• immune checkpoint inhibitors
• immunity, cellular
• immunotherapy
• tumor biomarkers

We have read with great interest the recent publication titled ‘Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors’ by Magahis et al.1 The study presents intriguing findings on the association between H. pylori infection status and the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with advanced gastric cancer. We commend the authors for their contribution to this critical field of cancer research. However, we wish to address several points that may benefit from further clarification and discussion.

The authors report that patients with gastric cancer with prior or current H. pylori infection exhibit significantly shorter median progression-free survival and overall survival post-ICI treatment compared with their H. pylori-negative counterparts. This observation is indeed noteworthy and suggests that H. pylori infection could be an important prognostic marker for response to ICI treatment in this patient population. The call for future research to unravel the specific mechanisms of immune regulation influenced by H. pylori is well justified, given that the previously described upregulation of immune checkpoints such as programmed cell death-ligand 1 by H. pylori does not appear to affect ICI efficacy in this study.

Within the studied cohort, a mere 49 out of the total 215 individuals possessed a documented medical record indicating an H. pylori infection. This number is significantly lower than the prevalence reported in existing literature, where seroprevalence rates of up to 94.4% and 75.6% have been described for non-cardia and cardia gastric cancer, respectively. Strikingly, Matsuo et al identified only 21 H. pylori-negative individuals out of a total of 3161 patients with stomach cancer examined over a span of 14 years.2 Despite the relatively lower prevalence rates reported in the USA (~36%), the ratio observed in the present investigation (22.8%) seems unexpectedly low.

One potential explanation for this discrepancy comes from the careful selection of patients in this study, which excluded all patients for whom H. pylori test results were unknown or not explicitly specified in the electronic medical records. However, a negative H. pylori test is arguably more likely to go unmentioned in patient records than a positive test result. Another explanation may stem from the fact that gastric cancer is often preceded by premalignant conditions such as atrophic gastritis and gastric intestinal metaplasia. The mucosal changes associated with these precancerous lesions renders the gastric environment less favorable to the growth of H. pylori, which may result in unique challenges for the detection of this bacterium.3 Indeed, an impaired sensitivity of conventional diagnostic methods, including ¹³C-urea breath testing and histology, was shown for patients with gastric atrophic gastritis or intestinal metaplasia.4 5 These findings underscore the need for a diagnostic approach that accounts for the diminished bacterial load and patchy distribution of H. pylori on the gastric tissue changes that accompany precancerous lesions. Serum antibody tests, despite their limitations in distinguishing between current and past infections, were shown to more accurately describe a history of H. pylori infection in such patients.4

Given the limitations in the detection of active H. pylori infection in gastric premalignant lesions, it is conceivable that in the study by Magahis et al—employing ¹³C-urea breath tests, stool antigen tests, and histology for diagnosis—H. pylori infection may have gone underdiagnosed. Thus, the study’s findings regarding the association between H. pylori infection and survival outcomes after ICI treatment should be interpreted with caution. The use of historical H. pylori records as predictive marker for ICI responsiveness should also be carefully considered. While medical records describing ¹³C-urea breath tests, stool antigen tests, and histology may underestimate H. pylori infection rates in this patient population, serum is in most cases not likely to be available for retrospective analysis. Thus, the safest course of action may be to consider H. pylori status only when it can be confirmed through both active infection tests and serology.

In conclusion, while the study by Magahis et al adds valuable insights into the prognostic significance of H. pylori in the context of ICI therapy, the points raised here highlight the need for a more nuanced understanding of the interplay between H. pylori infection and gastric cancer. We advocate for the use of more sensitive and comprehensive diagnostic approaches to ascertain H. pylori infection status and for a careful examination of other factors that may influence treatment outcomes.