Introduction

Gastric cancer affected 0.97 million people worldwide in 2022, making it the fifth-most common cancer and cause of cancer death globally that year1. In Japan, gastric cancer was the leading cause of death by cancer site until 1998 and ranked third in 20222.

Helicobacter pylori (H. pylori)infection is listed as a Group 1 Carcinogen by the International Agency for Research on Cancer (IARC). It is the most critical factor in the development of gastric cancer3,4. Gastric cancer develops in 5% of H. pylori-positive individuals over ten years, according to estimates of the Japanese population5. The effect of infection varies according to the infecting H. pyloristrain and is not uniform worldwide6,7. A meta-analysis that included randomized control trials confirmed that H. pylori eradication is associated with a reduced incidence of gastric cancer8. However, whether eradication prevents gastric cancer in the general population has not been determined9.

Here, we conducted a pooled analysis of ongoing population-based cohort studies in Japan to determine the risk of developing gastric cancer after H. pylori eradication in a general population setting.

Materials and methods

Study population

The study was conducted using prospective cohort study data of residents aged 40–74 years in four areas: Yamagata, Saku, Yokote, and Chikusei, Japan. The Yamagata area initiated the study in 2009 under the Yamagata Study protocol. Blood samples were collected with consent at the time of health examinations, and questionnaires were conducted at baseline and the 5-year follow-up survey. Medical information derived from health insurance records, cancer diagnoses by cancer registries, and deaths were captured during follow-up. The Saku, Yokote, and Chikusei areas initiated the study under the protocol of The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study), which was initiated in 2011 and targeted residents in each area. Questionnaire surveys and blood sampling were conducted at baseline and at the time of the 5-year follow-up survey. Participants were followed for vital status, cause of death, and residential relocation by the residential registry or death certificates, with consent. Both the Yamagata Study and JPHC-NEXT Study were designed to identify lifestyle, environmental, and genetic factors in the development of lifestyle-related diseases. The two large cohort studies are described in detail elsewhere10,11.

We conducted two main analyses. Analysis 1 included only the baseline survey results, while Analysis 2 included only those who responded to the baseline and 5-year follow-up surveys.

We initially included 49,140 residents aged 40–74 in the four areas who participated in the baseline survey and had blood sampling. After those with a history of gastric cancer as determined by self-report or the cancer registries before baseline were excluded (n = 610), 48,530 participants were regarded as eligible for analysis (Analysis 1). Among these, 32,196 participants answered the questionnaire of the 5-year follow-up survey. After excluding those who were treated for H. pylori eradication before the baseline survey (n = 3,658), were both H. pylori antibody- and PG test-negative (n = 13,240) or were treated for eradication at an unknown time (n = 2,214), participants who were H. pylori antibody-positive and/or PG test-positive (n = 13,084) were included in further analysis (Analysis 2).

The study flow is shown in Fig. 1.

Fig. 1
figure 1

Selection flowchart.

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Assessment of H. pylori infection status

This study used serum samples obtained during health examinations or study-specific blood sampling opportunities. Serum anti-H. pylori IgG antibodies were measured using enzyme-linked immunosorbent assay (ELISA; E-Plate Eiken or E-Plate II Eiken; Eiken Chemical Co., Ltd., Japan). We defined values of 10 U/mL or higher as positive, the standard cut-off point when the study was initiated. As a marker of atrophic gastritis, serum levels of pepsinogen (PG) I and II were measured by latex agglutination (LZ test “Eiken” Pepsinogen I, II; Eiken Kagaku). The PG test was determined to be negative at PG I > 70 ng/mL or PG I/II > 3.0, or positive at PG I ≤ 70 ng/mL and PG I/II ratio ≤ 3.012. Participants were then categorized into five groups by H. pylori infection status according to the results for serum anti-H. pylori IgG antibodies and PG test, namely H. pylori-negative and PG test-negative; H. pylori-positive and PG test-negative; H. pylori-positive and PG test-positive; H. pylori-negative and PG test-positive; and self-reported history of H. pylori eradication before baseline survey.

Assessment of H. pylori eradication history

In the Yamagata Study, we inquired about participants’ H. pylori eradication status using the following questions: (1) “Have you ever been tested for H. pylori?” (Yes/No) (2) “Have you received H. pylori eradication?” (Yes/No), (3) “At what age did you receive H. pylori eradication?” In the JPHC-NEXT, we asked, “Have you ever received H. pylori eradication?” (No history/Received). Participants who reported previous eradication were additionally asked about the length of time between eradication and baseline (< 1 year, 1 year to < 6 years, ≥ 6 years). We matched the eradication age in the Yamagata Study participants to the JPHC-NEXT response categories. Those who underwent eradication after gastric cancer diagnosis were reclassified as no-eradication. The validity of this study’s self-reported H. pylori eradication history has been confirmed elsewhere13,14.

