Oesophageal and Proximal Gastric Adenocarcinomas Are Rare After Detection of Helicobacter pylori Infection

Shria Kumar; David C. Metz; Gregory G. Ginsberg; David E. Kaplan; David S. Goldberg

Disclosures

Aliment Pharmacol Ther. 2020;51(8):781-788. 

In This Article

Conclusions

In the largest cohort of US patients with confirmed H pylori, we demonstrate that rates of oesophageal and proximal gastric cancers after detection of H pylori are low: the cumulative incidence at 5, 10 and 15 years was 0.15%, 0.26% and 0.34%, respectively. Importantly, we found that H pylori treatment and eradication status were not associated with future oesophageal and proximal gastric cancers.

Our results can be loosely compared to future cancer incidence after identification of known risk factors and precursor lesions. For example, we previously conducted the largest study of gastric cancer among US patients with diagnosed H pylori, and demonstrated that the incidence of non-proximal gastric adenocarcinomas after H pylori diagnosis at 5, 10 and 20 years was 0.37%, 0.5% and 0.65%, respectively. Thus, the incidence of oesophageal and proximal gastric cancers after H pylori detection is markedly lower than non-proximal gastric cancer after H pylori detection. It is more difficult to compare oesophageal and proximal gastric cancers incidence after H pylori to baseline estimates. The American Cancer Society estimates a lifetime risk of oesophageal cancer in the United States is about 1 in 132 (0.76%) in men and about 1 in 455 (0.22%) in women.[25] Our study demonstrates that rates of oesophageal and proximal gastric cancers after treatment of H pylori are low, but may be so since our data does not capture a true lifetime estimate.

Most importantly, we demonstrate that treatment or eradication of H pylori is not associated with future oesophageal and proximal gastric cancers. As we note above, there are a large number of studies, both in Western and Eastern countries, that demonstrate an inverse relationship between oesophageal and proximal gastric cancers and H pylori.[8,10,11] Not all studies have demonstrated this, however, especially when accounting for virulence factors associated with H pylori.[17,26] This has led to differing opinions on the impact of H pylori detection and eradication, and whether we are truly eradicating a class 1 carcinogen, or in fact, unintentionally altering acid secretion and the human microbiome, or even potentially causing the rise of other malignancies. While guidelines have suggested there is no evidence that H pylori eradication alters acid secretion on its own, its role in the microbiome and in carcinogenesis of other cancers have not been fully defined.[27] Our study is the largest, to our knowledge, investigating the relationship between oesophageal and proximal gastric cancers and H pylori. It is further limited to US patients, which is important given the heterogeneous prevalence of H pylori among various countries, and the particularly concerning the rise of both oesophageal and proximal gastric cancers in the US.[28–30] These two factors make a US-based study such as ours critical to fill knowledge gaps. Since H pylori eradication's role in oesophageal and proximal gastric cancers remains controversial, our study provides a unique perspective in (a) identifying true H pylori infection (versus serology indicating previous exposure), (b) granular data, (c) prescription of treatment and (d) whether that treatment was truly effective in eradicating H pylori. We have previously demonstrated in the same cohort that H pylori eradication decreases future risk of non-proximal gastric adenocarcinomas. Here, we demonstrate that H pylori eradication does not impact the risk of future oesophageal and proximal gastric cancers.

Patients of older age were more likely to develop future oesophageal and proximal gastric cancers, and age is a known risk factor for all cancers.[31,32] Similarly, smokers were more likely to develop future oesophageal and proximal gastric cancers, consistent with previous literature.[33–35] Our findings regarding race and ethnicity are also similar to previously published studies. Those of Black, Asian, and Native Hawaiian/Pacific Islander were less likely to develop future oesophageal and proximal gastric cancers, as were those of Hispanic or Latino ethnicity, though this was not statistically significant. Asian Americans, Hispanics and African Americans, as well as immigrants and native populations, are known to have a disproportionate burden of gastric cancer in the US, particularly distal cancers.[36–39] Non-Hispanic whites, on the contrary, are more affected by oesophageal and proximal gastric cancers.[40–43] While these findings are not novel, they validate prior studies, and demonstrate how our cohort has risks consistent with other patient populations, and reinforce the external validity of our results.

There are several limitations to this study. First, its retrospective nature diminishes the ability to determine causality. Second, the cohort has some inherent selection bias (those tested for H pylori are being tested for some clinical reason), and we are unable to compare to it a confirmed background or control population without H pylori. Third, that we used the Veterans Health Administration also limits the generalisability of the study somewhat, as it is a predominantly male (>90%) veteran population. However, our findings are consistent with known trends in oesophageal and proximal gastric cancers, as evidenced by our findings regarding age, smoking, race and ethnicity. This suggests external validity of our findings. This point is further underscored by our previously published study using the same cohort, identifying the incidence and risk factors for nonproximal gastric adenocarcinoma after H pylori detection.[19] In that study, we identified that compared to persistent H pylori infection, eradication of H pylori had a SHR of 0.24 (95% CI: 0.15–0.41, P < 0.001) for future non-proximal gastric adenocarcinoma. A recently published randomised control trial evaluating the impact of H pylori eradication among those at high risk of gastric cancer found a near-identical point estimate (HR 0.27; 95% CI: 0.10–0.70) when comparing the development of cancer in those who had persistent infection versus those who had confirmed eradication of H pylori.[44] This finding of real-world data providing a nearly identical point estimate for the decreased risk of gastric cancer after H pylori eradication provides strong evidence for the external validity of our cohort. Fourth, there are possibilities for false-negative/positive testing. Fifth, there could be measurement issues, leading to misclassification. These include patients receiving care outside the Veterans Health Administration, limiting available oncologic diagnoses and cancer registry inputs or H pylori diagnoses. However, misclassification of H pylori status would only affect inclusion into the cohort, and misclassification of the outcome, inadvertently including a distal gastric adenocarcinoma, would only bias toward the null since risk factors for distal and proximal cancer differ in terms of age, race and ethnicity.[45] For oesophageal cancers, administrative codes do not distinguish between adenocarcinoma and squamous cell, but are labelled anatomically. The majority of oesophageal adenocarcinomas are found distally, and the majority of squamous are proximal. Inadvertent inclusion of squamous oesophageal cancers would only increase the outcome incidence rate, which is already demonstrably low. Lastly, we were unable to determine eradication status for a number of patients. This may have underpowered our statistical analysis, and limited our ability to detect a difference, though in our previous study low re-testing rates did not limit power.[19]

The strengths of our study lie mainly in our robust cohort and ability to identify granular data with broad and longitudinal follow-up. Previous literature has focused on an association between H pylori and oesophageal and proximal gastric cancers, but this is the first study to identify the incidence of oesophageal and proximal gastric cancers after H pylori detection. We demonstrate that neither prescription of H pylori treatment nor eradication of H pylori are associated with future oesophageal and proximal gastric cancers. Given the previously demonstrated higher risk of distal gastric cancer after H pylori, benefits of H pylori treatment may outweigh the risk of future oesophageal and proximal gastric cancers in particular groups, including Blacks, Asians, and Native Hawaiians/Pacific Islanders. Future studies should continue to identify which cohorts would benefit most from H pylori screening and eradication.

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