| 【Background】 Gastric cancer is one of the leading causes of cancer deaths.Nowadays,surgery is still the only way to cure gastric cancer.In recent years,the addition of adjuvant chemotherapy has further improved survival.The implementation of adjuvant chemotherapy for gastric cancer is mainly based on the postoperative pathological TNM(p TNM)staging.There is an agreement on the treatment of patients with stage IA(p T1N0)gastric cancer.After radical surgery,they will directly enter the follow-up observation.However,the indication of adjuvant chemotherapy remains controversial for the stage IB(p T2N0 or p T1N1)as the lacking of sufficient evidence of evidence-based medicine.Patients with stage IB gastric cancer generally have an excellent prognosis after curative resection,but there is recurrence in 7.5%-21.3% of patients within 5 years.Therefore,it is necessary to screen high-risk patients with stage IB gastric cancer for adjuvant therapy to improve the prognosis.In the first part of this study,we relied on multicenter cohorts,focusing on clinical and pathological factors,to explore the postoperative risk factors and the patients who can benefit from adjuvant chemotherapy.Surgery combined with adjuvant chemotherapy has been established as a standard treatment for stage II-III gastric cancer.However,compared with observation,the improvement of 5-year overall survival(OS)with adjuvant chemotherapy is far from meeting the clinical requirement.Postoperative adjuvant chemotherapy only increased the 5-year OS rate by about 10%.Thus,how to accurately select the patients for postoperative adjuvant chemotherapy has been a hot issue in chemotherapy research.Although the pathological TNM staging provides an important role for clinically identifying patients at high risk of recurrence,the staging system is not accurate enough.Therefore,simple and easy-to-use biomarkers that can predict the prognosis and chemotherapy response of gastric cancer are urgently needed to supplement the current pathological TNM staging.Human epidermal growth factor receptor 2(HER2)is an important target for gastric cancer targeted therapy.The proportion of patients with HER2 overexpression is less than 10% in all gastric cancer patients,and its relationship with the prognosis of patients is complicated.HER2 overexpression is not only related to clinical-pathological features that predict good prognosis,such as relatively good differentiation,but also significantly related to factors that predict poor prognoses,such as advanced age and gastroesophageal junction cancer.Therefore,the relationship between HER2 expression and the prognosis of patients with resectable gastric cancer is still controversial;furthermore,few studies have focused on the impact of HER2 expression on the efficacy of adjuvant chemotherapy.In addition,caudaltype homeobox transcription factor 2(CDX2)is a key nuclear transcription factor involved in the regulation of intestinal metaplasia of the gastric mucosa.Studies have shown that lacking of CDX2 expression in colon cancer patients was associated with poor prognosis and benefit from adjuvant chemotherapy.However,the relationship between CDX2 expression and prognosis is still unclear in gastric cancer patients,and no prior study has reported the association between CDX2 expression and benefits from adjuvant chemotherapy in gastric cancer patients.Therefore,in the second and third parts of this study,we focused on the application value of HER2 and CDX2 expression in postoperative risk stratification and chemotherapy efficacy prediction for patients with stage II-III gastric cancer.In addition to the biological characteristics of the tumor,in recent years,the value of systemic inflammatory markers and nutritional indicators in the evaluation of the prognosis of gastric cancer patients has attracted wide attention,but most of them are small sample studies and lack of subgroup analysis for specific patients.Their combined associations with prognoses are not well studied.Therefore,in the fourth part of this study,the neutrophil-tolymphocyte ratio(NLR)and body mass index(BMI)were used to quantify systemic inflammation and nutritional status.Accordingly,we examined the independent and combined clinical values of NLR and BMI at diagnosis in prognostic evaluation in patients with stage I-III gastric cancer based on a large prospective cohort.【Objective】 1.A retrospective multicenter study was performed to evaluate the risk factors of patients with stage IB gastric cancer and assess the association between adjuvant chemotherapy and survival in the presence and absence of high-risk features.2.A retrospective multicenter study was performed to investigate the correlation between the expression of HER2 and survival outcomes and chemotherapy response in stage II-III gastric cancer.3.Two cohorts of patients(a prospective evaluation cohort,and a retrospective validation cohort)were included to evaluate the correlation between the expression of CDX2 and survival outcomes and chemotherapy response in stage II-III gastric cancer.4.An observational study based on a large prospective cohort of gastric cancer was performed to evaluate the association of NLR and BMI with outcomes in patients with stage I-III gastric cancer.