Follow-up and identification of gastric cancer

Participants were followed from the date of study entry at baseline until gastric cancer diagnosis, movement out of the study area, death, or the end of follow-up (December 31, 2018), whichever occurred first. Data on survival, movement out of the study area, and death were identified from residence records. Information on the study outcome – gastric cancer (Code C16.0–16.9) diagnosed during the study period – was obtained from major local hospitals as well as regional (until 2015) and national cancer registries (from 2016) by the Cancer Registry Promotion Act and prepared for analysis in this study and processed independently. Cases were coded using the International Classification of Diseases for Oncology (ICD-O), Third Edition15.

Statistical analysis

Hazard ratios (HRs) and 95% confidence intervals (CIs) for developing gastric cancer by category of years since eradication were determined using Cox proportional hazards models, controlling for the following potential confounders: sex, age at baseline (5-year categories), body mass index (< 20 kg/m2, 20 to < 25 kg/m2, 25 to < 30 kg/m2, or ≥ 30 kg/m2), smoking status (never, current, former), and alcohol consumption (pure ethanol per week; never or rarely, < 150 g/week, 150 to 300 g/week, 300 g/week or more). These variables were selected based on associations identified in a previous study16. Missing values were also incorporated as missing indicator variables in the analysis. Heterogeneity across the study areas was accounted for by including the study area as a strata variable in the Cox model. We also estimated HRs stratified by H. pylori infection status. Some participants who completed the 5-year follow-up survey underwent eradication between baseline and the 5-year follow-up survey. Additional sensitivity analyses were conducted based on complete-case analysis, excluding cases with missing values and participants with inconsistent responses between the baseline and 5-year follow-up survey. Testing of the proportional hazards assumption using Schoenfeld and scaled Schoenfeld residuals found no violation of proportionality. The p-values for differences in the Tables were calculated using ANOVA (normal distribution) or Pearson’s chi-squared test and reported as two-sided, with p < 0.05 set as the statistical significance level. All statistical analyses were performed using Stata 17 (Stata Corp).

Results

Analysis 1 included 48,530 participants for analysis (20,762 men and 27,768 women; average age at baseline, 60.3 years). During 283,379 person-years of follow-up (average follow-up period: 5.8 years), a total of 649 participants (463 men and 186 women) were newly diagnosed with gastric cancer. In Analysis 2, there were 323 diagnoses of gastric cancer during a mean follow-up period of 6.1 years. (Fig. 1). The baseline characteristics of the study participants according to their self-reported history of H. pylori eradication are shown in Table 1. A total of 11.7% of participants had an H. pylori eradication history at the baseline survey, with the largest proportion of participants from the Chikusei area (14.6%). Men had a higher proportion of eradication treatment history than women (14.4% vs 9.6%). With regard to drinking history, there were no significant differences in the distribution of whether and how much alcohol was consumed between the eradicated and non-eradicated groups for both men and women. Concerning smoking history, the proportion of current smokers was not significantly different between the eradicated and non-eradicated groups in men and women. Selected characteristics of the study participants according to H. pylori infection status and serum PG1 and PG2 assays are shown in Table S1.

Table 1 Baseline characteristics according to self-reported history of H. pylori eradication.
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Table 2 shows the results of gastric cancer risk by length of time between eradication and baseline (Analysis 1). Among those with no history of eradication, participants who were H. pylori-positive and/or PG test-positive had a higher risk of gastric cancer (HR 5.89, 95%CI: 4.41–7.87) compared with those who were H. pylori-negative and PG test-negative. Further, the risk was increased in those who were H. pylori-positive and PG test-negative (HR 3.62, 95% CI: 2.60–5.03) and further increased in H. pylori-positive and PG test-positive (HR 7.67, 95% CI: 5.69–10.34) and in H. pylori-negative and PG test-positive (HR 8.79, 95%CI: 6.04–12.80). When analysis was restricted to participants with H. pylori infection (including those both with and without a history of eradication), compared with those with no history of eradication as reference, risk was increased for those who had undergone eradication less than one year before baseline (HR 1.74, 95%CI: 1.18–2.57) but decreased for those who had undergone eradication 1–6 years and 6 or more years before baseline (HR 0.81, 95%CI: 0.59–1.11; HR 0.44, 95%CI: 0.28–0.68, respectively). Although there was a statistically significant difference between the H. pylori-seropositive and PG test-negative group and the H. pylori-seropositive and PG test-positive group (p = 0.04), there was no significant difference between the H. pylori-seropositive and PG test-positive group and H. pylori-seronegative and PG test-positive group (p = 0.54). For those with gastric mucosal atrophy confirmed by a PG test, the difference in risk of developing gastric cancer was not observed by H. pylori infection status, either seropositive or seronegative.

Table 2 Hazard ratios and 95% confidence intervals of gastric cancer risk by H. pylori infection status and H. pylori eradication history (Analysis 1).
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Table 3 shows gastric cancer risk by period after H. pylori eradication based on the 5-year follow-up survey (Analysis 2). Among participants who followed from baseline to the 5-year follow-up survey, only those with a positive H. pylori infection status (H. pylori-positive and/or PG test-positive) and who self-reported an eradication history at the baseline and 5-year follow-up surveys were included. Compared to those with no eradication, gastric cancer risk declined after eradication between baseline and the 5-year follow-up survey, which was not statistically significant (HR 0.84, 95%CI: 0.56–1.26 for < 1 year at the 5-year follow-up survey; and HR 0.80, 95%CI: 0.63–1.03 for 1–6 years at the 5-year follow-up survey).

