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: Clinical correlation of plasma amino acid profile of post-surgical gastric cancer patients and metastatic gastric cancer patients for establishing biomarker of metastasis

Objectives: This research is aimed to evaluate plasma free amino acid in gastric cancer patients without metastasis (early gastric cancer post gastrectomy) and with metastasis (advanced gastric cancer). Amino acids level of postoperative gastric cancer (M0) patients are compared with metastatic gastric cancer (M1) patients in search of biomarker which can predict the metastasis of gastric cancer. We have made clinical correlation of patients’ vital signs, respiratory rate, pulse rate, blood pressure, body temperature, disease stages, chief complaints, complications and survival curve within light of metastatic and nonmetastatic domain. Background: Majority of cancer patients are diagnosed after seeding of metastatic cells to adjacent organs and distant sites. At this point, treatment is palliative and supportive. The cellular propagation of cancer cells and tumor micro-environment plays vital role in genesis of gastric cancer. Genetic alteration leading to faulty nucleotides to amino acids, then to protein, and finally formation of tumor is the natural sequence of pathogenesis of gastric cancer. Prediction of metastasis by use of plasma free amino acid profile may be of great significance because it will help to tailor the patient specific cancer treatment. Plasma Amino acids are ideal for being developed as tool for prediction of metastasis as they are affordable, less expensive and convenient. Method: This study includes total 54 patients, among which 27 had metastasis of Gastric cancer and rest 27 had undergone gastric surgery at early stage with no recurrence at the time of the study. Twenty-three amino acids were studied. Student’s t test was performed to find out statistically significant values of amino acids. The p value of ≤ 0.05 was considered statistically significant. Amino acids with significant p values were investigated with multivariate logistic regression. Partial Least Squares Discriminant Analysis (PLS DA) was done using Microsoft SPSS 23 version software®. Variable Importance of Projection (VIP) was estimated, values ≥ 1 was considered statistically significant. Result: Performance Score (PS) (p= 0.004) and Body Mass Index (BMI) (p= 0.035) were statistically significant between M0 and M1 groups. Staging (I, II vs. III, IV) (p< 0.001) was significant. Seven amino acids, Asp, Cys, Hcy, His, Leu, Orn and Ser were significant between M0 and M1 in first month evaluation. Eight amino acids, Cys, Hcy, His, Leu, Met, Thr, Trp and Tyr were significant between M0 and M1 in sixth month evaluation. PLS DA regression analysis, VIP test showed Cys, Ser, Hcy, Thr, His, Met, Tyr, Trp to be more important amino acids of significance. Kaplan Meier Overall Survival (OS) = 34.979 months. Mean survival time in M0 was 43.53± 1.741 months. Mean survival in M1 was 26.29± 2.635 months. Conclusion: We found BMI and PS as most important variables in defining and determining the disease status of gastric cancer patients. Nutrition and physical activity is very much characteristic of disease outcome from a physician’s perspective. This study propounds amino acids can be valuable biomarkers of predictive and prognostic importance in metastasis in gastric cancer patients. Author Name: Samim Akhtar1, Zhenhua Wang1, Abhishek Chaturbedi 2, Xiaoyu Wang 1, Fangzheng Sun1 1 Department of Medical Oncology, Gastrointestinal tumors Unit III, First Affiliated Hospital, Jinzhou Medical University, Liaoning, China 2 Manmohan Memorial Medical College and Teaching Hospital, Kathmandu, Nepal Corresponding Author: Samim Akhtar, MD. Consultant Oncologist, NCHRC, Nepal Citation: Samim Akhtar, Dept of Gastrointestinal Tumors, Jinzhou Medical University, Clinical correlation of plasma amino acid profile of postsurgical gastric cancer patients and metastatic gastric cancer patients for establishing biomarker of metastasis Received Date: 30th Jan 2021 Published Date: 20th Feb 2021 Copyrights: Samim Akhtar, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


INTRODUCTION:
Cancer of stomach can spread through local extension to regional lymph nodes or develop lymphatic, peritoneal, hematogenous spread to distant sites. Gastric cancer is second most common cause of cancer-related deaths in the world, the epidemiology of which has changed within last decades [1] . Approximately 50% gastric cancer are localized and surgically resect able, during initial diagnosis. Effective cure by surgery alone isn't adequate in many patients. Cancer relapse in patients who undergo complete surgery for gastric cancer, often occurs commonly in tumor bed, nodal regions and systemically [2]. In early upper GI cancers absence of particular presenting symptoms often enables these lesions to progress in an obscure way till they reach advanced stage and metastasize. Thus, discovery of biomarkers is exigent to help in the early diagnosis and treatment [3,4]. Overall prognosis of metastatic gastric cancer remains poor. Currently endoscopy, biopsy and histopathology examination are implemented for diagnosis of early gastric cancer or tumor recurrence [5,6]. This is an invasive procedure and can lead to complications. Diagnosis depends on quality of instrument and experience of operator [7]. In early stages of gastric cancer mostly patients don't have specific symptoms. There are insufficient screening techniques now, thus advanced stage accounts for approximately 90% diagnosed cases. Five-year survival rate is 20% or less. This shows us the importance of research in mechanism of gastric cancer occurrence, which involves up-and down-regulation of numerous metabolomes. It can lead to identification of specific protein and amino acids markers for diagnosis and treatment of the disease [8]. The tumor microenvironment, including the immune cells and related cytokines, is crucial during all the steps of gastric carcinogenesis. Metabolomic products are seen in various physiological and pathological processes, which can be used as prognostic marker [9]. Gastric cancer is most frequently diagnosed malignancy in adults. China has substantial health burden of GC. Patients with metastatic GC prognosis is unfavorable, with median survival does usually not exceeding 1 year. It is very important to explore new diagnostic biomarkers and therapeutic targets for GC [10].  [11]. Cancer cells utilize continuous nutrition to pull energy and amino acids for their rapid growth, which is also a hallmark of carcinogenesis [12].