【Methods】 1.Patients who underwent radical surgery and were pathologically diagnosed with stage IB gastric adenocarcinoma in 4 large 3a hospitals of China from October 2008 to December 2017 were included.The Kaplan-Meier method was utilized for the survival analysis.The Cox regression model and propensity score-matched analysis were used to adjust for confounders.The influence of adjuvant chemotherapy on the prognosis of specific patients was explored through subgroup analysis.2.Patients with stage II-III gastric adenocarcinoma who underwent radical surgery and the HER2 protein expression was detected by immunohistochemical(IHC)staining after surgery in 3 large 3a hospitals of China from May 2010 to September 2017 were included.The Kaplan-Meier method was utilized for the survival analysis.The Cox regression model and stratified analysis were used to adjust for confounders.Wald test was used to analyze the interaction between HER2 expression and adjuvant chemotherapy on the prognosis of patients.3.The study included two cohorts of patients with resectable stage II-III gastric adenocarcinoma based on the date of surgery: in the prospective evaluation cohort,the consecutive patients undergoing radical surgery for gastric adenocarcinoma between January 2016 and September 2017 were included;in the validation cohort,the patients undergoing radical surgery for gastric adenocarcinoma with paraffin-embedded tissues in the biobank of our hospital before June 2015(follow-up over 5 years)were included.CDX2 expression was examined by IHC staining using whole tumor sections.The Kaplan-Meier method was utilized for the survival analysis.The Cox regression model and stratified analysis were used to adjust for confounders.Wald test was used to analyze the interaction between CDX2 expression and adjuvant chemotherapy on the prognosis of patients.4.Patients undergoing radical surgery for gastric adenocarcinoma from January 2009 to December 2014 were included.Systemic inflammation was quantified by the preoperative neutrophil-to-lymphocyte ratio(NLR).High systemic inflammation was defined as NLR ≥ 3,and underweight was defined as BMI < 18.5 kg/m2.The Kaplan-Meier method was utilized for the survival analysis.The Cox regression model and stratified analysis were used to adjust for confounders.【Results】 1.(1)A total of 1,115 patients from 4 hospitals with stage IB gastric adenocarcinoma were enrolled,including 730 patients who received adjuvant chemotherapy and 385 patients who only underwent surgical resection.(2)Patients undergoing adjuvant chemotherapy were younger,tended to have poorer differentiation,nerve invasion and lymphovascular invasion than patients undergoing surgery alone(all P < 0.05).(3)In the whole cohort,the 5-year OS of patients in the adjuvant chemotherapy group was 94.5%,and the 5-year OS of patients in the surgery only group was 90.6%.There was no significant difference in OS between two groups [hazard ratio(HR),0.686,95% confidence interval(95% CI): 0.463-1.015,P = 0.059].(4)After matching,the cohort consisted of 300 patients in each treatment arm.All clinical-pathologic confirmations were well balanced(all P > 0.1).There was still no difference in OS between both groups(HR 0.900,95% CI: 0.551-1.470,P = 0.674).(5)In terms of risk factors,the Cox multivariate analysis showed that increasing age(HR for per year increase,1.044,95%CI: 1.013-1.076,P = 0.005),and high level of carcinoembryonic antigen(CEA)(HR,2.197,95% CI: 1.020-4.734,P = 0.044)were independently associated with worse survival.But the use of adjuvant chemotherapy was not significant ly associated with improved survival rates.In subgroup analysis,adjuvant chemotherapy was associated with significant survival benefit in patients with p T1N1(HR,0.092,95%CI: 0.022-0.386,P = 0.001),lymphovascular invasion(HR,0.139,95%CI:0.058-0.335,P < 0.001),poor differentiation(HR,0.583,95%CI: 0.351-0.966,P = 0.036)and high level of CEA(HR,0.253,95%CI: 0.077-0.831,P = 0.024).2.(1)A total of 5,621 patients from 3 hospitals with stage II-III gastric adenocarcinoma were enrolled.The IHC results were obtained for HER2 expression as follows: score 0,2,889;score 1+,1,574;score 2+,780;and score 3+,378.(2)Multivariate logistic regression model showed that differentiation and pathological N stage were the independent factors related to HER2 overexpression(IHC 3+).(3)In terms of the effect of HER2 expression on survival,in stage II patients,the Cox regression analysis showed that HER2 expression was independently associated with survival.Compared with patients without HER2 expression(IHC score 0),patients with HER2 IHC score 3+ had a significantly increased risk of death(HR,2.038;95%CI: 1.407-2.953;P < 0.001).Multivariate analysis showed that HER2 expression was not an independent prognostic factor for stage III gastric cancer.(4)In terms of the effect of HER2 expression on adjuvant chemotherapy response,in patients with stage II disease,among patients with no HER2 expression and 1+,adjuvant chemotherapy was associated with improved survival(P < 0.05).But among patients with HER2 IHC 2+,there was no significant difference in OS between the adjuvant chemotherapy group and the surgeryonly group(5-year OS: 81.8% in the chemotherapy group vs.83.5% in the surgery-only group,P = 0.760).The relation among patients with HER2 IHC 3+ was similar to the patients with 2+,adjuvant chemotherapy was not associated with improved OS(5-year OS: 67.0% in the chemotherapy group vs.79.2% in the surgery-only group,P = 0.636).In patients with stage III disease,adjuvant chemotherapy was significantly associated with improved OS in all subgroups according to the expression levels of HER2(all P < 0.001).