How do we improve outcomes for gastric cancer?
Associate Professor Khay-Guan Yeoh, Department of Medicine, National University Hospital, 5 Lower Kent Road 119074, Singapore. Email: firstname.lastname@example.org
Although the incidence of gastric cancer is decreasing globally, it remains the second leading cause of cancer death, accounting for 600 000 deaths annually worldwide. It is particularly common in Asia and especially in China, Japan and Korea. In Singapore, it is the fourth commonest cancer in men, who have a 1:50 lifetime risk of developing gastric cancer. Gastric cancer traditionally carries a poor prognosis because of late presentation at an advanced stage of disease. If diagnosed at an early stage, it is a curable disease. Four strategies will systematically help to improve outcomes for gastric cancer: (i) early detection by screening of high-risk groups; (ii) clarification of the hypothesis that Helicobacter pylori eradication in endemic areas with a high incidence of gastric cancer is an effective primary prevention strategy; (iii) improvement of treatment by well-designed clinical trials, coupled with molecular characterization of tumors; and (iv) improving our biological understanding of gastric carcinogenesis.
Early detection of gastric cancer by screening of high-risk groups
Gastric cancer remains the second leading cause of cancer death, accounting for 600 000 deaths annually worldwide,1 but it can be cured if diagnosed at an early stage. Depending on the stage, resection can be achieved by surgery or endoscopic methods. Recently, endoscopic submucosal dissection (ESD) has been added to the repertoire of endoscopic techniques, enabling a deeper clearance and wider margin compared with endoscopic mucosal resection (EMR); however, the detection of early gastric cancer is difficult and only systematic mass screening by endoscopy as practiced in Japan and Korea has been shown to improve early detection. Screening for gastric cancer in an asymptomatic population has been shown to increase the detection of early gastric cancer.2 Overall, 5-year survival is significantly better for tumors detected by screening compared with those detected by an open access clinic.3 In countries other than Japan and Korea, population screening has been deemed not to be cost-effective because disease incidence is lower. In the absence of screening, patients present with advanced disease, and prognosis is poor. Recently, Dan et al. published the first cost–benefit economic analysis of endoscopic screening for gastric cancer.4 Screening by endoscopy was shown to be cost-effective in moderate- to high-risk populations. For example in Singapore, this would include Chinese men (age-standardized rate, ASR 25.9/100 000) above 50 years; other population subgroups such as Chinese women and Malay and Indian ethnic groups have a low risk. The risk increases further for Chinese men with Helicobacter pylori infection (estimated ASR 42.8/100 000). For Chinese men of age 50–70 years, the number needed to screen to prevent one gastric cancer death was 267. Targeted screening of high-risk populations should be explored as a feasible strategy to improve outcomes for gastric cancer.
Enhancement of endoscopic detection of early gastric cancer
The ability to detect gastric cancer or precancerous lesions may be enhanced by chromoendoscopy5 employing dye spray and with new technologies such as magnification endoscopy,6 narrow band imaging and autofluorescence. Recently, our group has also evaluated confocal endomicroscopy7 for detection of gastric cancer and intestinal metaplasia.
Can a novel blood test help us diagnose early gastric cancer or predict a high risk of cancer? Predictive serum markers that have been studied include serum pepsinogen, H. pylori antibodies and various host genetic polymorphisms that regulate inflammatory response. Serum pepsinogen is a marker of gastric atrophy and has been well studied in Japanese and Finnish populations. By itself, it is not a reliable predictive marker, particularly in populations with a low prevalence of gastric atrophy such as in Singapore.8 El-Omar reported interleukin-1 gene cluster polymorphisms associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer.9 Subsequently, different gene polymorphisms were found to be important in other populations; for example, Chinese in Taiwan10 and China.11 Recently, using the SELDI protein-chip technology, Poon et al. reported a distinctive pattern of serum proteomic fingerprint in the sera of gastric cancer patients.12 There is no validated serum biomarker for gastric cancer and further progress may depend on the discovery of new candidate biomarkers using novel technologies such as serial analysis of gene expression (SAGE).13
Longitudinal follow up of a large cohort of subjects at risk of gastric cancer combines benefit to subjects by way of systematic surveillance with the opportunity to serially follow histologic and molecular developments. This provides invaluable insight into interval rates of de novo cancer development, which is required for planning of optimal surveillance intervals, and enables a better understanding of the actual risk of putative precancerous lesions such as intestinal metaplasia. In Singapore, the Gastric Cancer Epidemiology and Molecular Genetics Programme (GCEP), established in 2003, aims to identify biomarkers suitable for use as a screening test to identify people with gastric cancer or who have very high risk of gastric cancer. The GCEP Cohort Study for subjects at high risk of gastric cancer was initiated in January 2004, with a planned enrollment of 4000 well-characterized high-risk patients undergoing systematic screening for early gastric cancer, supported by an annotated clinical database and the banking of high-quality gastric tissue and plasma specimens. The GCEP Cohort Study enrolls people aged >50 years who are at high risk of gastric cancer and offers screening by endoscopy with systematic prospective follow up over a minimum of 5 years. Participation is voluntary and participants receive detailed explanation and counseling on the benefits of the study, as well as the requirements of the study. This study has been approved by the Institutional Ethics Review Boards (IRB) in four major hospitals in Singapore. The study captures comprehensive clinical information in a state-of the-art database and stores blood, sera, white-cell DNA, gastric biopsy tissue and gastric juice specimens, collected prospectively according to a standardized protocol. Since 2004, 650 subjects have been prospectively recruited and at the time of writing, the study group incidence rate for development of de novo cancer is approximately 0.5% a year (one in 200 patient-years). The surveillance alters the natural history of cancer in the patient, because for cancers detected early, endoscopic resection is possible with preservation of gastric anatomy and physiology.