DISCUSSION:
We detected several associations between clinicopathological features including patient's age, gender, ECOG performance score, BMI, temperature pulse rate blood pressure, degree of differentiation, local tumor invasion, lymph node metastasis, and stage of disease to metastatic recurrence in our study. The demographic characteristics like age (p=0.723) and gender (p=0.484) are not related to type of gastric cancer (Table 1.0). They are statistically not significant. In Netherlands, Dassen AE et al., conducted large research from 1990 to 2007, also showed no correlation of gastric cancer with age (p=0.2) and gender (p=0.7). No relationship between age and gender has been shown by several studies [13].
The chief presenting complaint of majority of patients with gastric cancer was abdominal pain followed by melena, and abdominal boating. It is similar to previous study done by Yang M et al., in 2018. In their study majority of patients presented with abdominal pain followed by dyspepsia and gastrointestinal bleeding [14]. Mainly onset of gastric cancer is asymptomatic and if it is presented than abdominal pain is the commonest complain. The majority of patients were T3 and T4 local invasion gastric cancer in our study comprised to 72.22% whereas T0T1T2 accounted only for 27.78%. Among metastatic group, all 27 patients were Stage IV. In nonmetastatic group, Stage III were 16, Stage II were 7 and Stage I were 4. The staging of patient's cancer 49 showed significant differences between metastatic and nonmetastatic groups (p< 0.001). Certainly, staging of cancer is a factor being affected by presence or absence of metastasis in gastric cancer. It is a proven fact that metastasis is the major cause of mortality among cancer related deaths. Thus, there is urgent necessity of developing new therapeutic methods for tracing potential metastatic gastric cancer [15,16]. It is shown in study related to cancer cell survival and amino acid uptake that mass spectrometry is valuable asset in estimating the concentration of increased and decreased levels of intracellular amino acids. Amino acids like His, Thr, Tyr and some more are important for survival of autophagy defective cells under starvation. These autophagy defective cells are cancer cells which increase and thrive. [17] The extracellular proteins which are products of digestion of entire living cells or apoptotic cells also release free amino acids in plasma. Amino acids can occur from intracellular sources such as organelles and proteins via a process of autophagy. Thus, metabolites derived can be both from cancer cells and normal tissue. [18] Presently the diagnosis of gastric cancer depends upon endoscopy, imaging and biopsy histopathology. But none of these tests can predict the potential of a tumor to grow fast and disseminate to other organs. Majority of deaths of patients with gastric cancer is due to occurrence of metastasis and complications. Regular biopsy and endoscopy and imaging are not feasible for all patients. Thus, it is very useful to look for a new biomarker which can truly predict the potential of a tumor to develop metastasis and complications. [19]. Use of conventional biomarkers such as CEA, CA19-9, CA 72-4 have less than 64% of sensitivity and are used basically in follow up patient. Amino acids and metabolomics using LC-MS/MS for this purpose [20]. It is seen in our study that amino acid Cysteine is profoundly altered in process of metastasis. In our study the level of Cysteine in metastatic gastric cancer in first month 1.43 (±0.067) μmol/L decreased to 0.91 (± 0.61) μmol/L in sixth months.  [29,30,31]. Prognosis is poor for these conditions. Peritoneal and hepatic are common distant metastasis sites as it was also seen in study done by Adachi Y et al., in 2000 [32, 33.34]. The pattern of metastasis has not changed in two decades. There was no statistically significant (p value =0.735) relationship between metastatic and non-metastatic gastric cancer due involvement of lymph node. We found presence of metastasis to regional lymph node does not rule out metastasis to distant sites or organ. This finding is also supported by previous researchers Sobin et al., 2009 andIchinoe M et al., 2015, demonstrated that there is no significance of metastatic lymph nodes in gastric cancer [35,36]. Construction of regression model PLS DA (Partial Least Squares Discriminant Analysis) was done followed by VIP (Variable Importance of Projection). Metastasis of cancer can be considered as an essential factor in prognosis and can be described by using amino acid levels in above model, Hu

CONCLUSION:
Plasma free amino acids are substantially altered during the progress of disease and metastasis. Gastric cancer related amino acid markers have the potential to be developed as biomarker.
Variations in plasma amino acid levels can be developed in the form of predictive biomarkers, which can then tell us about metastasis occurrence. It can be useful tool for assessment of gastric cancer patients. It can be used to monitor recurrence of tumor in patients after tumor resection or therapy. We are not very far from developing comprehensive set of biomarkers which can be very handy tool to be used in outpatient clinics and oncology wards in hospitals.