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Cancer
Association between Helicobacter pylori and its eradication and the development of cancer
  1. Sven Heiko Loosen1,
  2. Alexander Mertens1,
  3. Isabel Klein2,
  4. Catherine Leyh1,
  5. Sarah Krieg1,
  6. Jennis Kandler1,
  7. Tom Luedde1,
  8. Christoph Roderburg1,
  9. Karel Kostev2
  1. 1 Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
  2. 2 IQVIA Germany, Frankfurt, Hessen, Germany
  1. Correspondence to Dr Alexander Mertens; alexander.mertens{at}med.uni-duesseldorf.de

Abstract

Background Helicobacter pylori (H. pylori) is a gram-negative gastrointestinal pathogen that colonises the human stomach and is considered a major risk factor for gastric cancer and mucosa-associated lymphoid tissue lymphoma. Furthermore, H. pylori is a potential trigger of a wide spectrum of extragastric cancer entities, extraintestinal chronic inflammatory processes and autoimmune diseases. In the present study, we evaluated the association between H. pylori infection and its eradication with the development of subsequent gastrointestinal and non-gastrointestinal cancer.

Methods We identified 25 317 individuals with and 25 317 matched individuals without a diagnosis of H. pylori from the Disease Analyzer database (IQVIA). A subsequent cancer diagnosis was analysed using Kaplan-Meier and conditional Cox-regression analysis as a function of H. pylori and its eradication.

Results After 10 years of follow-up, 12.8% of the H. pylori cohort and 11.8% of the non-H. pylori cohort were diagnosed with cancer (p=0.002). Results were confirmed in regression analysis (HR: 1.11; 95% CI 1.04 to 1.18). Moreover, a non-eradicated H. pylori status (HR: 1.18; 95% CI 1.07 to 1.30) but not an eradicated H. pylori status (HR: 1.06; 95% CI 0.97 to 1.15) was associated with a subsequent diagnosis of cancer. In subgroup analyses, H. pylori eradication was negatively associated with bronchus and lung cancer (HR: 0.60; 95% CI 0.44 to 0.83).

Conclusion Our data from a large outpatient cohort in Germany reveal a distinct association between H. pylori infection and the subsequent development of cancer. These data might help to identify patients at risk and support eradication strategies in the future.

  • HELICOBACTER PYLORI
  • CANCER
  • HELICOBACTER PYLORI - TREATMENT
  • CANCER PREVENTION
  • CANCER EPIDEMIOLOGY

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjgast-2024-001377

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • While the role of H. pylori infection in gastric cancer and primarily intestinal diseases is obvious, extraintestinal diseases from H. pylori, for example, cancer, and the potential role of H. pylori eradication remain a matter of debate.

    WHAT THIS STUDY ADDS

    • Our study reveals the impact of H. pylori infection on extraintestinal cancer prevalence as well as the role of H. pylori eradication for bronchus and lung cancer.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Our study may help to identify patients at risk for extraintestinal cancer related to H. pylori infection as well as to identify patients who will benefit from H. pylori eradication therapy.

    Introduction

    Helicobacter pylori (H. pylori) is a common human-to-human transmitted (usually fecal-oral or oral-oral) gram-negative spiral-shaped bacterium that persists in the stomach, with approximately 50% of the world’s population infected.1 The individual risk for an H. pylori infection depends on numerous factors, above all on geographic and ethnic affiliation, socioeconomic status, higher age and lower hygiene conditions. Germany belongs worldwide and within Europe to the countries with comparatively low H. pylori prevalence rate of 20%–40%.2 3 H. pylori plays a major role in the pathogenesis of chronic gastritis, peptic ulceration and malignant diseases, for example, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma.4 5 It has been classified as a class 1 carcinogen since 1994.6–8 H. pylori risk is associated with a host-dependent genetic predisposition to carcinogenesis and intrinsic H. pylori virulence factors (eg, cytotoxin-associated gene A (CagA) antigen-producing strains).9–13 On the other hand, the effect of H. pylori eradication in gastric cancer (GC), as well as the influence of H. pylori in the development of extra gastric non-malignant diseases (eg, autoimmune, cardiovascular) and malignant diseases (eg, cancer of the lungs, pancreas, and colon), are still controversial.8 14 The long-term H. pylori-triggered immune and inflammatory responses are postulated as the main underlying mechanisms for extradigestive pathologies.15

    In the present study, we evaluated the association between H. pylori infection and its eradication with the development of subsequent gastrointestinal (GI) and non-GI cancer over a long observational period of 10 years for the individual cases in Germany, the most populous country in the European Union.

