Differences In Gastric Cancer Risk Research Articles

An overview of the preclinical discovery and development of trastuzumab deruxtecan: a novel gastric cancer therapeutic

ABSTRACT Introduction Gastric cancer is common worldwide, and while multiple therapeutic options exist, the prognosis remains poor. Tumors may overexpress HER2. While targeting HER2 with trastuzumab provides a survival benefit, options following progression are limited. Subsequent trials of HER2-targeted agents failed to improve outcomes. Recently, DESTINY-Gastric01 demonstrated a survival benefit utilizing the antibody-drug conjugate (ADC) trastuzumab deruxtecan in gastric cancer patients that progressed on trastuzumab. Areas Covered /The authors give background to gastric cancer/HER2 and discuss prognostic implications of HER2 overexpression. They also describe initial trials of anti-HER2 therapy, resistance mechanisms, and ADC development/optimization. Finally, the authors review DESTINY-Gastric01 and provide future perspectives. Expert opinion While the 2010 ToGA trial demonstrated efficacy of trastuzumab in HER2 positive gastric cancer, subsequent trials of HER2-directed therapy have disappointed. Downregulation of HER2 after trastuzumab may play a role; however, trastuzumab deruxtecan maintains some efficacy in low-level HER2 expressing tumors. The DESTINY-Gastric01 cohort was from South Korea/Japan; authors have reported differences in gastric cancer risk factors/physiology between Eastern and Western populations. DESTINY-Gastric02 will evaluate trastuzumab deruxtecan in Western patients to confirm generalizability. Pulmonary side effects are notable;physicians must be cognizant of overlapping toxicities with combination therapy.

Histological Features of Gastric Mucosa Serologically Diagnosed as Gastric Atrophy without Helicobacter pylori Infection

Background/Aims: Although gastric atrophy is primarily caused by Helicobacter pylori infection, it is unclear why patients serologically diagnosed with gastric atrophy without H. pylori infection exhibit greater atrophy. We investigated histopathological features in serologically diagnosed gastric atrophy without H. pylori infection. Methods: Thirty-four patients with positive serum pepsinogen and negative serum H. pylori antibody tests underwent gastric biopsy and histological evaluation. The presence of enterochromaffin-like cells (ECL) was also evaluated. Gastric cancer risks for each histological feature according to the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM) were assessed. Results: Twenty-five (74%) patients had histological gastric atrophy. Among those, the following histological subgroups were identified: eight had H. pylori but no ECL, 13 had neither H. pylori nor ECL, and 4 had ECL without H. pylori. Nine patients without histological atrophy had neither H. pylori nor ECL. Patients with H. pylori on histological diagnosis had significantly higher scores on OLGA and OLGIM. Conclusions: Various histological features, with significant differences in gastric cancer risk, were identified in the gastric mucosa serologically diagnosed with atrophy without H. pylori infection. Therefore, serological screening for gastric cancer risk tests has several limitations, and additional evaluations should be considered.

