Controlling Gastric Cancer in a World of Heterogeneous Risk.

Gastric cancer (GC) is a leading cause of global mortality but also a cancer whose footprint is highly unequal. This review aims to define global disease epidemiology, critically appraise strategies of prevention and disease attenuation, and assess how these strategies could be applied to improve outcomes from GC in a world of variable risk and disease burden. Strategies of primary prevention focus on improving the detection and eradication of the main environmental risk factor, Helicobacter pylori. In certain countries of high incidence, endoscopic or radiographic screening of the asymptomatic general population has been adopted as a means of secondary prevention. By contrast, identification and targeted surveillance of individuals with precancerous lesions (such as intestinal metaplasia) is being increasingly embraced in nations of low incidence. This review also highlights existing knowledge gaps in GC prevention as well as the role of emerging technologies for early detection and risk stratification.

Helicobacter pylori testing prior to or at gastric cancer diagnosis and survival in a diverse US patient population.

BACKGROUND: Gastric cancer (GC) accounts for the greatest disparity in cancer mortality between Black and White Americans. Although clinical trials have shown that Helicobacter pylori (Hp) treatment reduces risk of GC, Hp testing and treatment is not consistently performed in the US, and may offer an opportunity to improve survival. METHODS: In a diverse retrospective cohort of 99 GC cases diagnosed at Duke University from 2002-2020 (57% Black; 43% white), we examined the association of Hp testing and treatment prior to or at cancer diagnosis with overall survival using Cox regression analyses to calculate adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Overall, 62% of patients were tested for Hp prior to or at GC diagnosis. Of those, 25% tested positive and were treated < 1 year prior to or at diagnosis, 15% tested positive and were treated ≥ 1 year prior to diagnosis, 6% tested positive without evidence of treatment, and 54% tested negative. Compared to never tested, Hp testing and treatment < 1 year prior to or at diagnosis was associated with a significantly reduced likelihood of death (HR 0.21, 95% CI 0.08-0.58). The benefit of any Hp test and treat prior to or at GC diagnosis was significant even among stage IV patients only (HR, 0.22; 95% CI 0.05-0.96). CONCLUSIONS: These findings support Hp testing and treatment for patients at risk of or diagnosed with GC, and suggest Hp treatment may provide an opportunity to reduce GC mortality disparities in the US.

Type 2 Diabetes Mellitus and Helicobacter pylori Eradication in a Clinical Population.

OBJECTIVES: Eradication of Helicobacter pylori reduces the risk of gastric cancer (GC). Individuals with type 2 diabetes mellitus (T2DM) are known to be at increased risk for GC. In a cohort of H. pylori-positive individuals, we assessed whether those with T2DM were at risk of persistent infection following H. pylori treatment compared with individuals without T2DM. METHODS: A random subset of all individuals diagnosed as having H. pylori without intestinal metaplasia at endoscopy from 2015 to 2019 were stratified evenly by race (Black and White). After excluding those with T1DM and those without eradication testing after H. pylori treatment, logistic regression analysis was used to determine the association of T2DM with the risk of persistent H. pylori infection following treatment. RESULTS: In 138 patients, H. pylori eradication rates did not differ between the 27% of individuals with T2DM compared to those without (81.1% vs 81.2%). After adjusting for age, race, and insurance status, we found no significant increased risk of persistent H. pylori infection for individuals with T2DM (odds ratio 1.40; 95% confidence interval 0.49-3.99). CONCLUSIONS: H. pylori eradication rates do not differ by T2DM status, providing support for clinical trials of H. pylori eradication to reduce GC incidence among high-risk populations in the United States, such as individuals with T2DM.

Supplement use and gastric cancer risk in the Southern Community Cohort Study.

PURPOSE: Gastric cancer remains a racial health disparity in the US, but few studies have examined supplements as a potential protective factor. We examined associations between regular supplement use and gastric cancer risk among the predominantly Black participants in the Southern Community Cohort Study (SCCS). METHODS: Of the 84,508 individuals recruited in the SCCS from 2002 to 2009, 81,884 responded to the baseline question: any vitamin or supplement taken at least once per month in the past year. Secondary analyses assessed specific supplement use. Associations with incident gastric cancer were examined using adjusted Cox proportional hazards models, stratified by histologic subtype and secondarily by healthy eating index (HEI). RESULTS: Approximately half of the participants (47%, n = 38,318) reported any regular supplement use. Among the 203 incident gastric cancers over the follow-up period (median, 7 years), 142 were non-cardia (NCGC), 31 cardia (CGC), and 30 unknown. Regular supplement use was associated with a 30% decreased risk of NCGC (hazards ratio (HR) 0.70; 95% confidence interval (CI) 0.49-0.99). Among participants below the HEI median, any regular supplement and multivitamin use were associated with a 52% and 70% decrease in risk of NCGC (HR 0.48; 95%CI 0.25-0.92 and HR 0.30; 95%CI 0.13-0.71), respectively. No associations were found for CGC. CONCLUSION: Regular supplement use, including multivitamins, was associated with a decreased risk of NCGC in the SCCS, particularly among participants with a lower quality diet. Inverse associations of supplement use and NCGC incidence provide support for clinical trials among high-risk populations in the US.