Table 3 Hazard ratios and 95% confidence intervals of gastric cancer risk by the period after H. pylori eradication (between baseline and 5-year follow-up survey) among subjects who were H. pylori-positive and/or PG test-positive (Analysis 2).
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The complete case analysis was performed as a sensitivity analysis, and the analysis by age group showed no significant differences from the original analysis (data not shown).

Discussion

We examined the risk of developing gastric cancer after H. pylori eradication treatment by combining data from population-based cohort studies in four areas comprising a total of 48,530 Japanese participants. To our knowledge, this is the first report to examine the association between H. pylori eradication and gastric cancer risk in a large-scale prospective cohort study of a general Japanese population. We observed that the risk of gastric cancer among those who underwent eradication before baseline decreased with increasing time. This followed a temporal increase in risk immediately after eradication compared to those with H. pylori infection and no history of eradication. This finding suggests that gastric cancer risk is decreased in the long term by H. pylori eradication for those at high risk in a general population setting (Table 2). One possible reason for the temporary increase in risk is the inevitable rise in the number of endoscopies before and after eradication aimed at the possible diagnosis of early gastric cancer. Additionally, oversight of early gastric cancer during pre-eradication endoscopy complicates accurate risk evaluation after eradication. Risk showed a decreasing trend among participants who first underwent eradication between baseline and the 5-year follow-up survey (Table 3). These differences from the risk trends in participants eradicated before baseline may be partly due to the inclusion of participants with shorter observation periods. H. pylori eradication was shown to be more likely to reduce gastric cancer risk if performed in the early phase of infection both in an experiment17and an epidemiological study for individuals with few symptoms or mild gastric atrophy18.

One mechanism underlying the association between H. pylori infection and gastric cancer development may be deoxyribonucleic acid (DNA) methylation induced by chronic H. pylori infection-associated inflammation19,20. Cytotoxin-associated Gene A (CagA), a toxic agent of H. pylori, plays an important role in carcinogenesis6by promoting genetic mutations through interaction with breast cancer susceptibility gene 1 (BRCA1)21. H. pylori eradication decreases the effects of DNA methylation abnormalities and CagA, suggesting a preventive effect on carcinogenesis. However, if abnormalities occur in gastric epithelial cells and stem cells22, they may persist after eradication, which might explain why carcinogenic risk does not fully recover to healthy levels23.

The main strengths of this investigation are its large, well-characterized Japanese cohort and collection of information before a diagnosis of gastric cancer, eliminating recall bias. Nevertheless, some methodological limitations also warrant mention. First, participants’ self-reported H. pylori eradication history was not confirmed using their treatment history. Eradication history may have been misclassified due to misidentification, with accidental eradication being a possible cause23. We assume that the results of medical records survey13and medical claims data14 have sufficient validity. Second, we did not consider the treatment assessment result or secondary eradication due to the high success rate of first-time eradication. This omission may cause the effect of eradication to be underestimated. In addition, some gastric cancers were diagnosed during the follow-up period among those classified as both H. pylori- and PG test-negative; these might be gastric cancers unrelated to H. pylori or attributable to misclassification by accidental eradication from other treatments or forgotten eradication reports. Third, we could not analyze gastric cancer risk by stratifying participants with a history of eradication, which should also be stratified by the presence or absence of mucosal atrophy at the time of eradication. The present study obtained information on gastric atrophy at the baseline survey only when the time had passed since eradication. As a result, we could not evaluate these data, which may have reflected gastric mucosal changes due to the eradication. Fourth, participants who had undergone eradication before baseline may have had advanced symptoms, such as peptic ulcers. This is because eradication was covered by health insurance for these individuals. Insurance coverage was subsequently extended to include “H. pylori-gastritis” after February 2013, which resulted in a marked nationwide increase in the number of patients undergoing eradication, from approximately 650,000 per year in 2001–2012 to 1.38 million per year in 201324. The effectiveness of eradication during the short follow-up period may have been influenced by the timing of eradication, specifically whether it was performed before or after the introduction of health insurance coverage. Additionally, the presence or absence of symptoms at the time of eradication may have also impacted the outcomes. In addition, a simulation study estimated that the 2013 coverage of eradication for H. pylori-gastritis in Japan will decrease the prevalence of H. pylori infection by 2050 to 5%, versus 22% if coverage had not been provided24. In the present study, initiating health insurance coverage for eradication of H. pylori-gastritis during the study period may have resulted in differences in participant backgrounds before and after the coverage began. However, we were unable to investigate these differences in detail. Given these changes in medical conditions, risk reduction by early eradication and early detection using appropriate long-term endoscopic examination should be considered essential components of any gastric cancer prevention strategy.

In conclusion, we found that H. pylori eradication was associated with a decrease in long-term gastric cancer risk in a large Japanese general population. However, a temporary risk increase was observed during the post-eradication observation period. These findings may aid risk stratification for strategic gastric cancer prevention and promote future prevention efforts.