Race, Ethnicity, Socioeconomic Status and Site-specific Risk for Gastric Cancer

Abstract Differences in gastric cancer risk by race/ethnicity have been reported but data on risk by anatomic subsite are lacking. We assessed site-specific differences in gastric cancer risk according to race/ethnicity and socioeconomic status. Methods: Participants included incident cases of gastric adenocarcinoma age >18 years in the Surveillance Epidemiology and End Results Program 2000–2014. Primary outcome was risk for incident gastric cancer, overall, and by anatomic subsite (cardia vs. non-cardia). Age-adjusted incidence rates were used to estimate adjusted incidence rate ratios (IRR) and their 95% confidence intervals (CI). Risk was assessed by race/ethnicity and neighborhood socioeconomic status (nSES). Results: We identified 77,881 cases of incident gastric cancer (n = 23,651 cardia; n = 35,825 non-cardia; n = 18,405 other). For all gastric cancers, adjusted IRRs (95% CI) were higher for blacks [1.72 (95% CI: 1.68–1.76)], Hispanics [1.77 (1.73–1.80)], and Asian/Pacific Islanders [2.12 (2.08–2.17)] compared to non-Hispanic whites. Opposite trends in risk for cardia vs. non-cardia cancer by race/ethnicity were observed. Compared to non- Hispanic whites, cardia IRRs (95% CI) were 0.55 (0.52–0.59) for blacks, 0.63 (0.60–0.66) for Hispanics, and 0.59 (0.56–0.62) for Asians/Pacific Islanders. Non-cardia IRRs (95% CI) were 2.78 (2.69–2.87) for blacks, 2.83 (2.75- 2.91) for Hispanics, and 3.86 (3.75–3.97) for Asians/Pacific Islanders relative to non-Hispanic whites. Increasing risk with decreasing nSES was observed for all gastric cancers (p trend < 0.0001), with moderate variation for non- cardia cancer but no substantial variation observed for cardia cancer. Conclusions. Gastric cancer incidence varies substantially by race/ethnicity and nSES, but with markedly different associations by anatomic subsite. Non-cardia cancer risk is higher among minorities than non-Hispanic whites and varies only moderately by nSES; while cardia cancer risk is lower among minorities and does not vary by nSES. Unique opportunities for addressing disparities exist for cardia and non-cardia gastric cancer.

Abstract 2276: Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort

Abstract Backgrounds: Attenuation by genistein, an isoflavone abundant in soybean, of gastric carcinogenesis induced by sodium chloride was reported in an animal study. Up to date, role of isoflavone as an effect modifier on the association between salt intake and gastric cancer risk is not clearly established. Methods: We randomly selected 640 subcohort subjects without cancer history at enrollment from the Korean multi-center cancer cohort participants. Ninety-nine gastric cancer cases were identified from the inside (N=8) and the outside (N=91) of the subcohort after the 12.2 years of median follow-up time. To estimate individual’s salt intake, we measured 24-hour urinary sodium excretion from spot urine using the Tanaka’s equation. Three isoflavone plasma concentrations (Genistein, daidzein, and equol) of 167 subjects among case-cohort subjects had been measured using time-resolved fluoroimmunoassay. Cubic spline curve for gastric cancer risk according to urinary sodium level was used to define optimal cut-off points of urinary sodium excretion concentration. Weighted Cox proportional hazard regression was used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs). Stratified analysis by isoflavone level was conducted to assess effect modification by isoflavone on the association between salt intake and gastric cancer. Results: Gastric cancer risk in the high salt intake group (urinary sodium excretion ≥6,000mg/day) was significantly increased (HR, 1.69; 95% CI, 0.99-2.90) compared to the reference group (urinary sodium excretion 4500-5,999mg/day). Magnitudes of gastric cancer risk by high salt intake were more strengthened in the group with low plasma isoflavone concentrations (One or no genistein, diadzein or equol levels over the median concentrations) (HR, 6.92; 95% CI, 1.80-26.56). Contrary to the low isoflavone group, no significant differences in gastric cancer risk according to salt intake levels were found in the group with high isoflavone concentration. Conclusions: High salt intake is associated with gastric cancer risk, but this association can be attenuated by high concentration of isoflavones. We suggest that sufficient intake of soybean products, the rich sources of isoflavone, may give protection against gastric cancer in the population with high salt intake. Citation Format: Jieun Jang, Yunji Hwang, Choonghyun Ahn, Kwang-Pil Ko, Aesun Shin, Keun-Young Yoo, Sue K. Park. Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2276. doi:10.1158/1538-7445.AM2017-2276

Rs744166 polymorphism of the STAT3 gene is associated with risk of gastric cancer in a Chinese population.

