| BackgroundGastric cancer(GC)is one of the most prevalent malignancies worldwide,and HER2-positive GC is a specific subtype of GC.The results of the large phase III To GA study showed that trastuzumab in combination with chemotherapy significantly prolonged the survival time of patients with HER2-positive GC compared with chemotherapy,and brought GC treatment into a new era of anti-HER2 targeted therapy.However,drugs that achieved significant efficacy in HER2-positive breast cancer such as pertuzumab(anti-HER2),lapatinib(TKI inhibitor)and Trastuzumab Emtansine——T-DM1(ADC)in later explorations failed to improve the overall survival of HER2-positive GC patients,and this result may be due to the different tumor biological characteristics and molecular expression profiles between them.HER2 is an independent prognostic risk factor for breast cancer,but it is still a controversial prognostic factor for gastric cancer.Prognostic factors related to HER2-positive gastric cancer are not completely clear,and there are relatively few studies on prognostic models.Therefore,it is very important to explore prognostic factors affecting HER2-positive gastric cancer patients and construct prognostic models.At present,the standard first-line treatment for HER2-positive GC is trastuzumab combined with fluorouracil and platinum.However,there is no standard protocol for the selection of second-line drugs after the progression of trastuzumab first-line treatment.The guidelines of CSCO and NCCN recommend single-drug chemotherapy(paclitaxel,irinotecan)and ramoluzumab combined with paclitaxel,etc.ADC drugs are also being explored,and many conclusions on whether trastuzumab can be cross-line treatment are inconsistent.There is a need to provide the best available second-line treatment for these patients.ObjectiveIn this study,by exploring the prognosis of HER2-positive GC patients undergoing radical resection and the risk factors affecting the prognosis,a clinical prognostic model of HER2-positive GC was constructed and verified.On the basis of literature review,meta-analysis was used to try to find the best second-line treatment plan after the progress of trastuzumab treatment for HER2-positive gastric cancer,and to analyze the clinical efficacy and safety.MethodsPart one: Patients with GC who visited our center from December 1,2015 to December 31,2020 and underwent radical resection were collected,and their general characteristics,disease characteristics,and treatment modalities were described;the Kaplan-Meier method and Cox regression analysis were used to assess patients’ survival rates as well as to screen prognosis-related risk factors,construct prognostic models and build nomogram to predict patients’ survival rates at 1,3,and 5 years,and internal validation was performed in the test set.Part Two: Literature related to second-line clinical studies on HER2-positive GC after the progression of trastuzumab first-line treatment was searched through search terms in Pub Med,Embase,Cochrane and Web of Science electronic databases,and data were extracted according to inclusion and exclusion criteria for screening,quality evaluation and data extraction.The optimal treatment plan was obtained by single group rate meta-analysis and Bayesian mesh meta-analysis.Results1.This study included 418 patients with GC,including 218 HER2-positive ca and200 HER2-negative;342(81.8%)were men and 76(18.2%)were women;There were129 patients(30.9%)with p TNM stage Ⅰ,107 patients(25.6%)with PTNM stage Ⅱ and182 patients(43.5%)with PTNM stage Ⅲ.The median follow-up time was 4.8 years(1.90 to 7.12 years),with 287 survivors(68.7%)and 131 deaths(31.3%)at the followup endpoint(December 26,2022).The 1-year survival rate of HER2-positive gastric cancer patients was 92.2% and the 3-year survival rate was 75.6%.The survival rate of HER2-negative gastric cancer patients was higher than that of HER2-positive gastric cancer patients(P=0.18).Survival analysis based on clinicopathological features in HER2-positive gastric cancer,Survival rates were higher in patients with distal gastrectomy(P < 0.001),female(P=0.047),intestinal type(P=0.002),maximum tumor diameter less than 5cm(P < 0.001),stage Ⅰ(P < 0.001),and superficial,sunken,and raised gastric cancer(P < 0.001).2.Multifactorial Cox analysis showed that age(P=0.027,HR 1.05,95% CI: 1.01-1.09),T-stage(P=0.033,HR 1.92,95% CI: 1.05-3.50),N-stage(P=0.038,HR 1.51,95%CI 1.02-2.03),maximum tumor diameter(P= 0.048,HR 1.82,95%CI: 1.01-3.28)and morphological staging(P=0.018,HR 2.09,95%CI: 1.13-3.86)were independent risk factors affecting patient prognosis,and the prognostic model was constructed by combining the five variables and creating a nomogram with good predictive efficacy.3.A total of 6 single-arm studies and 8 controlled studies were included in the meta-analysis.The results showed that the ORR of trastuzumab combined with taxanes(23.8%)was superior to that of other chemotherapy agents(11.7%)(P < 0.05),and the ORR of DS-8201 was 49.1%.To summarize the results of meta-analysis,for HER2-positive gastric cancer,DS-8201 is the best choice of second-line drug after the treatment of first-line trastuzumab containing trastuzumab,followed by paclitaxel monotherapy.For trastuzumab cross-line treatment,the combination of paclitaxel is superior to the combination of docetaxel or irinotecan and other chemotherapy drugs,and T-DM1 has the shortest OS.Most of the adverse events of trastuzumab combined with chemotherapy were hematological toxicity.DS-8201 should be closely watched for the occurrence of interstitial pneumonia.Conclusions1.Through single-center data review,it was found that the tumor is located distal to the stomach,female,intestinal type,maximum tumor diameter less than 5cm,and stage Ⅰ p TNM had a relatively high survival rate.Based on the five independent prognostic factors of age,T stage,N stage,maximum tumor diameter and morphological type,the histogram has good predictive efficacy,which is conducive to the individualized treatment of patients.2.After the progress of anti-HER2 treatment for HER2-positive GC,DS-8201 is recommended first,followed by trastuzumab combined with taxus and other chemotherapy agents based on the analysis of the existing literature.The third is chemotherapy alone(except paclitaxel).If the patients receive T-DM1 in second-line treatment,the OS is the worst,and adverse reactions should be closely paid attention to in treatment. |
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