In recent decades, the decline in the incidence of Helicobacter pylori infection, improvement in lifestyle habits, and continuous development of targeted therapy and immunotherapy have contributed to the decline in the incidence and mortality of gastric cancer in most parts of the world[24]. However, the 5-year OS (even the 3-year OS) and quality of life of patients with gastric cancer are far from satisfactory, particularly for those with stage IV cancer[3]. In most parts of the world, the 5-year survival rate of patients with gastric cancer is nearly 20–30%, which is significantly lower than that of patients with other malignant tumors[13]. Gastric cancer symptoms usually appear at an advanced stage, which often leads to a poor prognosis. Patient prognoses must be accurately assessed, and individualized treatment options must be adopted to improve the patients’ quality of life. Increasing evidence suggests that malnutrition significantly shortens the survival duration of patients, particularly those with cancer. The crucial role of serum biomarkers in the management of advanced disease and in the prognoses of various cancers is constantly being investigated. In this study, we evaluated the association between cachexia status and serum biomarker levels and the 3-year OS of patients with gastric cancer. We further developed an innovative risk prediction model based on the results of cachexia diagnosis and serum biomarker assessment. The ROC curve exhibited the exact consistency of the model. Ultimately, a novel nomogram was constructed based on the independent risk factors identified, with a great potential for broad clinical applications.
A previous study reported that 50–90% of patients with malignant tumors experience weight loss and malnutrition, particularly those with malignant digestive tract tumors and gastric cancer [14]. The high incidence of malnutrition in patients with gastric cancer is related to the location of the tumor. At least 20% of patients die from malnutrition and related complications rather than malignancy. Quality of life, prognosis, and survival differ markedly between well-nourished and malnourished patients. However, to the best of our knowledge, there is no current gold standard for the accurate assessment of patient survival and disease prognosis. Studies on the nutritional assessment of patients with gastric cancer are scarce. Since its inception, the concept of cachexia has been widely used in the management of advanced disease, particularly in patients with advanced cancer. Cachexia can comprehensively reflect the patient’s protein and energy balance. Severity of cachexia can be classified according to energy storage and protein consumption. In clinical practice, weight loss has been used as an evaluation index for many years because of the lack of accurate diagnostic criteria. This limits cachexia diagnosis in term of nutritional assessment, prognosis evaluation, and quality of life assessment in patients with cancer. The standardization of cachexia has become increasingly clear in recent years, and it has been increasingly applied in clinical practice. Patient-generated subjective global assessments have been reported to be a promising screening tool for cachexia [25]. Furthermore, additional features such as anorexia, muscle loss, fatigue, and other indicators are also gradually being used to screen for cachexia. In their recent study, Zhang et al. reported that systemic inflammation is significantly associated with the survival of patients with tumor cachexia [26]. Using serum and urine metabolomics, Yang et al. developed a unique diagnostic model for tumor cachexia[27]. All of the aforementioned methods may continuously improve the clinical application value of cachexia. However, to the best of our knowledge, no studies to date have evaluated the use of cachexia diagnosis combined with the assessment of other indicators to predict disease prognosis and patient survival.