The aim of this study was to explore the association between polymorphisms in signal transducer and activator of transcription protein 3 (STAT3) and the risk of gastric cancer. In the present study, a case-control study was conducted in which rs2293152 and rs744166 polymorphisms in STAT3 were analyzed in 209 Chinese patients with gastric cancer and 294 cancer-free controls. The genotypes were determined by polymerase chain reaction restriction fragment length polymorphism method. For the rs744166 polymorphism, the TC genotype (adjusted OR = 0.60, 95% CI = 0.39–0.92, and P = 0.020) and CC genotype (adjusted OR = 0.41, 95% CI = 0.21–0.80, and P = 0.009) were associated with a decreased risk of gastric cancer compared to the TT genotype. However, rs2293152 did not show any difference in gastric cancer risk between patients and controls in the CG/CC genotype compared to the GG genotype. Besides, the SNP effects were additive to the effects of environmental factors without any interaction between them in the susceptibility to gastric cancer. Collectively, rs744166 polymorphism might be significantly associated with a decreased risk of gastric cancer in a Chinese population. Additionally, polymorphisms in STAT3, along with environmental factors, might be associated with the development of gastric cancer.

Serologic Evidence that Ascaris and Toxoplasma Infections Impact Inflammatory Responses to Helicobacter pylori in Colombians

Helicobacter pylori-infected children from coastal Tumaco, Colombia, have more parasitism, and adults have lower gastric cancer risk compared with high-altitude Pasto/Tuquerres residents. Because helminth and Toxoplasma gondii infections alter helicobacter gastritis in rodent models, we determined whether seropositivity to Ascaris lumbricoides or T. gondii was associated with Th2-IgG1 or Th1-IgG2 responses to H. pylori. Sera (240) from the two populations were evaluated for A. lumbricoides and T. gondii seropositivity and results correlated with IgE and IgG isotype responses to H. pylori. Most Tumaco children and adults were seropositive for A. lumbricoides (89%, 66%), T. gondii (59%, 98%), or both (45%, 66%). In contrast, seropositivity among Pasto/Tuquerres children was much lower (9%A. lumbricoides, 11%T. gondii, and 2% dual positive) but increased in adults (58%A. lumbricoides, 82%T. gondii, and 41% dual positive). A. lumbricoides seropositivity correlated with elevated IgE and anti-inflammatory Th2-IgG1 responses to H. pylori, while T. gondiigondii seropositivity was linked to elevated IgE, pro-inflammatory Th1-IgG2, IgG3, and IgG4 responses to H. pylori. Individuals with high T. gondii titers had reduced Th1-IgG2, IgG3, and IgG4 responses to H. pylori. Results support regional differences for childhood parasitism and indicate A. lumbricoides and T. gondii infections may impact inflammatory responses to H. pylori and partially explain differences in gastric cancer risk in Colombia.

Fresh and pickled vegetable consumption and gastric cancer in Japanese and Korean populations: A meta‐analysis of observational studies

It is widely known that vegetable consumption contributes to reducing the risk of gastric cancer (GC). However, the incidence rates of GC remain high in both Japanese and Korean populations, even though they have a high consumption of total vegetables. This may be due to the fact that Japanese and Koreans mainly consume processed vegetables, such as cooked, salted, or pickled vegetables, rather than fresh vegetables. To determine whether the intakes of fresh and pickled vegetables have different effects on the risk of GC in Japanese and Korean populations, we carried out a meta-analysis of published epidemiological reports. Eight studies on the consumption of fresh vegetables and 14 studies on the consumption of pickled vegetables related to GC risk were included in this meta-analysis. Four studies exploring differences in GC risk in men and women were considered separately. We observed that a high intake of fresh vegetables was significantly associated with a decreased risk of GC (overall summary OR = 0.62, 95% CI = 0.46-0.85) but that a high intake of pickled vegetables was significantly associated with an increased risk of GC (overall summary OR = 1.28, 95% CI = 1.06-1.53). The results of this meta-analysis provide evidence that a high intake of pickled vegetables may increase GC risk and suggest that a high consumption of fresh vegetables, rather than a large total amount of vegetables including pickled vegetables, is important to reduce GC risk.

