December 5, 2023 | Under the leadership of the Nagoya University Graduate School of Medicine in Japan, researchers have identified a biomarker for gastric (stomach) cancer that could fill the need for a more affordable and less complicated and time-consuming option than currently available tests based on exosomes, circulating tumor DNA, and serum noncoding RNA that have had limited adoption in real-world healthcare. The sensitivity and specificity of tumor markers CEA (cancer embryonic antigen) and CA19-9 (carbohydrate antigen) are so low that neither are recommended for screening purposes by the Japanese Society for Gastric Cancer.
So says gastroenterological surgeon Takahiro Shinozuka, M.D., first author on a study recently published in Scientific Reports (DOI: 10.1038/s41598-023-42201-2) describing the new liquid biopsy-based diagnostic marker. As clinical surgeons specializing in gastric cancer, he and his fellow investigators well know that the prognosis for patients when the disease is detected in an advanced stage is typically poor but when a tumor is small and contained the prognosis is generally good. That motivated their quest to find a better biomarker that can screen for early gastric cancer.
To that end, researchers collected serum samples from 582 patients with gastric cancer and other types of solid tumors seen at Nagoya University Hospital between 2014 and 2020 plus another 80 healthy volunteers. They then measured their serum stromal cell-derived factor 4 (SDF4) protein levels. SDF4 was selected as the best diagnostic marker for the study based on pilot experiments measuring blood levels of 10 candidate proteins in healthy controls and gastric cancer patients.
SDF4 is expressed by various normal human tissues, including gastric tissues. The investigators report that, to their knowledge, no prior studies have looked at serum SDF4 levels and their clinicopathological relevance in cancer patients.
One key discovery here is that SDF4 reliably detects different types of cancer early on when it is more treatable, Shinozuka says. Elevated levels of the protein were detected in blood samples taken from patients with gastric, esophageal, colorectal, pancreatic, breast, and liver cancer relative to their healthy counterparts.
SDF4 proved to be particularly useful as a biomarker for stomach cancer, but only because nearly 70% of subjects enrolled in the study had that condition, he continues. For gastric cancer, the group found that SDF4 had a sensitivity of 89%—well about that of CEA (13%) and CA19-9 (17%)—and a specificity of 99%. They previously reported on candidates of novel serum protein biomarkers for gastric cancer, all of which proved unsatisfactory in terms of the sensitivity or specificity.
The utility of SDF4 in screening for early-stage cancer is a subject for future research, as is its utility in determining the risk of developing cancer at all, Shinozuka says.
Inexplicably, SDF4 values helped identify stage IV gastric cancer as well as early-stage disease. The study does not explain what triggers the pathology, says Shinozuka, but it can be reasonably hypothesized that “SDF4 begins to rise even in the precancerous stage” since levels of the protein were elevated in the stage 1 samples. The plan is to test this theory by collecting samples from patients with dysplasia, an increase in abnormal cell growth.
According to Shinozuka, he and his colleagues have begun acquiring monoclonal antibodies to improve the accuracy of the enzyme-linked immunoassay (ELISA) laboratory technique and will develop kits using these antibodies. They also intend to conduct an international prospective observational study to validate the diagnostic performance of the ELISA kit in a larger population of patients.
“The primary purpose of this test is screening of cancers, but whether it can also be applied to determine treatment efficacy and to monitor recurrence remains to be verified,” he says. Obtaining regulatory approval to market in vitro diagnostics “often takes longer in Japan than in Western countries. However, the incidence of gastric cancer is higher [here]... so there is a great need for such drugs.”
According to the International Agency on Research for Cancer, stomach cancer caused more than 750,000 deaths in 2020 and ranks as the fourth leading cause of cancer deaths in both genders combined. More than one million new cases were diagnosed in 2020 and about 75% of the new cases and deaths are reported in Asia.
“Worldwide, rates of cancer-related mortality and morbidity remain high, says Shinozuka. But with early detection “it is often possible to cure the disease and lead a normal life.”
Endoscopy remains the standard method for screening and diagnosis of gastrointestinal cancers, including gastric cancer, but as with the tumor biomarkers has its drawbacks. It is invasive, comes with a risk of complications, is a time-intensive tissue evaluation, and can be costly, all of which make it unsuitable for large-scale screening.
Of course, the development of better screening methods is “meaningless if people do not receive them,” Shinozuka says. “Preventive medicine, such as diet, is important, but we also want people to be highly aware of the importance of taking screening tests.”