An Approach to the Primary and Secondary Prevention of Gastric Cancer in the United States.

BACKGROUND & AIMS: Gastric cancer (GC) remains a leading cause of mortality among certain racial, ethnic, and immigrant groups in the United States (US). The majority of GCs are diagnosed at advanced stages, and overall survival remains poor. There exist no structured national strategies for GC prevention in the US. METHODS: On March 5-6, 2020 a summit of researchers, policy makers, public funders, and advocacy leaders was convened at Stanford University to address this critical healthcare disparity. After this summit, a writing group was formed to critically evaluate the effectiveness, potential benefits, and potential harms of methods of primary and secondary prevention through structured literature review. This article represents a consensus statement prepared by the writing group. RESULTS: The burden of GC is highly inequitably distributed in the US and disproportionately falls on Asian, African American, Hispanic, and American Indian/Alaskan Native populations. In randomized controlled trials, strategies of Helicobacter pylori testing and treatment have been demonstrated to reduce GC-specific mortality. In well-conducted observational and ecologic studies, strategies of endoscopic screening have been associated with reduced GC-specific mortality. Notably however, all randomized controlled trial data (for primary prevention) and the majority of observational data (for secondary prevention) are derived from non-US sources. CONCLUSIONS: There exist substantial, high-quality data supporting GC prevention derived from international studies. There is an urgent need for cancer prevention trials focused on high-risk immigrant and minority populations in the US. The authors offer recommendations on how strategies of primary and secondary prevention can be applied to the heterogeneous US population.

The U-shaped association between body mass index and gastric cancer risk in the Helicobacter pylori Biomarker Cohort Consortium: A nested case-control study from eight East Asian cohort studies.

The association between body mass index (BMI) and noncardia gastric cancer (NCGC) risk remains controversial. The purpose of our study was to examine the association of BMI with NCGC risk with consideration of Helicobacter pylori (HP) biomarkers. This international nested case-control study, composed of 1,591 incident NCGC cases and 1,953 matched controls, was established from eight cohorts in China, Japan and Korea, where the majority of NCGCs are diagnosed worldwide. HP antibody biomarkers were measured in blood collected at cohort enrollment by multiplex serology. The NCGC risk according to baseline BMI was estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CIs). We found a U-shaped association between BMI category and NCGC risk. Compared to those with reference BMI (22.6-25.0 kg/m2 ), those with lower and higher BMI had an increased NCGC risk (BMI <18.5 kg/m2 , OR = 1.56, 95% CI = 1.04-2.34; BMI >27.5 kg/m2 , OR = 1.48, 95% CI = 1.15-1.91; adjusted for age, sex and smoking). The U-shaped association was persistent among subjects with HP infection and high-risk biomarkers (HP+ CagA+: BMI <18.5 kg/m2 , OR = 1.60, 95% CI = 1.00-2.55; BMI >27.5 kg/m2 , OR = 1.59, 95% CI = 1.21-2.11; and Omp+ HP0305+: BMI <18.5 kg/m2 , OR = 1.88, 95% CI = 1.04-3.42; BMI >27.5 kg/m2 , OR = 1.70, 95% CI = 1.20-2.42, respectively). Our study provides evidence of significantly increased NCGC risk among individuals with low or high BMI, including in subjects with high-risk HP biomarkers (HP+ CagA+, Omp+ HP0305+) in the high-risk area of East Asia.

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

Differences in antibody levels to H. pylori virulence factors VacA and CagA among African Americans and whites in the Southeast USA.

