Non-invasive blood test to help prioritise individuals at risk of gastric cancer for endoscopy

According to Cancer Research UK statistics[1] there are 6,600 new cases of gastric cancer (GCa) per year in the UK, 70% of which are diagnosed at a late stage leading to poor prognosis and limited treatment options. The percentage of sufferers that survive for more than 5 years with the disease is just 21.6%, far fewer than our counterparts in Europe, and there are 4,400 deaths per year. However, when GCa is diagnosed at the earliest stage, the prognosis is significantly better – 69-82% survive more than 5 years – hence the key to achieving better outcomes is early detection and diagnosis.

The pathway to GCa follows a well-defined linear cascade of progressive steps known as Correa’s Cascade.[2] This sequence begins with gastritis, ends with invasive GCa, and is initiated by Helicobacter pylori (H. pylori) infection (41% cases) and, in rarer cases, autoimmune disease. Along this cascade is a pre-cancerous stage called atrophic gastritis (AG), which is a chronic condition of the gastric mucosa characterised by a marked loss of functional gastric glands that presents as focal neoplastic lesions in the stomach. AG predisposes individuals to GCa and is considered the highest risk factor. 1 in 50 individuals will develop GCa within 20 years of diagnosis of AG[3]. Although individuals with AG are at increased risk of GCa, curable pre-cancerous lesions and early cancers are frequently found in stomachs with severe atrophy, making AG a viable target for early detection and diagnosis.

Infographic adapted from “Correa’s cascade” model of gastric carcinogenesis. [2]

Diagnosis of AG

Chronic AG can either be asymptomatic or present as vague, non-specific abdominal symptoms, making the condition difficult to identify clinically. The two main diagnostic methods used for identifying AG are via enhanced-image endoscopy with targeted biopsy histology, and by non-invasive plasma biomarker analysis. To date there is insufficient evidence to support the use of endoscopy or biomarkers to screen for AG in the general population, however it is agreed among experts that selecting those individuals who are at risk using non-invasive methods before endoscopy is key to early GCa detection and improved survival[4].

Current guidelines from the UK[4,5] and Europe[6] stress the importance of identifying and monitoring pre-malignant conditions endoscopically, which from a health outcomes perspective is encouraging and has the potential to save lives. But such strategies rely heavily on the incidental diagnosis of AG during endoscopy, (i.e. after the patient has been referred), or risk identifying late stage disease. Without specific guidance showing how to identify individuals with AG before endoscopy, say for instance in a primary care setting, there is a real risk of missing patients with pre-cursors to cancer whilst waiting for them to present with advanced disease in an endoscopy or emergency setting.

Helicobacter pylori – a risk factor for cancer

H. pylori is known to be causative in 41% cases of GCa. Current guidance recommends either testing for H. pylori or prescribing of proton pump inhibitor (PPI) therapy as part of the clinical investigation of dyspepsia[7], although PPIs are contraindicated in AG due to the already impaired gastric acid secretion in the atrophied stomach. Although H. pylori is the main cause of AG, it is not the sole cause, and besides, testing for H. pylori alone cannot identify or predict AG. Furthermore, H. pylori, the bacterium that colonises the stomach and over time causes extensive chronic inflammation of the gastric mucosa, cannot colonise pre-cancerous cells[8] making the infection self-limiting in individuals with a pre-cancerous stomach. This means that individuals who were previously infected with H. pylori and have progressed to AG, may produce a negative H. pylori test result, and in the absence of any information about the condition of the stomach mucosa, therefore be assumed to be healthy. This is not solely a limitation of the tests currently employed for diagnosing H. pylori, but also of the clinical pathway employed.

Could testing for AG in a primary care setting help get high-risk individuals to endoscopy sooner?

At present, national and European guidelines set out evidence-based and expert recommendations for the diagnosis and monitoring of precursors to GCa endoscopically. On the pathway leading to endoscopy however, there is a paucity of guidance to help healthcare professionals identify and select those individuals at risk for referral. Risk is currently based on clinical assessment in primary care and includes identification of alarm symptoms and family history, which themselves have poor predictive value for GCa.[9,10] So what can be done to help overcome the challenges of early detection and diagnosis of GCa?

