Current best practices and rationalistic perspectives in causation-based prevention, early detection and multidisciplinary treatment of breast and gastric cancer

Volume 1- Number 2 -October/December 2002



Background of Chemoprevention in Gastric Cancer: Four reasons towards optimism

Dimitrios H. Roukos, MD and Epameinondas V. Tsianos, MD
From the Department of Surgery (DHR), and the Department of Internal Medicine (EVT), Ioannina University School of Medicine, 45110 Ioannina, Greece,

Chemoprevention of epithelial cancers has increasingly been recognized as a promising intervention to control cancer. Among the most common epithelial cancers, gastric cancer seems to be an attractive target for preventive interventions. Promises for the potential effectiveness of preventive intervention arises a recent chemoprevention trial[1] but the results are inconclusive and previous efforts with carotene in the prevention of gastric cancer[2] or lung cancer,[3] and of green tea for gastric cancer[4] were unsuccessful.

We might design effective interventions to disrupt such a progression to invasive cancer by understanding the mechanisms of initiation and progression of gastric carcinogenesis and identifying the factors which influence and drive this process. It is likely that such a strongly causation-based prevention strategy may meet the expectations for an effective substantial reduction of cancer incidence.

Here, we discuss whether the background of chemoprevention allows hopes for the realization of the goal to combat gastric cancer.

(1) Magnitude of genetic and environmental contribution to gastric carcinogenesis

The proportion of contribution of environmental and genetic risk factors in the causation of cancer has been highly debated. Epidemiological studies of migrant population and in twins are the gold standards for distinguishing genetic from environmental traits. Recent large epidemiological studies overwhelmingly implicate a substantial and significant contribution of heritable effects in the causation of prostate, colon, and breast cancer, but a limited only (non-significant) contribution of inherited genetic factors in the causation of sporadic gastric cancer.[5,6] Environmental effects are the major causes for gastric cancer. This assessment is clinically important because identifying and eliminating the environmental exposures it would be possible to inhibit the progression to cancer. By contrast for cancers in which no environmental exposure has been identified to increase the risk of cancer development, as for example prostate cancer, such a prevention intervention with elimination of the environmental factor is not feasible.

(2) The role of Helicobacter pylori as an exogenous factor in gastric carcinogenesis

Worldwide, approximately 3 billion people (half of the world's population) are actually infected by Helicobacter pylori although there is now a declining prevalence in the developed world.[7] This inflammation of the stomach tissue will ultimately lead a small minority either to gastric or duodenal ulcer or to gastric neoplasia (gastric adenocarcinoma, gastric MALT lymphoma), but the majority of infected persons (>80%) will never develop a significant clinical disease in their lifetime. The paradox is that H. pylori-induced gastritis leads to duodenal ulcer, characterized by antral-predominant gastritis, high acid secretion and duodenal ulcer on one hand and to corpus-predominant gastritis, gastric atrophy and hypochlorhydria that increase gastric cancer risk to the other.[8] The reasons for this diverged clinical outcome as well as why high prevalence of H. pylori infection in Africa is not associated with high rates of gastric cancer have remained poorly understood. Two major theories have been reported for explaining this, that of H. pylori virulence factors and bacterial gene polymorphisms[9] and that of host genetic factors.[10] It is very likely that interactions of both result in a diverged outcome.

Although the World Health Organization and the International Agency for Research on Cancer classified H. pylori as a class I carcinogen in 1994[11] subsequent meta-analyses indicated a weak only relative risk (around 2) of noncardia cancer when a conventional IgG Elisa serology was used.[12] However, this weak relationship may be caused by misclassification of exposure. Most recently, a more accurate assessment of H. pylori infection status with CagA antibodies[13] or with all three methods i.e., histology, serology and rapid urease test[14] or serology many years before tumor detection[15] indicate a much stronger relationship between H. pylori and gastric cancer. This odds ratio (OR) roses from 2.2 (95% confidence interval (CI) 1.4-3.6) using IgG ELISA only, to 21.0 (95% CI, 8.3-53.4) using CagA+ technique.[13] In the study by Uemura at al.[14] gastric cancer was not developed among uninfected subjects. Estimates based on the revised excess risk, if it is true, indicate that even in the general population of low-risk Western world (Sweden), about 70%[13] of noncardia cancers are attributable to H. pylori and thus preventable. In high-risk countries, as for example Japan,[14] this preventable H. pylori-attributable gastric cancer risk is probably even higher. Based on these current findings, some investigators[16] support that the association between H. pylori infection and gastric cancer ranks with the association between smoking and lung cancer.

(3) Gene-environment interactions

Cancer genetics has been focused for many years on mutational events that have their primary effect within the cancer cell. Recently that focus has widened, with evidence of the importance of epigenetic events that lie outside the cancer cell, suggesting new targets for interventions.[17]H. pylori-attributable gastric carcinogenesis is a superb model of gene-environment interaction. Individuals with proinflammatory high interleukin-1b production (polymorphisms in IL-1b genes) and infected by the bacterium are at significantly higher risk (OR 7.5 [95% CI, 1.8-31] of developing hypochlorhydria and gastric atrophy, and also gastric cancer but in a weaker relationship (OR 1.6 [95% CI 1.2-2.2]).[18] In addition to the IL-1b gene, El-Omar et al. have recently confirmed a positive but weaker role of polymorphisms in the TNF-a gene that correlates with high tumor necrosis factor (TNF)-a levels.[10] It is very likely that several other polymorphic genes, encoding proinflammatory and anti-inflammatory mediators, will also contribute to the host genetic constitution that determines the outcome to H. pylori infection and risk of gastric cancer. A proinflammatory host genetic makeup therefore facilitates the development of a hypochlorhydric, atrophic phenotype that increases the risk of gastric cancer.[19] However not everyone infected by H. pylori and with such a genetic makeup develops gastric cancer indicating that, as El-Omar[18] points out, many other still unidentified host genetic and environmental factors determine the progression of atrophy to invasive cancer. Indeed, as gene-environment interactions are intrinsic to the mode of action of low-penetrant genes[17, 19-21] is highly possible that, as for example the mode smoking-lung cancer, a large number of low-penetrant genes is also involved in gastric carcinogenesis. The search of such a large number of low-penetrant genes is difficult but may be facilitated by the recent completion of human genome project and the use of microarray technology. This technology has already started to be applied in the investigation of both H. pylori[22] and host[23] gene-expression profiling of gastric cancer.

