Eradication of Helicobacter pylori and its impact on the incidence of gastric cancer

Gastric cancer (GC) ranks 5th worldwide in new cancer cases and also holds the 5th position in cancer-related mortality (1). In 2022, approximately 968,350 new GC cases and 659,853 GC-related deaths were documented globally (1). The primary risk factors associated with GC carcinogenesis include genetic alterations, diet (rich in nitrosamines, cholesterol, and salt), smoking, alcohol consumption, and Helicobacter pylori (H. pylori) infection, the latter being the main contributor to GC development (2,3).

From this perspective, understanding the epidemiological impact of H. pylori infection across different populations and its statistical relationship with GC development has become a key research focus. In this context, Pan et al., in a study published in Nature Medicine, presented a robust randomized clinical trial conducted in Linqu County, China, with the objective of to assess the potential for H. pylori mass screening and eradication as a public health policy for GC prevention in high-risk settings (4).

In their study, Pan et al. conducted a cluster-randomized, community-based, controlled, superiority intervention clinical trial in Linqu County, China, which included H. pylori-positive individuals divided into an intervention group (10-day quadruple therapy: omeprazole 20 mg, tetracycline 750 mg, metronidazole 400 mg, and bismuth citrate 300 mg) and a control group (treatment for symptom relief with a single daily dose of omeprazole and bismuth citrate) (4). The study monitored 180,284 patients from 980 villages over 11.8 years and concluded that H. pylori-positive patients treated with eradication therapy had a modest reduction in GC incidence [hazard ratio (HR) =0.86, 95% confidence interval (CI): 0.74–0.99] compared to the control group. A more significant effect was noted in the group with successful H. pylori eradication (HR =0.81, 95% CI: 0.69–0.96) (4).

In this context, Ford et al. conducted a meta-analysis based on multiple randomized clinical trials, mostly from East Asia, including one conducted in Linqu County, China (5). The findings showed that among healthy H. pylori-positive individuals who received eradication therapy, there was a marked reduction in GC incidence (RR =0.54, 95% CI: 0.40–0.72) (5). Similarly, Sugimoto et al. performed a meta-analysis of clinical studies conducted in East Asia and observed that H. pylori-positive patients who received eradication therapy had a significantly lower risk of developing GC (RR =0.67, 95% CI: 0.47–0.96) (6).

When comparing the Pan et al. study (4) with other studies on this topic, it is evident that their study conducted a robust randomized clinical trial involving a large population, and its results align with those of previously mentioned meta-analyses. Other studies have also reached similar conclusions (7,8).

However, it is necessary to consider additional perspectives relevant to the epidemiological impact of GC, such as other established risk factors. Besides analyzing a large cohort, Pan et al. stratified individuals according to personal characteristics like age, smoking, alcohol use, history of gastric disease, and family history of cancer (4). This approach allowed for the assessment of H. pylori eradication success across various subgroups, adding an essential layer to epidemiological analysis. Pan et al. found GC incidence and mortality were modestly reduced in those aged < 45-year at baseline but not in the over 45-year age group (4). H. Pylori eradication also appeared to offer greater GC protection for smokers compared to nonsmokers (4). The findings suggest that, with H. pylori eradicated, other risk factors may influence GC onset in eradication-treated groups, highlighting the complex nature of GC carcinogenesis when all variables are considered (4). This subgroup analysis is crucial because eliminating H. pylori brings other risk factors to the fore, as seen in a study by Poorolajal et al., which examined the impact of each factor on oncogenesis (9).

A recent meta-analysis further underscores the potential benefits of maintaining long-term monitoring of H. pylori infection status, as unsuccessful eradication or reinfection was associated with a 1.86 times greater risk of developing GC (10). This point is particularly relevant to the Pan et al.’s study, which achieved a 72.9% eradication success rate in the intervention group (4). One of the limitations of the study, acknowledged by Pan et al., was their failure to provide secondary eradication treatment for primary treatment failures (4). This highlights the importance of follow-up, as unsuccessful eradication poses a greater risk for carcinogenesis; the lack of long-term testing was also noted as a limitation in the Pan et al.’s study (4,10).

Another key perspective is the genetic diversity of H. pylori strains and how it affects their carcinogenic potential, impacting clinical trial outcomes across different regions. The H. pylori CagA protein has phosphorylation sites known as EPIYA motifs (Glu-Pro-Ile-Tyr-Ala), classified into four groups (EPIYA-A to EPIYA-D) (11). Studies have shown a higher carcinogenic potential associated with EPIYA-C and EPIYA-D motifs. Asian H. pylori strains generally carry EPIYA-D, while western strains are more commonly associated with EPIYA-C (11-14). This genetic variability supports the need for large-scale studies, such as Pan et al. (4), across various regions, as these data can help clarify the epidemiological impact of strain-specific genetic differences. This could also guide the future inclusion of H. pylori eradication as a primary GC prevention protocol in high-prevalence areas.

Another relevant factor is the growing antimicrobial resistance of H. pylori, which has had a direct impact on eradication treatment protocols (15). Numerous studies report resistance to key antimicrobials, such as clarithromycin, amoxicillin, metronidazole, and levofloxacin, thus reducing H. pylori eradication rates and complicating GC prevention efforts (16). Pan et al. used tetracycline and metronidazole in their eradication regimen; however, significant resistance, particularly to metronidazole, may partially explain the study’s suboptimal 72.9% eradication rate (4,17,18). Consequently, antimicrobial resistance should be a key consideration in clinical studies on H. pylori eradication and GC prevention, as the failure to confirm eradication due to resistance leaves patients vulnerable to carcinogenesis (19,20).

