Gastric cancer in the United States has poor survival outcomes, with an estimated 32% 5-year survival (1). High-incidence nations, such as Japan and South Korea, have implemented gastric cancer screening with success in improving overall survival (2); this has been attributed to increased numbers of early-stage gastric cancer diagnoses. Up to three-fourths of all gastric cancers in the United States are diagnosed at an advanced stage (3). Although the overall incidence of gastric cancer in the United States remains low, certain racial/ethnic groups are at increased risk, particularly in diverse racial/ethnic communities (4,5). In addition, family history of gastric cancer has been shown in previous studies as an independent risk factor of gastric cancer development (6,7) and to be associated with increased risk of progression to gastric cancer among patients with gastric intestinal metaplasia (GIM) (8,9).
We conducted a prospective pilot screening program of patients with a confirmed first-degree relative with gastric cancer to evaluate the feasibility and prevalence of precursor lesions such as GIM or dysplasia on biopsy. This was a prospective study starting in March 2017 until COVID-19 shelter-in-place orders interrupted the program in March 2020. Endoscopic screening took place at 2 high-volume endoscopy centers within Kaiser Permanente, Southern California. Patients were invited to participate in screening if (i) their electronic health record showed a family history of gastric cancer, as previously noted through routine clinical ascertainment, and (ii) they were at least 40 years or younger than 10 years before diagnosis of gastric cancer in their first-degree relative. Patients referred for open-access upper endoscopy were included if their primary care provider noted the family history of gastric cancer and found them appropriate for screening.
Patients with hereditary cancer syndromes or a personal history of gastric cancer were excluded. Patients with established diagnosis of hereditary diffuse gastric cancer or autoimmune atrophic gastritis were not included in this study. Biopsies were obtained according to the Sydney protocol: sampling from both lesser and greater curvatures of the body, antrum, and incisura and then placed into separate containers. Outcomes of interest included Helicobacter pylori infection, GIM, or dysplasia. Extensive GIM was defined as GIM seen in 2 or more biopsy sample locations. This study was approved by the Institutional Review Board of Kaiser Permanente, Southern California.
A total of 61 patients agreed to participate and completed screening by upper endoscopy with a mapping biopsy protocol. The average age was 59.3 years (SD 9.9), with 34 females (56%). The most frequently screened racial/ethnic group was Asian: 33 (54%), followed by Latinx: 26 (43%) and White: 2 (3.3%). Of the 61 patients, 14 (23%) had either H. pylori gastritis on biopsy or a history of H. pylori infection. Ten of the 14 patients (71%) with active H. pylori infection or H. pylori history were also found to have GIM. Among those with H. pylori infection, all 14 (100%) were eradicated of the infection, demonstrated either through negative confirmatory stool antigen or negative biopsy results.
With the use of the mapping protocol, 27 of the 61 patients (44%) were found to have GIM and 4 of the 61 patients (6.6%) were found with low-grade dysplasia. Among those with GIM (n = 27), 21 (78%) were defined as extensive GIM. Among the Asian patients screened (n = 33), 21 (64%) had the presence of GIM in at least 1 biopsy sample while among the screened Latinx population (n = 26), 5 (19%) had evidence of GIM. One of the 2 White patients who underwent screening had GIM. Cases of GIM were placed into routine surveillance programs for repeat upper endoscopy with biopsies. Of the 4 cases with low-grade dysplasia, 1 was of Latinx race/ethnicity and the remaining 3 were of Asian race/ethnicity. Three of the 4 cases of low-grade dysplasia underwent endoscopic submucosal dissection, with the last opting for surveillance. There were no adverse events in performing upper endoscopy examinations or with follow-up procedures such as endoscopic submucosal dissection.
Identification of precursor lesions in a high-risk population is important in determining the interval of future surveillance examinations and classification of overall risk of gastric cancer. Oftentimes, a single biopsy is obtained from the greater curvature of the antrum as a means to suffice for sampling; however, this method would have only captured 19 of 31 patients with GIM or dysplasia. An inadequate biopsy protocol may miss up to 38% of GIM or dysplasia diagnoses based on the study findings, which would significantly alter protocols for surveillance or even localized resection within this high-risk population.
A significant proportion of the patients undergoing screening had H. pylori gastritis or a history of H. pylori infection. H. pylori is an established carcinogenic agent for the development of gastric cancer and its precursor lesions, such as GIM or dysplasia. A recent double-blinded, placebo-controlled trial in South Korea demonstrated that H. pylori treatment among those with a family history of gastric cancer reduced risk of gastric cancer (6). The ability to successfully eradicate H. pylori in a screened population was confirmed in this study by either noninvasive or endoscopic testing.
There were several limitations to this pilot study. This study did not apply the Operative Link on Gastritis Assessment and Operative Link on Gastritis/Intestinal Metaplasia Assessment systems because these parameters are not routinely reported in the context of standard clinical practice. In addition, this study comprised a large proportion of Asian and Latinx patients. Owing to the limited sample size, we were unable to tease apart the relative contribution of family history vs race/ethnicity in relation to the prevalence of GIM in this study. This is an important aspect for future investigation to better define high-risk populations for targeted screening in the future.
In summary, our pilot screening program identified a high prevalence of precursor lesions for gastric cancer among asymptomatic patients with a first-degree relative with gastric cancer, particularly in patients of Asian or Latinx descent. Rates of extensive GIM were also high among those found with GIM at baseline. Careful endoscopic inspection and standardized biopsy protocols may aid in prompt identification of these precursor lesions in those at risk of gastric cancer. We believe this to be among the first pilot studies for a systematic gastric cancer screening program using a standardized biopsy protocol for first-degree relatives within the United States. Endoscopic screening with biopsies seemed to be feasible for detecting precancerous lesions at baseline. Long-term studies are needed to demonstrate the efficacy of endoscopic screening and potential impact of early detection of gastric cancer on outcomes for patients in the United States.
CONFLICTS OF INTEREST
Guarantor of the article: Bechien U. Wu, MD.
Specific author contributions: E.Y.D. conceived and designed the work, acquired, analyzed, and interpreted data for the work; drafted the manuscript; provided final approval for the published version; and agreed to be accountable for all aspects of the work. A.Q.G. interpreted the data for the work, revised the work critically for intellectual content, provided final approval for the published version, and agreed to be accountable for all aspects of the work. E.L. interpreted the data for the work, revised the work critically for intellectual content, provided final approval for the published version, and agreed to be accountable for all aspects of the work. B.U.W. interpreted the data for the work, revised the work critically for intellectual content, provided final approval for the published version, and agreed to be accountable for all aspects of the work.
Financial support: None to report.
Potential competing interests: None to report.
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