Abstract B104: A meta-analysis of fresh and pickled vegetable consumption and gastric cancer in Japanese and Korean populations

Abstract It is widely known that vegetable consumption contributes to reducing the risk of gastric cancer (GC). However, the incidence rates of GC remain high in both Japanese and Korean populations, although they have a high consumption of total vegetables. It may be due to the fact that Japanese and Koreans mainly consume processed vegetables, such as cooked, salted, or pickled vegetables, rather than fresh vegetables. To determine whether the intakes of fresh and pickled vegetables have different effects on the risk of GC in Japanese and Korean populations, we conducted a meta-analysis of the epidemiological literature. Eight studies on the consumption of fresh vegetables and 14 studies on the consumption of pickled vegetables related to GC risk were included in this meta-analysis. Four studies exploring differences in GC risk in men and women were considered separately. We observed that a high intake of fresh vegetables was significantly associated with a decreased risk of GC (overall summary OR=0.62, 95% CI=0.46–0.85) but that a high intake of pickled vegetables was significantly associated with an increased risk of GC (overall summary OR=1.28, 95% CI=1.06–1.53). The results of this meta-analysis provide evidence that a high intake of pickled vegetables may increase GC risk and suggest that a high consumption of fresh vegetables, rather than a large total amount of vegetables including pickled vegetables, is important to reduce GC risk. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B104.

Early Helicobacter pylori Eradication Decreases Risk of Gastric Cancer in Patients With Peptic Ulcer Disease

Helicobacter pylori (H pylori) is a risk factor for gastric cancer. We investigated whether early H pylori eradication is associated with gastric cancer risk in patients with peptic ulcer diseases. This nationwide cohort study was based on the Taiwan National Health Insurance Database (NHID), which provided data on 80,255 patients who were hospitalized for the first time between 1997 and 2004 with a primary diagnosis of peptic ulcer diseases and received H pylori eradication therapy. The patient population was divided into early (within 1 year) and late (after 1 year) eradication cohorts; standardized incidence ratios (SIRs) and hazards ratios (HRs) were determined. There was no significant difference in gastric cancer risk between patients who received early H pylori eradication and the general population (SIR, 1.05; 95% confidence interval [CI]: 0.96-1.14), but late eradication was associated with an increased risk (SIR, 1.36; 95% CI: 1.24-1.49). In gastric ulcer patients who received early eradication, SIRs of gastric cancer decreased from 1.60 at 3-4 years to 1.05 at 7-10 years after hospitalization; the SIRs decreased from 0.57 to 0.33 for duodenal ulcer patients over the same period. Among patients who received late eradication, SIRs decreased from 2.14 to 1.32 for those with gastric ulcers and from 0.90 to 0.66 for those with duodenal ulcers. Early H pylori eradication (HR, 0.77) and frequent aspirin or nonsteroidal anti-inflammatory drug use (HR, 0.65) were independent protective factors for gastric cancer. Early H pylori eradication is associated with decreased risk of gastric cancer in patients with peptic ulcer diseases.

Helicobacter pylori Genotyping and Sequencing Using Paraffin‐Embedded Biopsies from Residents of Colombian Areas with Contrasting Gastric Cancer Risks

cagA-positive and vacA s1 and m1 genotypes of Helicobacter pylori are associated with an elevated risk of gastric cancer (GC). We determined these genotypes using paraffin-embedded gastric biopsy specimens harvested from infected individuals and compared genotype distributions in two Colombian populations residing in geographic regions with a high and low incidence of GC. DNA from paraffin-embedded gastric biopsies from 107 adults was amplified using primers specific for cagA, for the cag'empty site', for the s and m alleles of vacA, and for H. pylori 16S rRNA. H. pylori infection was detected by molecular assays in 97 (90.7%) biopsies. Complete genotyping of cagA and vacA was achieved in 94 (96.9%) cases. The presence of cagA was detected in 78 of 97 cases (80.4%); when considered separately, cagA and vacA s regions were not significantly associated with a particular geographic area. The vacA m1 allele and s1m1 genotypes were more common in the area of high risk for GC (p = .037 and p = .044, respectively), while the vacA m2 allele and s2m2 genotypes were more prevalent in the low-risk area. The prevalence of the combination of cagA-positive, vacA s1m1 genotypes was 84.3% and 60.5% for high and low risk areas, respectively (p = .011). H. pylori cagA and vacA genotyping from paraffin-embedded gastric biopsies permitted reliable typability and discrimination. The more virulent cagA-positive s1m1 strains, as well as vacA m1 genotype, were more prevalent in high risk than in low risk areas, which may contribute to the difference in GC risk between those two regions.