PURPOSE: Helicobacter pylori (H. pylori) is the leading cause of gastric cancer. High antibody levels to H. pylori virulence factors Vacuolating cytotoxin A (VacA) and Cytotoxin-associated gene A (CagA) have been suggested as gastric cancer risk markers. In the USA, H. pylori sero-prevalence is twofold higher in African Americans compared to whites. We sought to assess whether African Americans also exhibit higher antibody levels to VacA and CagA. METHODS: Antibody responses to H. pylori proteins were measured by multiplex serology in 686 African Americans and whites of the Southern Community Cohort Study. Among VacA- and CagA-seropositives, we analyzed the association of race with antibody level using logistic regression models to produce odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Sero-positive African Americans had significantly higher mean antibody levels to both VacA and CagA, which resulted in increased odds for the highest quartile of antibody levels compared to sero-positive whites (VacA, OR: 6.08; 95% CI 3.41, 10.86; CagA, OR: 3.77; 95% CI 1.61, 8.84). CONCLUSION: Our findings support future studies to assess the association of differential antibody responses by race with risk of gastric cancer in the USA, which could then aid in developing targeted H. pylori eradication strategies.

Performance of multiplex serology in discriminating active vs past Helicobacter pylori infection in a primarily African American population in the southeastern United States.

PURPOSE: To feasibly analyze associations of Helicobacter pylori (H. pylori) with disease in large cohort studies, assays are needed to assess H. pylori prevalence in existing biospecimens. However, serology has traditionally been unable to distinguish active from past infection. We sought to determine the sensitivity of seropositivity to H. pylori proteins to detect active infection. METHODS: We measured antibody responses to 13 H. pylori proteins using multiplex serology in serum samples of a training (n = 78) and validation set (n = 49) collected concurrently from patients undergoing urea breath test (UBT). To determine sensitivity of seropositivity to H. pylori proteins for active infection, a cutoff was applied to achieve 90% specificity. Antibody levels were retested in a subset of participants (n = 16) 6 months after baseline. RESULTS: With a specificity of 91%, seropositivity to H. pylori proteins VacA, GroEl, HcpC, and HP1564 ascertained active infection from 100% to 75% sensitivity. Positivity to a combination of these proteins (≥2 out of the 4) resulted in specificity of 90% and sensitivity of 100%. The validation set replicated results from the training set. Among those participants with successful H. pylori eradication after baseline, antibody levels decreased significantly for VacA, HcpC, and HP1564 when assessed 6 months later. CONCLUSION: Utilizing the cutoffs for seropositivity established through comparison with UBT, seropositivity to ≥2 of the H. pylori proteins VacA, GroEl, HcpC, and HP1564 determines active H. pylori infection at high specificity and sensitivity and may approximate the prevalence of active H. pylori infection in large cohorts.

The Durham Initiative for Stomach Health (DISH): a pilot community-based Helicobacter pylori education and screening study.

BACKGROUND: Approximately 15% of all cancers are due to infection. The bacteria Helicobacter pylori is the single leading carcinogenic infectious agent and the main cause of stomach cancer. Prevalence of H. pylori, and, correspondingly, stomach cancer incidence and mortality, is significantly greater among African Americans than whites in the United States. In the present study, we conducted a pilot community-engaged H. pylori education and screening study in partnership with a predominantly African American church in Durham, North Carolina. METHODS: Initially, we consulted with community advisory boards and convened stakeholder meetings with local community members and primary care physicians. We then developed this pilot study through an iterative collaboration with church partners. Our main outcomes were feasibility and acceptability as measured by participation in a one-day H. pylori screening initiative, and participation in follow-up for those who tested positive. We also sought to determine prevalence and determinants of active H. pylori infection in this population. RESULTS: Community engagement informed the event logistics, messaging, educational materials provided, and follow-up plans. A total of 92 individuals participated in the primary study event, 25% of whom had a current H. pylori infection. Of those, 87% returned for the follow-up events, among whom 70% had successfully cleared their infection. CONCLUSIONS: Through community engagement, community-based H. pylori screening and stomach cancer prevention is feasible and acceptable. This is a necessary step in order to move stomach cancer prevention forward to population-based precision H. pylori screening and eradication.

Epstein-Barr Virus Antibody Titers Are Not Associated with Gastric Cancer Risk in East Asia.