In conclusion, the Pan et al.’s study (4) offers significant contributions to the scientific community by analyzing H. pylori eradication’s role in GC prevention using a large cohort. The study also supports the feasibility of implementing mass H. Pylori screening and treatment from early adulthood as a public health policy in high-risk community settings. This randomized study employed rigorous methodology, addressing factors like comorbidities and lifestyle, and demonstrated the impact of H. pylori eradication on reducing GC incidence. Additional studies of this scale are needed globally to provide comprehensive data on GC prevalence and H. pylori’s role in various regions, recognizing strain-specific oncogenic potential. Moreover, future studies should account for antimicrobial resistance due to its direct impact on eradication outcomes. Establishing solid data, as proposed by Pan et al. (4), represents a crucial step toward primary GC prevention through large-scale H. pylori eradication in high-prevalence regions, which could yield significant benefits for the most affected populations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-238/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-238/coif). The authors have no conflicts of interest to declare.

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References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 2023;20:338-49. [Crossref] [PubMed]
3. Toro DH, Bofill-Garcia A, Anzalota-Del Toro M. Helicobacter Pylori and Gastric Cancer: An Update in the Literature. P R Health Sci J 2024;43:9-17. [PubMed]
4. Pan KF, Li WQ, Zhang L, et al. Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial. Nat Med 2024;30:3250-60. [Crossref] [PubMed]
5. Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut 2020;69:2113-21. [Crossref] [PubMed]
6. Sugimoto M, Murata M, Yamaoka Y. Chemoprevention of gastric cancer development after Helicobacter pylori eradication therapy in an East Asian population: Meta-analysis. World J Gastroenterol 2020;26:1820-40. [Crossref] [PubMed]
7. Lin Y, Kawai S, Sasakabe T, et al. Effects of Helicobacter pylori eradication on gastric cancer incidence in the Japanese population: a systematic evidence review. Jpn J Clin Oncol 2021;51:1158-70. [Crossref] [PubMed]
8. Fan F, Wang Z, Li B, et al. Effects of eradicating Helicobacter pylori on metachronous gastric cancer prevention: A systematic review and meta-analysis. J Eval Clin Pract 2020;26:308-15. [Crossref] [PubMed]
9. Poorolajal J, Moradi L, Mohammadi Y, et al. Risk factors for stomach cancer: a systematic review and meta-analysis. Epidemiol Health 2020;42:e2020004. [Crossref] [PubMed]
10. Luo X, Qi S, Chen M, et al. Maintaining H. pylori Negativity After Eradication Can Consolidate Its Benefit in Gastric Cancer Prevention: A Meta-Analysis. Clin Transl Gastroenterol 2024;15:e00742. [Crossref] [PubMed]
11. Freire de Melo F, Marques HS, Rocha Pinheiro SL, et al. Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis. World J Clin Oncol 2022;13:866-79. [Crossref] [PubMed]
12. Lemos FFB, Freire de Melo F. Interplay of homologous-recombination genes and Helicobacter pylori in gastric cancer susceptibility. Transl Cancer Res 2023;12:2984-8. [Crossref] [PubMed]
13. Li Q, Liu J, Gong Y, et al. Association of CagA EPIYA-D or EPIYA-C phosphorylation sites with peptic ulcer and gastric cancer risks: A meta-analysis. Medicine (Baltimore) 2017;96:e6620. [Crossref] [PubMed]
14. Takahashi-Kanemitsu A, Knight CT, Hatakeyama M. Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell Mol Immunol 2020;17:50-63. [Crossref] [PubMed]
15. Dascălu RI, Bolocan A, Păduaru DN, et al. Multidrug resistance in Helicobacter pylori infection. Front Microbiol 2023;14:1128497. [Crossref] [PubMed]
16. Medakina I, Tsapkova L, Polyakova V, et al. Helicobacter pylori Antibiotic Resistance: Molecular Basis and Diagnostic Methods. Int J Mol Sci 2023;24:9433. [Crossref] [PubMed]
17. Huang X, Wu B, Chen Q, et al. Antibiotic resistance profile of Helicobacter pylori to 14 antibiotics: a multicenter study in Fujian, China. PeerJ 2023;11:e15611. [Crossref] [PubMed]
18. Wei W, Wang Z, Li C, et al. Antibiotic resistance of Helicobacter pylori in Nanjing, China: a cross-section study from 2018 to 2023. Front Cell Infect Microbiol 2023;13:1294379. [Crossref] [PubMed]
19. Mannion A, Dzink-Fox J, Shen Z, et al. Helicobacter pylori Antimicrobial Resistance and Gene Variants in High- and Low-Gastric-Cancer-Risk Populations. J Clin Microbiol 2021;59:e03203-20. [Crossref] [PubMed]
20. Li Y, Lin R, Jin Y, et al. Genotyping Helicobacter pylori antibiotic resistance and virulence-associated genes in patients with gastric cancer in Wenzhou, China. Arab J Gastroenterol 2021;22:267-71. [Crossref] [PubMed]