Apatinib In Advanced Gastric Cancer: Efficacy Analysis Based On Real-World Data And Exploratory Study On Inrtinsic Resistance Associated Mutations By Whole-Exome Sequencing

Anti-angiogenic therapy is a new treatment strategy.Apatinib has been approved for advanced gastric cancer after faliure to second-line chemotherapy and most of patients can tolerate.However,two major problems still exist.Firstly,owing to the strict grouping criteria,clinical trials can't represent the actual clinical situation.Secondly,resistance can be observed in some patients the first time they take apatinib,but there are no predictive factors to identify benefit population.Thus,we evaluated clinical efficacy and adverse events based on real-word data,and explored the potential mutations associated with inrtinsic resistance by whole-exome sequencing.This study includes the two parts:Part 1.Apatinib in Advanced Gastric Cancer: Efficacy andSafety Analyses Based on Real-World Data.ObjectTo evaluate the clinical efficacy and safety of patients with advanced gastric cancer treated with apatinib.MethodA total of 144 patients with advanced gastric adenocarcinoma recieved apatinib in Henan cancer hospital attached to Zhengzhou University from 2015-11 to 2018-05 were retrospectively reviewed in this study.Clinical efficacy,adverse events and survival were recorded,and associations with clinical characteristics were evaluated.Result:1)Association of efficacy and clinical characteristics: Among 144 patients,objective response rate(ORR)was 11.1%,and disease control rate(DCR)were 62.5%.Both ORR and DCR in low-dose group(<500 mg)were lower than in high-dose group(4.6% vs.16.5%,P=0.024;52.3% vs.70.9%,P= 0.022).DCR in combination group was significantly higher than monotherapy group(71.4% vs.53.0%,P=0.006).2)Associations of survival with clinical characteristics: Among 144 patients,the median follow-up time was 186 days.The median disease progression survival(mDFS)was 65 days and the median overall survival(mOS)was 155 days.Gender,lines,and combination therapy were associated with PFS,and combinaton was also associated with OS.Females,after failure to second-line chemotherapy were independent factors for shorter PFS,and monotherapy and low-dose were independent factors for shorter OS.3)Adverse events: The incidences of fatigue,vomiting,and leukocyte/neutropenia were significantly higher in the combination therapy group,and the difference was statistically significant(47.5% vs.25.3%,P=0.006;27.9% vs.13.3%,P=0.029;42.6% vs.20.5%,P=0.004).ConclusionApatinib is effective and safe in the treatment of advanced gastic cancer.Patients can benefit from combination therapy more than monotherapy companing higher rate of AEs,and clinical managements should be based on patient's comprehensive situation.Part 2.Exploratory Study on Inrtinsic Resistance AssociatedMutations by Whole-Exome Sequencing.ObjectTo explore inrtinsic resistance associated mutations for Apatinib.MethodIn order to rule out the effect of chemotherapy on tumor mutation spectrum,we selected 6 patients with gastric adenocarcinoma who refused to use standard chemoradiotherapy and required apatinib monotherapy from the first part of the study.Among the 6 patients,3 patients are assessed as PR/SD and another 3 as PD.Cancerous tissue and peripheral blood leukocytes were collected for whole-exome sequencing and bioinformatics analysis.ResultsInrtinsic resistance to apatinib may be associated with mutations in NUDT15-rs116855232 and CYP2A7-rs73032311.In addition,a total of 9 candidate driver mutations were screened: TP53,PAX2,ZEB1,CTGF,CBL,CHEK2,STK11,SDHB and AFF1.ConclusionThe mutations in NUDT15-rs116855232 and CYP2A7-rs73032311 mutation are predictive factors of inrtinsic resistance to apatinib.