Delineating the underlying reasons for the racial disparity in gastric cancer incidence in the United States.
One major reason for disparities in GC relates to the most common cause, infection with the bacteria, Helicobacter pylori (H. pylori). H. pylori is more prevalent among non-whites and Hispanics than non-Hispanic whites (approximately 50% vs. 30% in the US, respectively). Importantly, risk of developing GC can be cut in half through H. pylori eradication treatment, a feasible and cost-effective two-week course of two antibiotics and a proton pump inhibitor and/or bismuth. In the high-GC-incidence countries in East Asia, H. pylori treatment along with GC screening has significantly reduced GC mortality rates. However, the US does not currently have a GC prevention program. Mass screening for H. pylori is inappropriate as only a small fraction of H. pylori-infected individuals will go on to develop GC, and there are global implications for antibiotic stewardship. Thus, to reduce the morbidity and mortality for this racially disparate disease, we need a validated risk assessment tool to determine individuals who are at highest risk for GC for whom we can eradicate H. pylori.
In our previous R01 conducted in a consortium of East Asian cohorts, we found that seropositivity to specific H. pylori virulence factors, including HP0305, HP1564, CagA, and VacA, demonstrate a strong association with GC. Additionally, another biomarker, serum pepsinogen (PG), is considered the best available non-invasive option to identify individuals with precancerous lesions in East Asia. However, these studies have not been validated in the US, and a gap in the literature exists in terms of the racial differences in the association between H. pylori virulence factors and GC.
Our team has obtained approval for and is currently in the process of analyzing data on 106 GC patients 220 controls in PLCO with existing H. pylori and pepsinogen data (PLCO-567) to examine the role of H. pylori and pepsinogen as biomarkers for GC risk. However, a larger sample size would be required to inform the development of stratified risk assessment tools validated for the US population. To accomplish this goal, we propose to build a nested case-control study of 728 non-cardia GC cases and 2:1 matched controls, utilizing prospective cohort data from a diverse population in the US (66% non-white) from 4 NCI-funded cohorts with pre-diagnostic specimens available: Multiethnic Cohort Study (MEC); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO); Southern Community Cohort Study (SCCS); and Women’s Health Initiative (WHI). The addition of PLCO would contribute immensely to the effort proposed in this project not only by increasing the numbers and but also the multi-site aspect of the specimens collected in PLCO would allow for greater generalizability to the US population.
Our goal is to identify those at highest risk of H. pylori-associated gastric cancer (GC) in the US to enable the development of a targeted GC prevention strategy that is appropriate for the racial/ethnic diversity in the US,.
We will use pre-diagnostic samples from four NCI-funded prospective cancer cohorts to conduct a nested case-control study of 728 prospectively ascertained non-cardia GC cases and 2:1 matched controls (including 130 PLCO non-cardia GC cases with available pre-diagnostic serum).
Specifically, we will:
Aim 1: Examine racial disparities in H. pylori-associated GC incidence by evaluating differences in the association by race of factors associated with immune response to infection, including quantitative levels of H. pylori antibodies and pepsinogen (a measure of gastric atrophy), smoking status, and body mass index.
Aim 2: Develop a novel race-stratified gastric cancer risk prediction model among two-thirds of the GC cases (n=485) and their matched controls. Then, compare this to the established gastric cancer screening algorithm in East Asia, which includes only H. pylori sero-status and pepsinogen levels, and both in dichotomized form only.
Aim 3: Validate the risk factor models from Aim 2 among the remaining one-third GC cases (n=243) and their matched controls. Then, use the validated model with the strongest predictive abilities to derive a gastric cancer risk assessment toll, and assess the need for race-specific models.
Understanding which factors related to racial/ethnic minorities with H. pylori being more likely to develop gastric cancer will allow us to identify those at highest risk for whom eradicating H. pylori is a high priority.
Our long-term goal is thus to reduce the burden of GC, a significantly disparate and often fatal, but highly preventable, disease, in the US. To accomplish this, our next step will be to test this GC risk assessment tool through a clinical trial of H. pylori eradication in the US.
Haejin In (Albert Einstein College of Medicine)
Meira Epplein (Duke University)