• Immune Checkpoint Inhibitor
• Infection

We thank Yu and Fuhler et al1 for their interest and insightful comments regarding our recent study entitled ‘Impact of Helicobacter Pylori Infection Status on Outcomes among Patients with Advanced Gastric Cancer Treated with Immune Checkpoint Inhibitors’.2

We agree with the commenting authors that there is a diagnostic advantage to using multimodal testing to determine H. pylori infection status. However, due to our study’s retrospective and observational design we did not have access to serum samples for dedicated antibody testing in this study and acknowledge this as a limitation. This lack of serologic testing reflects the current clinical reality faced by many gastroenterologists and oncologists, given that routine H. pylori serologic testing has largely been phased out in the USA. The American Gastroenterological Association and American College of Gastroenterology guidelines do not recommend serology-based testing for either diagnosis of infection or evaluation of treatment response and instead endorse breath tests and/or stool antigen tests, while endoscopic biopsies remain the gold standard.3–5 In addition to the inability to differentiate prior and active infection, H. pylori antibody titers have been shown to wane significantly over time, with one recent Japanese study reporting 59% of patients as seronegative within <1 year of treatment,6 and so even seropositivity may not be a completely reliable measure.

The relatively lower number of H. pylori-positive patients in our study may be due to a mixture of biological, epidemiological, and social factors. While our inclusion criteria was strict, we felt that in the absence of serologic testing it was necessary to ensure that only patients with adequately documented H. pylori infection status were included. It is established that the prevalence of H. pylori is lower in the USA than regions such as Japan, and contributions from the relative proportion of intestinal versus diffuse histologies and other risk factors such as autoimmune gastritis may play a role in differences in prevalence. As aptly mentioned by the commenting authors, lower H. pylori colonization rates in individuals with advanced precursor lesions may also make detection of active H. pylori infection more challenging, though endoscopic biopsies remain the gold standard for diagnosis.

In the absence of serologic testing, there may have been a potential underdiagnosis of prior H. pylori infection in our study. We tried to mitigate this through ensuring adequate documentation of H. pylori infection status (whether positive or negative) as part of our inclusion criteria, though we acknowledge this has limitations. For example, since most infected individuals are exposed to H. pylori in childhood, it is possible they may be incidentally exposed to antibiotic therapies for other reasons and may have been treated without documentation, or may under-report remote prior H. pylori treatment. Despite these limitations, we believe our study provides valuable insights into the impact of H. pylori infection status on outcomes of gastric cancer treated with immune checkpoint inhibitors, and we remain encouraged that our results are consistent with other studies conducted in patients with non-small cell lung cancer, advanced melanoma, and a smaller cohort of patients with gastric cancer. We appreciate the opportunity to respond to these points and strongly agree that further prospective research in which multimodal testing can be employed will be critical to further explore this important area of research and optimize H. pylori infection testing approaches.