    Materials and methods

    Database

    This retrospective cohort study was based on data from the Disease Analyzer database (IQVIA), which contains drug prescriptions, diagnoses and basic medical and demographic data obtained directly and in anonymous format from computer systems used in the practices of general practitioners and specialists.16 The database covers approximately 3% of all medical practices in Germany. The sampling method for the Disease Analyzer database is based on summary statistics from all doctors in Germany published yearly by the German Medical Association. IQVIA uses these statistics to determine the panel design according to the four strata, including specialist group, German federal state, community size category and age of physician. It has previously been shown that the panel of practices included in the Disease Analyzer database is representative of general and specialised practices in Germany.16 Finally, this database has already been used in previous studies focusing on cancer.17 18

    Study population

    This study included adult patients (≥18 years) with an initial diagnosis of H. pylori infection in 1284 general practices in Germany between January 2005 and December 2021 (index date; figure 1). As physicians used different codes of ICD-10 (International Statistical Classification of Diseases and Related Health Problems, Version 10) to code H. pylori, we used original diagnosis text to identify H. pylori patients. Further inclusion criteria were an observation time of at least 12 months before the index date and a follow-up time of at least 6 months after the index date. Patients with a diagnosis of cancer (ICD-10: C00–C97), in situ neoplasms (ICD-10: D00–D09) and neoplasms of uncertain or unknown behaviour diagnoses (ICD-10: D37–D48) before the index date, on the index date or within 3 months after the index date were excluded.

    Figure 1
    Figure 1

    Selection of study patients.

    After applying similar inclusion criteria, individuals without H. pylori were matched to H. pylori patients based on age, sex, index year, average yearly consultation frequency during follow-up and Charlson Comorbidity Score using propensity score matching (1:1). The Charlson index is a weighted index that accounts for the number and severity of comorbidities in administrative database studies and includes a wide range of comorbidities (macrovascular diseases, pulmonary diseases, GI, liver, and renal diseases, diabetes, AIDS and others).19 For the cohort without H. pylori, the index date was a randomly selected visit between January 2005 and December 2021 (figure 1).

    Study outcomes

    The outcomes of the study were the initial diagnoses of cancer in total (ICD-10: C00–C97) as well as GI cancers, including oesophagus (ICD-10: C15), stomach (ICD-10: C16), colorectal (ICD-10: C18, C20), liver (ICD-10: C22) and pancreatic (ICD-10: C25) cancer and respiratory cancers including the larynx (ICD.10: C32), bronchus and lung (ICD-10: C34) cancer within up to 10 years following the index date as a function of H. pylori. The H. pylori cohort was then divided into two subgroups depending on the prescription of an eradication therapy between the index date and 2 months after the index date to analyse both eradicated and non-eradicated H. pylori patients compared with patients without H. pylori in terms of a subsequent cancer diagnosis.

    Statistical analyses

    Differences in baseline characteristics and the prevalence of diagnosis between the cohorts with and without H. pylori were compared using the Wilcoxon signed-rank test for continuous variables, the McNemar test for categorical variables with two categories and the Stuart-Maxwell test for categorical variables with more than two categories. The 10-year cumulative incidence of cancer in the cohort with H. pylori with or without eradication versus the cohort without H. pylori was further studied with Kaplan-Meier curves. Curves were compared using the log-rank test. Patients were censored at the time of loss to follow-up (last visit to physician), last date in the database (31 January 2022), or cancer diagnosis, whichever occurred first. The average follow-up time was 5.9 (SD: 3.8) years. Finally, an univariable conditional Cox regression analysis was performed to assess the association between H. pylori and its eradication and cancer in total, as well as GI and respiratory cancers. Results of the Cox regression model are displayed as HRs and 95% CIs. A p value of p<0.01 was considered statistically significant due to multiple comparisons. Analyses were conducted using SAS V.9.4 (SAS Institute).

    Patient and public involvement

    This study included adult patients (≥18 years) with an initial diagnosis of H. pylori infection in general practices in Germany between January 2005 and December 2021. The database used for this study analysis contains anonymised electronic patient records. Patient data were analysed in aggregated form without individual data being available. Participant consent was waived because this was a retrospective study, and data were anonymised entirely.