(5)Then patients were divided into HER2 low expression group(IHC 0/1+)and HER2 high expression group(2+/3+)according to HER2 expression level.A test for an interaction between HER2 expression and adjuvant chemotherapy indicated that,in stage II disease,the benefit from adjuvant chemotherapy was superior among patients who had HER2 low expression tumors than among those with HER2 high expression tumors(P = 0.019 for the interaction).However,the interaction test in stage III disease did not show significant results between patients who with HER2 high expression tumors and those with HER2 low expression tumors(P = 0.240 for the interaction).(6)The association between HER2 status and benefit from adjuvant chemotherapy was not confounded by risk factors that are known to affect the survival rates among patients with stage II disease.These risk factors include the cycles of adjuvant chemotherapy(no chemotherapy vs.1-4 cycles vs.≥ 5 cycles),the depth of invasion of the primary tumor(T1/2 vs.T3/4),and the number of metastatic lymph nodes(N0/1 vs.N2/3).3.(1)A total of 1,168 patients were included(782 in the evaluation cohort,386 in the validation cohort).In terms of the correlations between CDX2 status and clinicopathological factors,the expression of CDX2 was associated with differentiation,and the positive rate of CDX2 in well differentiated tumors is relatively high.However,there was no significant relationship with gender,age and tumor stage.(2)We found no significant association between the status of CDX2 and disease-free survival(DFS)in both cohorts(P = 0.416 and 0.059,respectively).In subgroup analysis,negative expression of CDX2 was significantly related to poor DFS in the surgery-only subgroup(P = 0.001 and 0.003,respectively),but not in the adjuvant chemotherapy subgroup in both cohorts.(3)Subsequent multivariate Cox analysis revealed that negative expression of CDX2 was an independent prognostic factor in the surgery only subgroup in the evaluation cohort(DFS: HR,1.774,95%CI,1.211-2.601,P = 0.003),and similar result was obtained in the validation cohort(DFS: HR,1.684,95%CI: 1.133-2.503,P = 0.010).(4)Time-dependent ROC curves indicated that incorporating CDX2 status into the TNM staging system could lead to better prognostic accuracy.(5)Further analysis revealed that the benefit from adjuvant chemotherapy was superior among CDX2-negative patients compared with CDX2-positive patients(DFS: P = 0.002 and 0.041 for interaction,respectively).4.(1)Among 2,542 patients with stage I-III gastric adenocarcinoma,NLR ≥ 3 and underweight were 627(25%)and 349(14%),respectively,and both NLR ≥ 3 and underweight was 98(3.9%).(2)In the whole cohort,multivariate analysis revealed that NLR ≥ 3 or underweight independently predicted worse OS(HR,1.236,95% CI: 1.069-1.430;and HR,1.600,95% CI: 1.350-1.897,respectively)and recurrence-free survival(RFS)(HR,1.230,95% CI: 1.054-1.434;and HR,1.658,95% CI: 1.389-1.979,respectively).(3)Patients with both NLR ≥ 3 and underweight(vs.neither)had much worse OS(HR,2.445,95% CI: 1.853-3.225)and RFS(HR,2.405,95% CI: 1.802-3.209).(4)Furthermore,in subgroup analyses according to the pathological stage,age,and postoperative chemotherapy also showed that the combination of NLR and BMI exerted a more potent prognostic effect than each index alone.Even stage I(HR: 5.419,95% CI: 1.453-20.204),young(< 55 years)(HR: 2.381,95% CI: 1.369-4.141),and adjuvant chemotherapy patients(HR: 2.481,95% CI: 1.754-3.511)with both elevated NLR and underweight(vs.neither)still had more than a 2-fold increased risk of death.【Conclusions】 1.Without screening for risk factors,stage IB alone was not associated with improved efficacy of adjuvant chemotherapy in patients with gastric adenocarcinoma.High-risk clinicopathologic features,including lymphonode metastasis,lymphovascular invasion,poor differentiation and high level of CEA,should be considered simultaneously when evaluating patients with stage IB gastric cancer for adjuvant chemotherapy,so as to screen the potential benefit patients of adjuvant chemotherapy.2.Overexpression of HER2 was identified as an independent,unfavorable prognostic factor in stage II gastric adenocarcinoma.Patients with high expression of HER2 cannot benefit from conventional adjuvant chemotherapy in stage II gastric adenocarcinoma.However,the expression of HER2 has no significant correlation with the prognosis and adjuvant chemotherapy benefits of patients with stage III gastric cancer.Therefore,the expression of HER2 can be used as an important biomarker to assess the outcome and guide the selection of postoperative adjuvant chemotherapy in patients with stage II gastric adenocarcinoma.3.Negative expression of CDX2 is an independent risk factor for survival in stage II-III gastric adenocarcinoma patients who do not receive adjuvant chemotherapy.Furthermore,this study suggests that negative expression of CDX2 is associated with adjuvant chemotherapy benefits.Therefore,stage II-III gastric cancer with negative CDX2 expression deserves more aggressive adjuvant chemotherapy.These findings provide a novel simple biomarker for individual therapy in patients with gastric cancer.4.Our results showed that preoperative elevated NLR or decreased BMI had a significant negative effect on survival in resectable stage I-III gastric adenocarcinoma patients.We also found that a low BMI combined with a high systemic inflammation index identified patients with more than a 2-fold risk of mortality compared to patients with neither condition.Taking active therapeutic measures to reduce inflammation and increase nutrition may help improve outcomes. |
PDF Full Text Request