Exploration Of New Precision Treatment Strategies Predictive Biomarkers For HER2 Positive Gastric Cancer

Background:Gastric cancer is a malignant tumor with high incidence and mortality in our country.With the advent of the era of precision treatment,breast cancer,melanoma,non-small cell lung cancer and other tumors have made great progress in the field of targeted therapy and immunotherapy.However,due to the high heterogeneity of advanced gastric cancer,its precision treatment is still lagging behind.Effective target and treatment options are scarce.Therefore,it is urgent to comprehensively evaluate the molecular characteristics and biomarkers of gastric cancer patients related to representative precision treatment,so as to continuously expand the potential beneficiary patient,discover new targets and new drugs,and help existing treatment programs overcome drug resistance and other problems.Markerdriven precise treatment of gastric cancer.Therefore,based on various techniques,our study conducted a multi-dimensional exploration of gastric cancer bio-markers on the most important targets of gastric cancer:HER2,and provided a reference for future precise monitoring and treatment.Materials and Methods:Our study collected peripheral blood and tissue specimens of patients treated by our research team,and explored markers for the most representative two kinds of precision treatment of gastric cancer.For targeted HER2 therapy,we use nextgeneration sequencing(NGS)to explore the relationship between ctDNA variation in dynamic peripheral blood samples and response at various evaluation points after treatment;For targeted HER2 combined immunotherapy,we use iFISH technology combined with karyotyping methods to explore the relationship between CTC variation in peripheral blood samples and efficacy from multiple blood sampling points after treatment.Results:For the exploration of predictive bio-markers of anti-HER2 therapy based on peripheral blood ctDNA second-generation sequencing technology,we found that ctDNA features(including ERBB2 CNV,TCL and TMB status)have a predictive effect on the response,prognosis and resistance of anti-HER2 therapy,compared with CT it could judge the tumor progression in advance;In addition to the copy number of ERBB2,the baseline TMB status had a significant impact on the efficacy of anti-HER2 therapy.Compared with with anti-HER2 therapy,ERBB2HighTMBHigh(ERBB2 CNV≥2,TMB≥8.5)was more likely to benefit from immunotherapy(19.85 months vs 3.07 months).As for peripheral blood circulating tumor cells to explore the efficacy markers of anti-HER2 combined immunotherapy,we have observed the effect of PD-L1 positive circulating cells as predictive bio-markers:the appearance of triploid PD-L1+CTC/CEC occurred at baseline and during treatment often indicated the patient’s poor efficacy and prognosis(P=0.013).Conclusions:Our study explored the characteristics of peripheral blood ctDNA gene in antiHER2 therapy and triploid karyotype PD-L1+CTC/CEC as biomarkers in anti-HER2 combined immunotherapy for efficacy monitoring and prognosis effect.ctDNA features have a predictive effect on the efficacy,prognosis and drug resistance of targeted HER2 therapy.Triploid PD-L1+CTC/CEC appeared during baseline and treatment indicated the poor efficacy and prognosis of patients with targeted HER2 combined immunotherapy.