    Results

    Baseline characteristics of the study cohort

    The present study included 25 317 H. pylori-positive individuals, and 25 317 matched individuals without a diagnosis of H. pylori. Of those diagnosed with H. pylori, 13 737 received eradication therapy from their general practitioner (GP) within 2 months of the index date. Baseline characteristics of the study patients are displayed in table 1. The mean age was 53.2 (SD: 15.8), and 58.2% were female. Patients had an average of 7.5 GP visits per year during follow-up. Baseline characteristics of H. pylori patients with and without eradication therapy are shown in the online supplemental table S1.

    Supplemental material

    View this table:
    Table 1

    Baseline characteristics of the study sample (after 1:1 matching)

    Association of H. pylori and a subsequent cancer diagnosis

    After up to 10 years of follow-up, 12.8% of the H. pylori cohort and 11.8% of the non-H. pylori cohort were diagnosed with cancer (p=0.002, figure 2). Based on the power analysis, with absolute patient samples and event rates, the estimated statistical power was 0.99. In the regression analysis, there was a small but significant association between H. pylori and a subsequent cancer diagnosis (HR: 1.11; 95% CI 1.04 to 1.18, p=0.002, table 2). In the stratified analyses by cancer type, there was a strong but not significant association between H. pylori and stomach cancer (HR: 1.59; 95% CI 1.00 to 2.53, p=0.049) and for pancreatic cancer (HR: 1.46; 95% CI 0.99 to 2.17, p=0.058, table 2).

    Figure 2
    Figure 2

    Cumulative incidence of cancer in patients with and without H. pylori.

    View this table:
    Table 2

    Association between H. pylori and subsequent gastrointestinal and respiratory cancer diagnosis in patients followed in general practices in Germany (univariable Cox regression models)

    The role of H. pylori eradication therapy

    Figure 3 and online supplemental table S2 show the cumulative incidence of cancer in eradicated and non-eradicated patients with H. pylori compared with patients without H. pylori. There was a significant difference between non-eradicated patients with H. pylori and patients without H. pylori (13.2% vs 11.8%, p<0.001), but no significant difference between eradicated patients with H. pylori and patients without H. pylori (12.5% vs 11.8%, p=0.231). In regression analyses, a non-eradicated H. pylori status (HR: 1.18; 95% CI 1.07 to 1.30) but not an eradicated H. pylori status (HR: 1.06; 95% CI 0.97 to 1.15) was associated with a subsequent diagnosis of cancer (table 2). In subgroup analyses, the only cancer entity with a significant effect of H. pylori eradication was bronchus and lung cancer. Here, H. pylori eradication was negatively associated with cancer of the bronchus and lung (HR: 0.60; 95% CI 0.44 to 0.83), and there was a strong trend towards an association between non-eradicated H. pylori and subsequent cancer of the bronchus and lung (p=0.035, table 2).

    Figure 3
    Figure 3

    Cumulative incidence of cancer in patients with and without H. pylori depending on eradication therapy.

    Discussion

    H. pylori has been classified as a group 1 carcinogen since 1994, with an uncontroversial role in GC and MALT lymphoma.6–8 On the other hand, the effect of H. pylori eradication in GC and the influence of H. pylori in the development of extra gastric non-malignant (eg, autoimmune, cardiovascular) and other malignant diseases (eg, cancer of the lungs, pancreas, and colon) is still a matter of debate.8 14 In the present primary care study, we evaluated the association between H. pylori infection and its eradication with the development of subsequent GI and non-GI cancer over a long observational period in Germany.

