactic stomach removal, but unfortunately, we are not there yet.”
With surgery, however, the risk for gastric cancer is removed, Katona said, although it carries significant risk, including mortality. The recovery can be long and can require further surgeries, he added.
Katona said these patients face long-term risks as well, especially regarding nutrition and bone health. “One [complication] that I find to be the most difficult to manage is changes in bone health over time, because the stomach is very important for helping individuals to absorb calcium. We are doing these surgeries [when patients are] in their 20s. I do worry about their bone health down the road.”
Select patients may be eligible to delay surgery and undergo annual endoscopic surveillance based on certain characteristics. Katona said patients younger than age 30 who are pursuing higher education or may want to have children may choose to delay gastrectomy. Additionally, patients who carry the mutation but have no family history of gastric cancer can also consider foregoing surgery and instead pursuing endoscopic surveillance.
“For annual surveillance, we do endoscopy and take multiple biopsies throughout the stomach, including biopsies of both abnormal and normal appearing mucosa, he said. “If any of these biopsies show a focus of signet ring cells, then the patient is referred for a total gastrectomy. However, even with negative biopsies on annual endoscopic surveillance, there can still be underlying signet ring cell cancer that was not sampled during surveillance.”
That said, results are generally positive for those who undergo surgery. Canadian investigators surveyed 53 CDH1-mutation carriers who underwent prophylactic total gastrectomy from 2004 to 2013. Most respondents were female (74%) and most (64%) were 50 years or younger at the time of surgery. Forty-seven patients (80%) had open surgery while the remaining 6 (11%) had laparoscopic surgery.5
The mean length of hospital stay was 8.9 days with a median of 7 days (range, 4-18 days), and the length of stay for 3 of the patients who received laparoscopic surgery was 4 to 7 days. Twenty-three participants experienced post-surgical complications either during the hospital stay or within 6 months of surgery.
Forty-seven (88%) of the participants said they were satisfied (9%) or very satisfied (79%) with their decision to have surgery.
“Maybe we don't have to remove everybody's stomach, maybe we can just remove stomachs from the people that are the at the highest risk,” Katona said. “But at this point, we don't have good ways for defining or determining who is at the highest risk and who’s not.”
Katona concluded that there are several important questions that still need to be asking.
“I hope that this is an area that will get increasing funding attention from [the National Institutes of Health],” he said. “It’s an exciting area. It’s a growing area with growing research interests.”