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Introduction
Gastric cancer is one of the most common tumor entities worldwide with an incidence of 13 newly diagnosed cases per 100,000 persons per year. In up to 50% of newly diagnosed cases, patients exhibit advanced, metastatic stage, which is incurable and exhibits a median survival of 6–9 months.1 Standard therapy in advanced stages consists of multimodal radio-chemotherapy and surgery, if resection is feasible. Overall survival (OS) is dependent on the stage at the time of diagnosis, and 5-year survival can be as high as 78% in early stages or as low as 4% in metastatic stages.2 The standard chemotherapeutic regimen in advanced stages consists of leucovorin (Ca-folinate), 5-fluorouracil (5-FU), and irinotecan. Although frequently employed, tumor markers, including carcinoembryonic antigen (CEA) and CA 19-9, exhibit a low sensitivity in advanced stage and no additional benefit in predicting treatment response.3 Therefore, current guidelines for gastric carcinoma do not recommend the use of tumor markers during therapy.4
The response to therapy is commonly monitored on clinical grounds and radiological imaging, while laboratory testing is being performed for safety. Tumor characteristics including the expression of neo-antigens or somatic tumor mutations (e.g. involving KRAS or MYC genes) have been studied to personalize the treatment. However, currently, no non-invasive marker is available to assess the disease stage or predict the therapeutic response in advanced gastric cancer. So-called “liquid biopsies” are being developed to assess tumor characteristics non-invasively, and in the future, these markers could help to reduce the necessity of direct tumor biopsies.
Cytokeratins are protein components of intermediate filaments and are expressed in epithelial and endothelial cells, constitute the cellular matrix, and are responsible for the mechanical stability of cells.5 The cleavage of cytokeratin-18 by activated caspases 3, 7, and 9 produces a neoepitope that has been termed M30.6 As caspase activation is a hallmark of apoptotic cell death and does not occur to the same extent during necrotic cell death, the concurrent detection of M65—full-length non-cleaved cytokeratin-18—allows for estimation of the relative amount of apoptotic versus necrotic cell death. Since these two protein fragments monitor cell turn-over—a hallmarks of cancer cells—they could be attractive candidates for biomarker studies. Previous studies have explored the role of M30 and M65 in patients with...