    Study cohort and H. pylori eradication

    We included 25 317 H. pylori-positive individuals, and 25 317 matched individuals without a diagnosis of H. pylori (figure 1). The mean age in our study was 53.2 (SD: 15.8) years and 58.2% were female (table 1). Worldwide data suggest a slightly higher prevalence of H. pylori in males.20 The higher rate of females in our study remains unclear. However, this may reflect the higher adherence of female patients to primary care and the higher number of females in the general population in Germany (50.7 vs 49.3%).21 Patients had an average of 7.5 GP visits per year during follow-up, which is approximately in line with current data in the general German population (average of 10 visits/year).22 Of those individuals diagnosed with H. pylori, 13 737 (54.3%) received eradication therapy from their GP within 2 months of the index date (figure 1). The proportion of the therapies carried out in our study is comparatively low, and it is important to mention that we were not able to evaluate which reasons led to the decision for (or against) eradication therapy in individual cases. For decades, the advice for H. pylori eradication therapy remained unchanged regarding peptic ulcer disease, low-grade gastric B-cell lymphoma (MALT lymphoma), atrophic gastritis and after gastric carcinoma resection. According to the 2022 updated German guideline, H. pylori infection is considered a bacterial disease of the stomach, regardless of symptoms or clinical appearance.3 Therefore, a positive test for H. pylori in adulthood is always an indication for therapy, even if the patient has no clinical symptoms. At the same time, the indication for testing (and therefore, in the case of H. pylori detection consecutive eradication) has been extended in the German guideline, which will likely lead to an increasing number of eradication therapies in the following years and therefore possibly a decreased prevalence of H. pylori in the general German population.3 On the other hand, other factors (eg, local preferences and experience, expertise of GPs) may contribute to the number of therapies carried out, and a future impact on the incidence of H. pylori-associated gastric and extragastric carcinoma remains unclear.

    Association of H. pylori and a subsequent cancer diagnosis

    After up to 10 years of follow-up, 12.8% of the H. pylori cohort were diagnosed with cancer (p=0.002, figure 2), and in the regression analysis, there was a small but significant association between H. pylori and a subsequent diagnosis of cancer (HR: 1.11; 95% CI 1.04 to 1.18). The role of H. pylori in gastric malignancies, particularly GC and gastric MALT lymphoma, is indisputable. H. pylori has been recognised as a class I carcinogen by the International Agency for Research on Cancer.4 23–25 Despite a close causal link between H. pylori infection and the development of gastric malignancies, the precise mechanisms involved in this process are still a matter of debate. Specific virulence factors such as CagA, vacuolating cytotoxin A, the host genotype, environmental factors such as diet and alternations in stem cell populations, and the microbiome act in complex and only partially understood ways in the development of gastric malignancies.26 27 Our data support a strong association between H. pylori and GC (HR: 1.59; 95% CI 1.00 to 2.53), but the results failed to reach statistical significance (p=0.049), table 2. It is important to mention that we could not record individual host or intrinsic H. pylori factors contributing to the risk of cancer (of any entity). However, due to the large cohort and matched CCS (table 1), these aspects are potentially less relevant. We have to state that a vast majority of H. pylori tests by GPs will probably have been carried out due to upper GI symptoms, reflecting a state of inflammation (eg, gastritis), but this remains speculative. Despite recording the timepoint of positive H. pylori testing, the time between the actual infection and the onset of cancer, like in most published studies, remains unclear (just as potentially subsequent infections) due to the usually long-term asymptomatic H. pylori infection. This is particularly relevant given the predominantly long-term effects of H. pylori infections and in long-term H. pylori-infected but asymptomatic individuals.

    According to published data, H. pylori is associated with a decreased risk of oesophageal squamous cell carcinomas and oesophageal adenocarcinomas.28 Our data support these findings: carcinoma of the oesophagus was negatively associated with H. pylori infection (HR: 0.49, 95% CI 0.26 to 0.89), but the results did not reach statistical significance (p=0.020).

    During the late 1990s, the first reports showing that H. pylori is associated with extradigestive diseases (autoimmune diseases, cardiovascular diseases, colonic and pancreatic diseases, haematological and respiratory diseases) appeared. These observations were most likely linked to the immune and inflammatory responses triggered by H. pylori infection.29–31 In this context, the role of H. pylori in triggering chronic respiratory disease (and lung cancer) is relatively well understood but still a matter of debate.24 31 In our study, H. pylori infection was not associated with a higher incidence of cancer of bronchus and lungs (HR: 0.88, 95% CI 0.69 to 1.11, p=0.278). This finding is contrary to other data, including a meta-analysis.32 The role of H. pylori in pancreatic cancer remains highly controversial.33–36 In the stratified analyses by pancreatic cancer, our data showed a strong but not significant association between H. pylori and pancreatic cancer (HR: 1.46; 95% CI 0.99 to 2.17, table 2). Other tumour entities showed no relevant association with H. pylori infection: colon and rectum, liver and larynx (table 2).