BACKGROUND: Epstein-Barr virus (EBV)-positive gastric cancers represent a distinct subtype of gastric cancers and account for nearly 10% of the gastric cancer burden, yet risk detection strategies for this cancer subtype are lacking. METHODS: We conducted a nested case-control study where we assayed 4 EBV antigens [viral capsid antigen (VCA), early antigen (EA), Epstein-Barr nuclear antigen (EBNA), and BZLF1-encoded replication activator protein (ZEBRA)] in either sera or plasma from 1447 gastric cancer cases and 1797 controls obtained from seven prospective cohorts representing individuals from the high gastric cancer-risk countries of China, Japan, and Korea. RESULTS: The prevalence of EBV sero-positivity was universal with the exception of one sero-negative individual, and the highest titers of the EBV antigens VCA (OR 0.95, 95% CI 0.78-1.17), EBNA (OR 0.88, 95% CI 0.72-1.08), EA (OR 0.97, 95% CI 0.79-1.19), and ZEBRA (OR 0.87, 95% CI 0.71-1.07) were not associated with risk of incident gastric cancer. When we stratified these data by H. pylori status, there was no change in the association. CONCLUSIONS: Multiplex serology of the aforementioned EBV antigens in serum may not be a suitable biomarker for predicting gastric cancer risk in East Asian populations.

A Prospective Study of Urinary Prostaglandin E2 Metabolite, Helicobacter pylori Antibodies, and Gastric Cancer Risk.

BACKGROUND: Previous studies suggest that a stable end-product of prostaglandin E2, the urinary metabolite PGE-M, is associated with colorectal cancer, and 1 study of relatively small sample size found an association with gastric cancer among women. In the present study we further investigate the PGE-M, Helicobacter pylori, and gastric cancer association. METHODS: The present analysis included 359 prospectively ascertained gastric cancer cases and 700 individually matched controls from the Shanghai Women's and Men's Health Studies. Urinary PGE-M was measured by a liquid chromatography/tandem mass spectrometric method. Seropositivity to 15 H. pylori recombinantly expressed fusion proteins was detected by H. pylori multiplex serology. RESULTS: Adjusting for H. pylori, increasing PGE-M was associated with higher risk of gastric cancer (quartile 4 vs 1: odds ratio [OR], 1.76 [95% confidence interval {CI}, 1.17-2.66], Ptrend = .004). This association remained after excluding those diagnosed within 2 years from sample collection (OR, 1.73 [95% CI, 1.12-2.65], Ptrend = .007). However it was no longer present among individuals with 10 or more years of follow-up (2-4.9 years: OR, 3.15 [95% CI, 1.11-8.91]; 5-9.9 years: OR, 2.23 [95% CI, 1.22-4.06]; ≥10 years: OR, 0.73 [95% CI, .31-1.70]). Compared to H. pylori-negative individuals with below-median PGE-M levels, H. pylori-positive individuals with above-median PGE-M levels had a 5-fold increase in the odds of gastric cancer (OR, 5.08 [95% CI, 2.47-10.43]). CONCLUSIONS: In China, higher PGE-M levels may indicate an increased risk of gastric cancer independent of the risk conferred by H. pylori infection status, particularly for cancers diagnosed within 10 years of sample collection.

Fruit and vegetable consumption, Helicobacter pylori antibodies, and gastric cancer risk: A pooled analysis of prospective studies in China, Japan, and Korea.

Epidemiological findings on the association between fruit and vegetable consumption and gastric cancer risk remain inconsistent. The present analysis included 810 prospectively ascertained non-cardia gastric cancer cases and 1,160 matched controls from the Helicobacter pylori Biomarker Cohort Consortium, which collected blood samples, demographic, lifestyle, and dietary data at baseline. Conditional logistic regression adjusting for total energy intake, smoking, and H. pylori status, was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer risk across cohort- and sex-specific quartiles of fruit and vegetable intake. Increasing fruit intake was associated with decreasing risk of non-cardia gastric cancer (OR = 0.71, 95% CI: 0.52-0.95, p trend = 0.02). Compared to low-fruit consumers infected with CagA-positive H. pylori, high-fruit consumers without evidence of H. pylori antibodies had the lowest odds for gastric cancer incidence (OR = 0.12, 95% CI: 0.06-0.25), whereby the inverse association with high-fruit consumption was attenuated among individuals infected with CagA-positive H. pylori (OR = 0.82, 95% CI: 0.66-1.03). To note, the small number of H. pylori negative individuals does influence this finding. We observed a weaker, nondose-response suggestion of an inverse association of vegetable intake with non-cardia gastric cancer risk. High fruit intake may play a role in decreasing risk of non-cardia gastric cancer in Asia.

Population-based cohort studies of type 2 diabetes and stomach cancer risk in Chinese men and women.

