Early detection of gastric cancer beyond endoscopy - new methods

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Abstract​

Early detection of gastric cancer is remaining a challenge. This review summarizes current knowledge on non-invasive methods that could be used for the purpose.
The role of traditional cancer markers such as CEA, CA 72-4, CA 19-9, CA 15-3, and CA 12-5 lies mainly in therapy monitoring than early detection.
Most extensive studied biomarkers (pepsinogens, ABC method) are aiming at the detection of precancerous lesions with modest sensitivity for cancer.
Tests based on the detection of cancer-specific methylation patterns (PanSeer), circulating proteins and mutations in circulating tumour DNA (CancerSEEK), as well as miRNA panels have demonstrated promising results bringing those closer to practice. More extensive research is required before tests based on the detection of circulating tumour cells, extracellular vesicles and cell-free RNA could reach the practice.
Detection of volatile organic compounds in the human breath is a promising development; sensor technologies for this purpose could be very attractive in screening settings.

 

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Introduction​

The overall survival for early gastric cancer (GC) either managed endoscopically or surgically may exceed 96% [1], whereas the majority of cancer cases in the Western world are diagnosed at late stages, and the cumulative 5-year survival is ranging 20–40% [2].

Typically, early-stage cancers are asymptomatic, therefore the clue for lowering the burden of advanced cancer is timely detection whether by upper endoscopy or non-invasive testing.

Endoscopic screening for GC that is recommended in South Korea and Japan would be hardly acceptable in the West, furthermore the cost-effectiveness of such interventions is not justified in the Western populations [3]. Therefore, non-invasive markers for identification of cancer at early stage or at the stage of precancerous lesions are of the highest interest, in particular, if such markers could allow detection of the disease in the window between its onset and symptom development [4]. If a marker is aiming at the detection of precancerous lesions (advanced atrophy, intestinal metaplasia, dysplasia), later regular surveillance of the patients at increased risk may lead to timely cancer identification at early stage [5].

In this review we are going to concentrate on the available and promising biomarkers for GC, but also for precancerous lesion detection.

 

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Section snippets​

Traditional cancer markers​

Carcinoembryonic antigen (CEA) and traditional cancer markers, namely, carbohydrate antigen 72-4 (CA 72-4), carbohydrate antigen 19-9 (CA 19-9), carbohydrate antigen 15-3 (CA 15-3) and carbohydrate antigen 12-5 (CA 12-5) may have a role mainly in therapy monitoring and prognosis rather than early detection or screening of GC [[6], [7], [8]].

Although they could be found at elevated levels in GC, they are neither sensitive, nor specific, furthermore they are commonly elevated at late stages of

Pepsinogens​

Pepsinogen detection as “a serological biopsy for gastric mucosa” has been proposed in 1982 by Michael Samloff [11]. This approach has been used in routine practice in Japan for decades, but during the recent decade has gained high attention also in Europe and other parts of the world [12]. This has to be emphasized, that pepsinogens are markers for atrophy, not GC; however, by considering that intestinal type of distal stomach cancer is developing mainly on the background of pre-existing

 

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Emerging blood-based biomarkers​

During the past decade, a variety of other blood-based biomarker assays, frequently referred to as liquid biopsies, have emerged. Liquid biopsies are samples of blood or other biofluids that are used for the analysis of cancer cells or cancer cell-derived molecules [41,42]. They are a very promising alternative to conventional tissue biopsies for the early detection of cancer and subsequent prognosis, monitoring disease progression and tracking tumour evolution [43]. The most common analytes in

Volatile markers​

Detection of volatile organic compounds in breath, urine, faeces, sweat for cancer detection, including for GC has experienced a significant progress during the recent decade. Two principal approaches are being used for the purpose – methods allowing to identify particular chemical substances (such as gas-chromatography coupled with mass spectroscopy – GC-MS) or sensor-based methods distinguishing between the disease and control cases based on a mathematical model (pattern recognition methods).

 

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Summary​

The traditional cancer markers as well as biomarkers for gastric precancerous lesions have a limited utility in wide-scale early cancer detection.

There is a space for improving non-invasive tests for gastric precancerous lesions, panel testing approach could find an applicability in general population settings.

Tests based on the detection of cancer-specific methylation patterns (PanSeer), circulating proteins and mutations in circulating tumour DNA (CancerSEEK), as well as miRNA panels have

Role of the funding source​

ML has been supported for writing of the manuscript from the European Regional Development Fund, project No. 1.1.1.1/18/A/184 "Optimisation of H. pylorieradication therapy for population-based gastric cancer prevention” and Latvian Science Council Fundamental and Applied Research (FLPP) project No. lzp-2018/1–0135 “Research on implementation of a set of measures for prevention of gastric cancer mortality by eradication“ and timely recognition of precancerous lesions”; AL has been supported for

Declaration of competing interest​

None.

Acknowledgements​

The authors would like to acknowledge Prof. Kazumasa Miki and Prof. Francesco Di Mario for their invaluable contribution to the field of biomarker development as well as sharing their expertise. We acknowledge the funding sources: Latvian Science Council and European Regional Development Fund that have supported the work.