Helicobacter pylori eradication as a primary prevention strategy in areas with a high risk of gastric cancer
The gastric pathogen H. pylori is regarded as the most important risk factor for gastric cancer, hence H. pylori eradication has been proposed as a primary prevention strategy.14 Several case–control studies have suggested that H. pylori eradication is effective in preventing or reducing the risk of gastric cancer; however, in a large, prospective, randomized study of H. pylori eradication in a high-risk area in China involving 1630 subjects randomly assigned to H. pylori eradication or placebo reported by Wong et al. in 2004, the authors found that after 8 years of follow up, the development of gastric cancer was significantly decreased only in the subgroup of H. pylori carriers without precancerous lesions.15 This suggests that once precancerous pathology has developed, the eradication of H. pylori is no longer effective in preventing gastric cancer. If this is confirmed to be true, then for eradication therapy to be effective for primary prevention, it has to be administered in youth, before the onset of gastric pathology. For adults who already have precancerous gastric pathology, secondary prevention by surveillance endoscopy is indicated.
Improving treatment of gastric cancer
Surgical techniques and understanding have made substantial progress. It is now well-established that extended lymph node dissection and node sampling (15 nodes or more) greatly improve the accuracy of staging and prediction of prognosis.16 Advances in chemotherapy have been modest when evaluated from the viewpoint of survival benefit.17 The generally poor response to chemotherapy is probably attributable, at least in part, to the heterogeneity of gastric cancer. There is therefore considerable interest in gene expression profiling of tumors, with the aim of guiding the selection of chemotherapy. In an example of this approach, Ichikawa and coworkers evaluated the expression of 5-FU pathway genes in pretreatment fresh, frozen specimens obtained from primary tumors, using quantitative real-time reverse transcriptional polymerase chain reaction (PCR).18 They reported that expression of orotate phosphoribosyltransferase (OPRT) and thymidylate synthase (TS) were independent variables for predicting response, and thymidylate synthase and thymidine phosphorylase were predictive of survival. Mimori et al. reported that tau-negative expression was selective for favorable response to Paclitaxel treatment in patients with metastatic gastric cancer.19 It has also been shown that pharmacogenetic profiling of specific polymorphisms in patients may provide important information on clinical outcomes of treatment.20 There is great potential for clinicians and scientists working together to improve treatment by well-designed clinical trials, coupled with molecular characterization of tumors and taking advantage of the recent advances in pharmacogenetics to select the optimal individualized treatment for patients.
Improving our biological understanding of gastric carcinogenesis
The genetic alterations underlying the development and progression of gastric cancer are complex. It is fairly certain that different genetic pathways lead to diffuse- and intestinal-type gastric cancer. Molecular abnormalities that have been described include microsatellite instability, inactivation of tumor suppressor genes, activation of oncogenes and telomerase. Alterations have been described in genes controlling or regulating growth factors, apoptosis and cell-cycle regulators, adhesion molecules, nitric oxide synthase (NOS) and cyclo-oxygenase (COX)-2.21 Germ line mutations of the E-cadherin gene were found in a large family from New Zealand in which diffuse-type gastric cancers developed at an early age.22 Subsequently, somatic mutations have also been observed in sporadic diffuse-type cancers. Activation of oncogenes beta-catenin and K-ras have been reported in human gastric cancer. Mutations in p53 have been reported in diffuse- and intestinal-type gastric cancer.
Our group recently reported that loss of expression of a novel tumor suppressor gene RUNX3 is causally related to the genesis and progression of gastric cancer.23 About 45% to 60% of surgically resected gastric cancer specimens and cell lines derived from these cancers do not express RUNX3 mainly due to hypermethylation of its promoter region. Inactivation of RUNX3 appears to occur at an early stage, as well as during progression, because silencing of RUNX3 has been observed in 40% of stage I and 90% of stage IV gastric cancers. In a separate series of 97 cases of human gastric cancer, RUNX3 was found to be inactive in 82% of cancers through either gene silencing or protein mislocalization in the cytoplasm.24 The very high frequency of inactivation suggests that RUNX3 silencing is a common and perhaps critical event in sporadic human gastric cancer. These improvements in our understanding of the molecular basis of gastric cancer hold the key to potential applications in diagnosis, discovering new targets for therapy, selection of optimal therapy and in prognostication.25
Great strides have been made in clinical care and in advancing our knowledge of gastric cancer, yet significant challenges remain in refining our biological understanding and bringing treatment benefits to the patient. These challenges can be overcome by multidisciplinary collaborative efforts, harnessing the combined expertise of clinicians, clinician–scientists and scientists, to improve outcomes for our patients.