Although positive associations have been found for diabetes and a number of cancer sites, investigations of stomach cancer are limited and the results lack consistency. In this prospective study we investigated the relationship between type 2 diabetes mellitus (T2DM) and stomach cancer risk in mainland China. We assessed the associations among T2DM, T2DM duration, and stomach cancer risk in two prospective population-based cohorts, the Shanghai Women's Health Study and the Shanghai Men's Health Study. Included in the study were 61 480 men and 74 941 women. Stomach cancer cases were identified through annual record linkage to the Shanghai Cancer Registry, and verified through home visits and review of medical charts. After a median follow-up of 7.5 years for the Shanghai Men's Health Study and 13.2 years for the Shanghai Women's Health Study, a total of 755 incident cases of stomach cancer (376 men and 379 women) were identified through to September 2013. Overall, we did not find any evidence that T2DM was associated with an increased risk of stomach cancer either in men (multi-adjusted hazard ratio = 0.83, 95% confidence interval, 0.59-1.16) or in women (multi-adjusted hazard ratio = 0.92, 95% confidence interval, 0.68-1.25). Our findings from two large prospective population-based cohorts suggest that T2DM was not associated with stomach cancer risk.

Diet, Helicobacter pylori strain-specific infection, and gastric cancer risk among Chinese men.

Evidence for the association of diet and gastric cancer is equivocal, and the majority of previous studies have not evaluated the interaction of diet and infection with Helicobacter pylori, the leading risk factor for gastric cancer. We examined these associations among 226 cases and 451 controls nested within a prospective cohort. Dietary intakes were calculated from validated food frequency questionnaires. Blood levels of 15 antibodies to Helicobacter pylori proteins were assessed using multiplex serology. Odds ratios (ORs) were calculated using logistic regression. Among individuals infected with high-risk Helicobacter pylori (sero-positivity to 5-6 virulent H. pylori proteins), increasing intake of red meat, heme iron, and sodium increased risk (comparing highest tertile to lowest: ORs [95% confidence interval {CI}]: 1.85 [1.01-3.40]; 1.95 [1.06-3.57]; and 1.76 [0.91-3.43], respectively) while increasing intake of fruit decreased gastric cancer risk (comparing highest tertile of intake to lowest: OR [95% CI]: 0.52 [0.28-0.94]). No associations of diet with risk were found among individuals infected with low-risk H. pylori (P for interaction for red meat and sodium: 0.02 and 0.01, respectively). In this population with over 90% prevalence of CagA-positive H. pylori infection, categorizing individuals using H. pylori multiplex serology may identify individuals for whom a diet intervention may be effective.

Prevalence of the cagA Virulence Factor Varies by Race Among Helicobacter pylori -Infected Patients Undergoing Upper Endoscopy.

INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori v irulence factor cagA in a retrospective cohort of patients with active H. pylori infection. METHODS: We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active H. pylori infection from 2015 to 2019. RESULTS: H. pylori + Black patients were 2 times more likely to be cagA + than H. pylori + White patients (82% vs 36%, P < .0001). DISCUSSION: Presence of cagA is common among endoscopy patients with active H. pylori infection; appropriate testing and treatment of H. pylori can both reduce gastric cancer risk and address health disparities.

Circulating cytokines and gastric cancer risk.

PURPOSE: Chronic inflammation has been hypothesized to play a significant role in the aetiology of cancer, including gastric cancer. In the present study, we sought to examine pre-diagnostic systemic cytokine levels in plasma, which can be seen as markers of aggregate inflammation, and risk of distal gastric cancer in a case-control study nested within the prospective Shanghai Men's Health Study. METHODS: Circulating levels of eight inflammation-related cytokines were measured in the plasma collected at baseline for 180 incident cases of distal gastric cancer and 358 matched controls. Helicobacter pylori sero-positivity was assessed using multiplex serology. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CI). RESULTS: Individuals with IL-8 levels above the lowest quartile were at twofold increased odds of gastric cancer [OR 1.91 (95 % CI 1.05-3.46), OR 2.10 (95 % CI 1.19-3.74), and OR 2.30 (95 % CI 1.26-4.19), for the second through fourth quartiles, respectively]. While there were suggestions of an increase in risk with increased level of many of the other cytokines measured (IL-1ß, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ), no significant associations were found at the p < 0.05 level. Infection with CagA-positive H. pylori did not modify these associations. CONCLUSIONS: In a population with high gastric cancer incidence and high H. pylori prevalence, increased circulating levels of IL-8 may indicate increased risk of gastric cancer. These findings add to our understanding of the disease and further efforts to uncover biomarkers of disease risk.