Serum tumor markers are widely applied in diagnosis, therapeutic effect assessment and disease recurrence monitoring [9], and a series of studies have explored the diagnostic and prognostic value of various serum tumor markers in gastric cancer [10]. However, most of these studies were based on patients who had undergone surgery with or without adjuvant therapy, and only a few focused on patients with NCT in gastric cancer [11, 12].
Other studies have shown that, CA125 was associated with the R0 resection rate [13], recurrence, peritoneal dissemination [14] and OS in unresectable advanced or recurrent GC patients [15]; CA199 was related to pN [7, 16-18] and pTNM stage [17]; and CA724 was related to the pathological stage and had a good diagnostic value for gastric cancer [19]. However, none of the patients in those studies underwent NCT.
In our study, the levels of CA199, CA125 and CA724 before and after NCT could predict prognosis, and the changes of CA199 and CA125 were related to the outcome. Similar results had been presented by many studies based on GC patients without NCT [8, 13, 19, 20]. Nevertheless, we found that only CA724 was an independent prognostic factor in the multivariable analysis before and after NCT. It is noteworthy that this independent significance was lost in the diff- group, which was different from the findings of some studies. Zou et al. [11] claimed that the change in CA724 could reflect the therapeutic effect of NCT. Another paper suggested that a decrease in CA724 could lead to a better prognosis [12]. The difference in findings might be because more clinicopathological factors were included in the multivariable analysis in our study. Despite this, CA724 was still an independent predictive factor for GC patients who had undergone NCT.
Although CA724 had a high diagnostic value in GC, its sensitivity was only approximately 45.0% [19]. Moreover, in China, CA724 has been suggested to be associated with Helicobacter pylori infection [21] and even geographical environmental factors, such as temperature [22]. These findings imply that there might be a bias to evaluate the condition of patients merely depending on CA724. Much work has been done to address this problem. For example, TKI, an enzyme involved in the regulation of the mammalian cell cycle, was another choice of marker in gastric cancer [19]. Moreover, the combination of CA724, CA199, CA125 and CEA could also improve the diagnostic capability. [9, 12, 19, 23].
Regarding pathological factors, we found that CA199, CA125 and CA724 before and after NCT were all correlated with lymph node metastasis and ypTNM stage. In previous studies of GC patients who underwent curative gastrectomy, preoperative CA199 could predict lymph node metastasis [17, 18] and pTNM stage [17]. CA724 was associated with nodal involvement [9] and pathological stage in advanced gastric cancer patients [19]. To supplement those findings, we confirmed them in patients with preoperative therapy. In addition, we found that CA125 was also related to ypN and ypTNM stage.
In our study, the VOLI rate was significantly higher in the positive post-CA724 group, while in pre-CA724 group, the difference was not significant. However, Sun et al. [12] suggested that pre-CA724 was related to vascular invasion. This finding might suggest that CA724 could be used to assess lymphatic or vascular invasion, but more evidence is needed.
It was unexpected that CEA was not related to prognosis in our study. The reasons might include that a different cutoff value was used in our study, and NCT might influence the predictive value of the tumor marker. Although a team from Japan supported a similar result [7], a large number of studies suggested the opposite result [10, 16, 18, 24]. Nevertheless, in our study, CEA was related to CA199 and CA125, which was in line with other studies [7, 19]. It is noteworthy that these connections weakened after NCT, which might mean that preoperative treatment could blur these relationships.
The limitations still exist in this study. First, due to the nature of retrospective research, some patients did not have all values of the markers, which hindered the exploration of the combination of markers. Second, the sample size was not large enough. The sample numbers of AFU and AFP in every group were so small that they were not included in the further analysis. This limitation might also contribute to the reason why some P values were more than 0.05 but smaller than 0.1. Third, we used the optimal cutoff values derived from the Youden index, which disturbed the comparison with other studies.
Despite these limitations, our study still has some merits. Our sample size is relatively small, but we focused on a specific group of patients. The cutoff values of tumor markers used in our study were calculated by statistical methods, because there is lack of strong evidence on the optimal cutoff values, which might vary according to the therapy, tumor location, and even geographical features. We not only illuminated the prognostic significance of these tumor markers, but also confirmed their abilities to predict lymph node metastasis and pathological stage. These results are useful for assessing the condition of patients and making further clinical decisions.