Serum biomarkers are widely used to determine cancer prognosis. Several studies have demonstrated that an elevated CEA level is an independent risk factor for the poor prognosis of patients with early-stage gastric cancer, and the upregulated expression of postoperative serum CEA is closely associated with tumor recurrence [28]. CA19-9 is also an important biomarker of gastric cancer. An elevated serum level of CA19-9 indicates that the patient has an increased risk of tumor metastasis and a decreased survival rate, making it an important prognostic factor in gastric cancer. The measurement of serum CA19-9 level is also often combined with that of AFP, CEA, and CA125 levels to determine the prognosis of gastric cancer. A recent study has demonstrated that the assessment of anti-HP antibody level combined with that of CA19-9 and CEA levels is highly valuable in determining postoperative recurrence, metastasis, and death risk in patients with early-stage gastric cancer [29]. Albumin reflects the systemic nutritional status of patients and has become a mature serum marker. In clinical practice, the measurement of certain biochemical indicators combined with that of serum albumin level is widely used to evaluate the survival of patients with tumor. The fibrinogen–albumin ratio can be used as a prognostic factor for first-line chemotherapy in patients with advanced gastric cancer. The ratio of C-reactive protein and albumin levels reflects the prognosis of gastric cancer [30]. Similarly, combined D-dimer level may be useful for predicting patients’ response to first-line chemotherapy and prognosis of advanced gastric cancer [31]. Therefore, we combined cachexia diagnosis with serum biomarker assessment to predict gastric cancer prognosis and patient survival. To compensate for the bias resulting from single-factor modeling, a more accurate and stable model must be established. Unlike previous studies, we innovatively used continuous serum biomarker values rather than “negative” or “positive” binary results.
As mentioned above, cachexia is difficult to detect at an early stage; moreover, conventional treatment is ineffective after a delayed diagnosis. Thus, the early diagnosis of cachexia has become a challenge for many clinicians. The continuous development of liquid biopsy technology and advancements in exosome research, has made it possible to identify a marker with high concentration, stability, easy collection, and high sensitivity and specificity. Exosomes can carry miRNAs into the circulatory system and promote cell-to-cell and tissue-to-tissue connections through paracrine, autocrine, and endocrine methods. With the discovery of exosomal miRNAs, many miRNAs have been confirmed to be involved in inflammatory responses, inducing metastasis, mediating cancer invasion, and participating in protein synthesis and degradation pathways in the skeletal muscle [32]. He et al. found that exosomes secreted by pancreatic and lung cancer cells delivered miR-21 to muscle cells through the blood and induced apoptosis of these muscle cells. Exosomal miR-21 regulates the recognition and activation of Toll-like receptor 7 in mouse myoblasts, thereby promoting myocyte apoptosis. Hudson et al. demonstrated that exosomal miR-182 inhibits muscle atrophy induced by the overexpression of FOXO3 in skeletal muscle cells[33]. Furthermore, miR-21 and miR-29 inhibit protein synthesis and promote protein degradation by activating the nuclear factor-κB signaling pathway[34]. Taken together, exosomal miRNAs are involved in many regulatory pathways in muscle cells. The most important feature of cachexia is the continuous loss of the skeletal muscle, which may be accompanied by fat wastage. The skeletal muscle constitutes approximately 40% of the body weight and is important for locomotion and metabolic homeostasis. However, there is no report that exosomal miRNAs cause skeletal muscle loss and lead to the development of cachexia. Thus, this study is the first to identify a correlation between plasma-derived exosomal hsa-miR-432-5p and gastric cancer cachexia, which is highly expressed in patients with gastric cancer cachexia, and has better sensitivity and specificity for the early diagnosis. Therefore, plasma-derived exosomal hsa-miR-432-5p has the potential for use as a biomarker for gastric cancer cachexia.
Our study has some limitations. Because this was a retrospective, single-center study, we presume a certain degree of selection bias; moreover, the model needs to be validated at other hospitals. In the future, we would like to gradually expand the number of studies and increase cooperation units to further validate the findings of our model and optimize the model using data obtained from large-sample, multicenter studies.
In conclusion, we developed a prognostic model based on cachexia diagnosis combined with serum biomarker assessment for patients with gastric cancer. The model exhibited a satisfactory predictive power. A novel nomogram was constructed to predict OS in patients with gastric cancer alone. The four independent factors included in the prediction model developed in this study are relatively easy to assess in clinical practice. They can be used to accurately predict the postoperative OS of patients with gastric cancer. When weight loss is not up to the standard, only the judgment based on cachexia has a considerable influence on individual subjective factors. However, the detection of exosomal miRNAs may largely make up for this shortcoming. The nomogram constructed in this study by combining four independent factors has a consistent clinical application value.