(4) Identification of environmental exposures

H. pylori infection causing transformation of normal mucosa through superficial gastritis to gastric atrophy and intestinal metaplasia is undoubtedly the initial step in gastric carcinogenesis. However, the factors which drive the dynamic of regression or progression to invasive cancer and the mechanisms by which this occurs once these premalignant lesions (atrophy, intestinal metaplasia) have been established are still to be determined and elucidated. Therefore, whether or not the available chemoprevention interventions are able to inhibit progression to cancer in persons with established atrophy, intestinal metaplasia or dysplasia is highly debated. It is suggested that still unidentified host genetic factors,[10] bacterial gene polymorphisms[9] and environmental exposures, such as infection, diet and lifestyle, interact in a complex fashion that determines the dynamic of regression or progression over a decades-long period of time. Several studies have recently been focused on the identification of environmental risk factors suggesting that H. pylori infection, low levels of dietary antioxidants (vitamin C), and cigarette smoking may enhance the progression of premalignant lesions to dysplasia and gastric cancer.[2]

Taken into account the little progress that has been made over the last decades in the multimodality treatment of gastric cancer it is time to rethink and probably change the current management towards more effective strategies.[24] The data reported provide evidence that chemoprevention curing H. pylori-infection at initial stage of carcinogenesis (H. pylori superficial gastritis) may be effective by disrupting further progression to atrophic gastritis and/or intestinal metaplasia. However, much more research is needed to improve our understanding of the underlying biological mechanisms that drive the progression of these pre-malignant lesions to invasive cancer. This is the scientific way to develop target molecular drugs that will provide a highly effective reduction of gastric cancer incidence due chemoprevention.


1. Correa P, Fontham ETH, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidants supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst 2000; 92: 1881-8.
2. You WC, Zhang L, Gail MH, et al. Gastric Dysplasia and Gastric Cancer: Helicobacter pylori, Serum Vitamin C, and Other Risk Factors. J Natl Cancer Inst 2000 Oct 4; 92(19):1607-1612.
3. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effects of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035.
4. Tsubono Y., Nishino Y., Komatsu S., Hsieh C.-C., Kanemura S., Tsuji I., Nakatsuka H., Fukao A., Satoh H., Hisamichi S. Green tea and the risk of gastric cancer in Japan. N Engl J Med 2001; 344:632-636
5. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer. N Engl J Med 2000; 343: 78-85
6. Hoover RN. Cancer - nature, nurture, or both. N Engl J Med 2000; 343:135-6.
7. Go MF. natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 2002 Mar;16 Suppl 1:3-15.
8. McColl KE, El-Omar E. Helicobacter pylori and disturbance of gastric function associated with duodenal ulcer disease and gastric cancer. Scand J Gastroenterol Suppl 1996;215:32-37
9. Blaser MJ. Linking Helicobacter pylori to gastric cancer. Nat Med 2000;6:376-7.
10. El-Omar EM, Chow WH, Rabkin CS. Gastric cancer and H. pylori. Host genetics open the way. Gastroenterology 2001;121:1002-4, editorial.
11. Infection with Helicobacter pylori. In: IARC monographs on the evaluation of the carcinogenic risks to humans. Vol. 61. Schistosomes, liver flukes and Helicobacter pylori. Lyon, France: International Agency for Research on Cancer, 1994:177-241.
12. Huang J-Q, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1999;114:1169-1179.
13. Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001;121:784-91.
14. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784-789.
15. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 cases control studies nested within prospective cohorts. Gut 2001;49:347-53.
16. Fox JG, Wang TC. Helicobacter pylori - Not a good bug after all. N Engl J Med 2001;345:829-31. editorial.
17. Ponder BAJ. Cancer genetics. Nature 2001; 411: 336-41.
18. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404:398-402.
19. Berwick M, Vineis P. Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review. J Natl Cancer Inst 2000; 92: 874-97. [PubMed]
20. Vineis P, Malats N, Lang M, et al. Metabolic polymorphisms and susceptibility to cancer--IARC Scientific Publication 148. Lyon: IARC, 1999.
21. Vineis P, Schulte P, McMichael AJ. Misconceptions about the use of genetic tests in populations. Lancet 2001;357:709-712.
22. Israel DA, Salam N, Arnold CN, et al. Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory response. J Clin Invest 2001;107:611-20.
23. Hippo Y, Taniguchi H, Tsutsumi S, et al. Global Gene Expression Analysis of Gastric Cancer by Oligonucleotide Microarrays. Cancer Res 2002 Jan 1;62(1):233-240.
24. Roukos DH, Fatouros M, Xeropotamos N, Kappas AM. Treatment of gastric cancer: early-stage, advanced-stage cancer, adjuvant treatment. Gastric Breast Cancer 2002; 1(1): 12-22.
25. Roukos DH. Time to move on from current strategy in gastric cancer? Gastric Breast Cancer 2002; 1(3): 51-52.

Online ISSN : 1109 - 7647
   Print ISSN : 1109 - 7655

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last update: 22 May 2003