    The role of H. pylori eradication therapy

    The cumulative incidence of cancer in eradicated and non-eradicated patients with H. pylori compared with patients without H. pylori in our study is shown in figure 3: there was a significant difference between non-eradicated patients with H. pylori and patients without H. pylori (13.2% vs 11.8%, p<0.001), reflecting the role of known but untreated H. pylori infection in carcinogenesis. As mentioned above, we could not evaluate which reasons led to the decision for (or against) eradication therapy in individual cases. In subgroup analyses, the only cancer entity with a significant effect of H. pylori eradication was bronchus and lung cancer. Here, H. pylori eradication was negatively associated with cancer of the bronchus and lung (HR: 0.60; 95% CI 0.44 to 0.83), and there was a strong trend towards an association between non-eradicated H. pylori and subsequent cancer of the bronchus and lung (p=0.035, table 2).

    In GC, eradication of H. pylori led to a decreased HR (1.48, 95% CI 0.78 to 2.83) compared with the non-eradicated group (HR: 1.7, 95% CI 0.87 to 3.32), but the results failed to show statistical significance. Therefore, our data could not reveal the findings other data suggested: in a systematic review and meta-analysis, the eradication of H. pylori infection was associated with a generally reduced incidence of GC with variation regarding the baseline GC incidence, but applicable to all levels of baseline risk.37 We have to state that we cannot rule out misclassifying some adenocarcinomas of the esophagogastric junction as oesophagus carcinomas in our study due to poor coding quality, and therefore, underestimate the role of eradication therapy in our study in the GC group. Furthermore, it is important to mention that we did not perform subgroup analyses regarding age and other individual factors influencing the risk for GC. Therefore, we did not record the effect of H. pylori eradication in the elderly and/or higher risk group, in which eradication should be most effective.

    Overall, there was no significant difference between eradicated patients with H. pylori and patients without H. pylori (12.5% vs 11.8%, p=0.231) regarding cancer development. In regression analyses, a non-eradicated H. pylori status (HR: 1.18; 95% CI 1.07 to 1.30) but not an eradicated H. pylori status (HR: 1.06; 95% CI 0.97 to 1.15) was associated with a subsequent diagnosis of cancer (table 2). This is in line with previously published data revealing a reduced incidence for certain tumour entities, particularly GC, but is largely lacking for different other entities.38 39 Other published data revealed elevated standardised incidence ratios up to 5 years of follow-up after H. pylori eradication in gastric and lung cancers.40 The authors concluded that although eradicating H. pylori may have a long-lasting protective effect against GC, H. pylori therapy may postpone the detection of malignancies, possibly underlying unspecific GI symptoms. It is important that H. pylori-associated carcinogenesis is usually a long-term process and, therefore, can occur and/or become clinically apparent years after H. pylori eradication.

    A main limitation of the study is that there was no detailed information on hospitalisations available because the database only includes data obtained by primary care physicians in their clinical practice. Diagnostic data from external specialists and hospitals are only recorded in the database if the primary care physician adds this information. Furthermore, no mortality data are available. Because of the potential for incomplete medical records, information bias may have been introduced in our database. Moreover, the database does not contain information about lifestyle-related factors (eg, smoking behaviour, physical mobility and alcohol use), socioeconomic factors (eg, marital status, profession and income) and genetic factors. Another important limitation is the lack of documentation about the H. pylori detection method, the used eradication regimen, length of therapy, eradication control and subsequent infections. It must be pointed out that due to the retrospective database evaluation, we are unable to draw any causal link between the reported proportions and cannot exclude pre-existing disorders or poor coding quality. Still, the reported frequencies are mostly in line with previously reported rates.

    The strengths of the study are its use of a nationwide primary care database that is representative of diagnoses and the comparatively long observational period of 10 years.16 Furthermore, recall bias was unlikely because of the use of original data collected in primary care.

    Conclusion

    Our study gives a detailed insight into the 10-year cancer prevalence of different entities regarding H. pylori infection and the effects of H. pylori eradication in a large GP cohort in Germany. We report higher cancer rates in the H. pylori cohort. Moreover, a non-eradicated H. pylori status but not an eradicated H. pylori status was associated with a subsequent diagnosis of cancer. In subgroup analyses, H. pylori eradication was negatively associated with bronchus and lung cancer.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

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    Footnotes

    • SHL and AM are joint first authors.

    • Contributors SHL, KK, AM and CR designed the study. KK performed statistical analyses and generated figures and tables. SK, JK and CL contributed to the interpretation of the results. SHL, AM, IK and CR wrote the manuscript. TL provided intellectual input. CR and KK are joint last authors. AM is responsible for the overall content as the guarantor. All authors agreed to the final version of the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.