Stomach specific biomarkers of BIOHIT GastroPanel

A simple blood test that combines the measurement of pepsinogen I (PGI), the PGI/II ratio, and amidated gastrin-17 (G17) provides a validated biomarker panel that indicates the presence, severity and location of AG in the stomach and can be used in any diagnostic setting.[11] The BIOHIT GastroPanel® blood test has consistently proven to be a reliable tool for the non-invasive diagnosis of AG that can be used to identify individuals at high risk of gastric cancer before endoscopy.[12]

In addition to PGI, PGII and G17, GastroPanel incorporates a test for H. pylori enabling the treating clinician to differentiate the cause of AG and help them to direct appropriate treatment. What’s more, the whole GastroPanel blood test costs less than an H. pylori test alone making it instantly cost effective.

A recent meta-analysis demonstrated the reliability of GastroPanel for the diagnosis of AG with a pooled sensitivity and specificity of 74.7% (95% CI 62.0%–84.3%), and 95.6% (95% CI 92.6%– 97.4%) respectively.[13] With a median prevalence of AG of 27%, this gave GastroPanel a negative and positive predictive value of 91% and 86% respectively in the diagnosis of chronic AG. This suggests that GastroPanel could be a useful tool for ruling out, and helping to identify AG non-invasively, thereby enabling endoscopy resources to be targeted to those at highest risk of AG, and provide an entry point to the endoscopic investigation and management of such individuals. Not only is GastroPanel a cost effective test, when mathematical modelling was applied to a cohort of US males, non-invasive screening using pepsinogens in the over 50s was cost effective and reduced the lifetime risk of non-cardia gastric adenocarcinoma by 26.4%[14]

If combining GastroPanel with Endoscopy health services can facilitate the early detection and diagnosis of AG, it is likely that cost savings can be made, prognosis of GCa can be improved, and lives lost to GCa can be reduced.[15,16]

Find out more about GastroPanel: www.biohithealthcare.co.uk/gastropanel

References

1. Cancer Research UK. Stomach cancer statistics | Cancer Research UK [Internet]. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/stomach-cancer.
2. Correa P, Haenszel W, Cuello C, et al. A model for gastric cancer epidemiology. Lancet 1975;2:58–60.
3. Song H, Ekheden IG, Zheng Z, et al. Incidence of gastric cancer among patients with gastric precancerous lesions: observational cohort study in a low risk Western population. BMJ 2015;351:h3867.
4. Banks M, Graham D, Jansen M, et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut 2019;0:1–31.
5. Beg S, Ragunath K, Wyman A, et al. Quality Standards in upper gastrointestinal endoscopy: a position statement of the British Society of Gastroenterology (BSG) and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS). Gut 2017;66:1886–99.
6. Dinis-Ribeiro M, Areia M, de Vries AC, et al. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 2012;44:74–94.
7. NICE Clinical guideline [CG184]. Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management. 2014.
8. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49:347-53.
9. Moayyedi P, Talley NJ, Fennerty MB, et al. Can the clinical history distinguish between organic and functional dyspepsia? JAMA 2006; 295:1566–1576.
10. Fransen GAJ, Janssen MJR, Muris JWM et al. Meta-analysis: the diagnostic value of alarm symptoms for upper gastrointestinal malignancy. Aliment Pharmacol Ther. 2004 Nov 15;20(10):1045-52.
11. Sipponen P, Ranta P, Helske T, et al. Serum levels of amidated gastrin-17 and pepsinogen I in atrophic gastritis: an observational case-control study. Scand J Gastroenterol. 2002 Jul;37(7):785-91.
12. Agréus L, Kuipers EJ, Kupkinskas L, et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol. 2012;47:136–147.
13. Zagari RM, Rabitti S, Greenwood DC, et al. Systematic review with meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis. Aliment Pharmacol Ther. 2017;46:657–667.
14. Yeh JM, Hur C, Ward Z, et al. Gastric adenocarcinoma screening and prevention in the era of new biomarker and endoscopic technologies: a cost effectiveness analysis. Gut. 2016 April; 65(4): 563–574.
15. Varis K, Sipponen P, Laxen F, et al. Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Helsinki Gastritis Study Group. Scand J Gastroenterol. 2000 Sep;35(9):950-6.
16. den Hollander WJ, Holster IL, den Hoed CM, et al. Surveillance of premalignant gastric lesions: a multicentre prospective cohort study from low incidence regions. Gut 2019;68:585–93.