Polymorphisms in Inflammation-related Genes and Risk of Gastric Cancer (Finland)

Helicobacter pylori infection is an important risk factor for gastric cancer, but <3% of carriers of this organism will ever develop gastric cancer. Since inflammation plays a significant role in gastric carcinogenesis, it has been suggested that polymorphisms in genes involved in inflammatory response may partly explain why only a subgroup of patients infected with H. pylori develop gastric cancer. We compared relative frequencies of 17 single nucleotide polymorphisms (SNPs) in eight inflammation-related genes between 112 gastric cancer patients and 208 controls. Cases and controls were selected from a large cohort of Finnish male smokers who were recruited into the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The studied SNPs were IL-1A (-889 C/T), IL-1B (-511 C/T and -31 T/C), IL-6 (-174 G/C and -597 G/A), IL-8 (-251 T/A, +396 T/G and +781 C/T), IL-8RA (Ex2 +860 G/C), IL-8RB (Exon 3 +1235 T/C, Exon 3 +811 C/T, and Exon 3 +1010 G/A), IL-10 (-819 C/T, -592 C/A, -1082 A/G), and TNF A (-308 G/A, -238 G/A). We found no statistically significant association between any of these SNPs, or the number of pro-inflammatory polymorphisms, with risk of gastric cancer. Our results do not support the hypothesis that polymorphisms in genes involved in the inflammatory response confer differences in gastric cancer risk among different individuals.

Activation of Peroxisome Proliferator-activated Receptor γ Suppresses Nuclear Factor κB-mediated Apoptosis Induced by Helicobacter pylori in Gastric Epithelial Cells

Helicobacter pylori colonization leads to epithelial cell hyperproliferation within inflamed mucosa, but levels of apoptosis vary, suggesting that imbalances between rates of cell production and loss may contribute to differences in gastric cancer risk among infected populations. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates inflammatory and growth responses of intestinal epithelial cells. We determined whether activation of PPARgamma modified H. pylori-induced apoptosis in gastric epithelial cells. PPARgamma was expressed and functionally active in gastric epithelial cell lines sensitive to H. pylori-induced apoptosis. PPARgamma ligands 15d-PGJ(2) and BRL-49653 significantly attenuated H. pylomicronri-induced apoptosis, effects that could be reversed by co-treatment with a specific PPARgamma antagonist. Cyclopentanone prostaglandins that do not bind and activate PPARgamma had no effects on H. pylori-induced apoptosis. The ability of H. pylori to activate nuclear factor (NF)-kappaB and increase levels of the NF-kappaB target IL-8 was blocked by co-treatment with PPARgamma agonists, and direct inhibition of NF-kappaB also abolished H. pylori-stimulated apoptosis. These results suggest that activation of the PPARgamma pathway attenuates the ability of H. pylori to induce NF-kappaB-mediated apoptosis in gastric epithelial cells. Because PPARgamma regulates a multitude of host responses, activation of this receptor may contribute to varying levels of cellular turnover as well as the diverse pathologic outcomes associated with chronic H. pylori colonization.

Gastric cancer risk in achlorhydric patients. A long-term follow-up study.

Achlorhydria, determined by the augmented histamine test, is the functional expression of the most severe atrophic gastritis and is followed by a 4- to 6-fold increased risk of gastric cancer, as we found 5 cancers in 114 patients after a mean observation period of 8.4 years. The cancers developed from 1 to 17 years after achlorhydria diagnosis--three cases after more than 9 years. The study showed no difference in gastric cancer risk between patients with and without pernicious anaemia. Spontaneous achlorhydria is the late result of atrophic gastritis, which should be regarded the premalignant condition. The development of gastric cancer from pharmacologically reduced acid secretion must be regarded as highly hypothetical, since this is not followed by atrophic gastritis.