The Correlation Between Single Nucleotide Polymorphism Of PI3K/Akt/mTOR Pathway Gene And The Toxicity Of Everolimus In Advanced Breast Cancer

BACKGROUNDSPI3K/Akt/mTOR pathway is considered to be an important mechanism of drug resistance for endocrine therapy in advanced breast cancer,and its cross-talk with ER signaling pathway can allow the immune escape of tumor.Everolimus is a new type of mTOR inhibitor,and BOLERO-2 study showed that everolimus combined with exemestane could significantly improve the PFS of advanced breast cancer,so in 2012,everolimus plus exemestane was approved by FDA for the treatment of postmenopausal women with estrogen receptor positive(ER positive),human epidermal growth factor receptor-type2 negative(HER2 negative)advanced breast cancer progressing or recurring during or following treatment with non-steroidal aromatase inhibitors.However,the therapeutic window of everolimus is very narrow,and there is high inter-patient variability in pharmacokinetics,and drug-related adverse events have become an important reason for everolimus dose reduction or discontinuation.The phase ? clinical trials in breast cancer,advanced renal cell cancer and pNET showed that about 10-35%patients discontinued the everolimus treatment due to severe adverse effects,so drug discontinuation became the important reason that restricted the patients from benefiting from everolimus in clinical treatment Several studies in organ transplantation or tumors showed that single nucleotide polymorphisms(SNPs)of some genes related to everolimus metabolic pathway or transportation and PI3K/Akt/mTOR pathway might be associated with the pharmacokinetics of everolimus.But there were few clinical studies focusing on the adverse events in patients and gene polymorphisms,and the data in breast cancer were limited.AIMSTo study the correlation between gene single nucleotide polymorphisms of metabolic genes and PI3K/Akt/mTOR pathway and everolimus treatment toxicity in hormone receptor positive(HR positive),HER2-,premenopausal advanced breast cancer patients.METHODThis study enrolled part of participants in a perspective phase ? clinical trial(Miracle trial)in our hospital.All the patients were enrolled from July 1st,2014 to March 15th,2019,and were the HR+,HER2-,advanced premenopausal breast cancer patients after tamoxifen/toremifene treatment,and they were followed up until May 10th,2019 or death,and their drug-related adverse events during the treatment were recorded and evaluated.13 common SNP mutation sites of everolimus metabolism and transportation-related genes and PI3K/Akt/mTOR pathway were detected with the peripheral blood samples of patients,to analyze whether there were relations between the adverse events and SNP.RESULTS95 premenopausal breast cancer patients were included,and the most common adverse events were stomatitis(74/95,77.9%),hyperlipidemia(77/95,81.1%),liver function injury(68/95,71.6%),rash(40/95,42.1%),hyperglycemia(39/95,41.4%),noninfectious pneximonitis(38/95,40.0%)and weight loss(36/95,37.9%).Correlation analysis showed that FGFR-4 rs351855 was significantly associated with stomatitis and hyperlipidemia,and CYP3A5*3/*3 had significant risks of hyperlipidemia,severe stomatitis,and severe hyperlipidemia compared with*1 carriers,and ABCB1 rs1045642 was significantly associated with leucopenia,and NRlI2 rs2276707 and rs6785049 were significantly associated with hyperlipidemia and liver function injury.Linkage analysis didn't show significant association between adverse events and ABCB1 haplotype.Patients with noninfectious pneumonitis,liver flinction injury,and hyperglycemia had a significantly longer PFS than those without adverse events.