| Purpose:Chemotherapy and radiotherapy are the main treatments for non-small cell lung cancer,and their therapeutic effects are largely limited by individual radiosensitivity and recurrence and metastasis.Clinical indicators are urgently needed to judge the patient's tolerance and sensitivity to radiotherapy and chemotherapy,and to observe whether the prognosis is good,and the clinician can adjust the treatment plan and dosage in time to make the patient benefit the most.Based on NGS gene sequencing technology,this study explores novel biomarkers at the genetic level to guide radiotherapy,chemotherapy dose,possible toxicity and prognosis in patients with non-small cell lung cancer.Patients and Methods:This study selected 167 patients with newly diagnosed NSCLC who underwent radiotherapy and chemotherapy at the Shandong Cancer Hospital from September 1,2014 to December 31,2017.A total of 39 patients who met the enrollment criteria and completed the NGS 474 gene panel were included.All patients received standard chemotherapy,radiation therapy,and regular follow-up.The efficacy of disease treatment was evaluated according to RECIST version 1.1 and classified into CR,PR,PD,and SD.The toxicity evaluation of radiotherapy was evaluated using CTC-AE version 5.0,which mainly evaluated radiation pneumonitis and radiation esophagitis,and the adverse events were classified into grade 1 to grade 5.The NGS 474 panel gene test was performed on the FFPE before the treatment,and the correlation between chemotherapy,radiotherapy efficacy,radiotoxicity and gene mutation was analyzed.Results:(1)Clinical features: Among the 39 patients with stage III NSCLC who could not be resected,lung squamous cell carcinoma(69.2%),male(92.3%)and smokers(82.1%)accounted for a higher proportion in the common lung cancer population.The overall incidence of grade 2 or higher toxic events caused by radiation therapy was 35.9%(39/14),and 17 patients(43.6%)did not develop radiotoxicity.The data follow-up deadline was July 1,2018,with a median follow-up of 16.2 months.By the deadline,a total of 15 people died and the median overall survival was 24.7 months.(2)Radiotherapy-related SNPs and somatic mutations: SNP(rs25487)in XRCC1 is closely related to the incidence of severe radiotoxicity(P = 0.01),and there are many homozygous deletions in NQO1(rs1800566),LIG4(rs1805388)and GSTT1.The state showed an increasing trend of severe radiotoxicity.Multivariate analysis of logistic regression showed XRCC1 in SNPs(P = 0.0013,OR = 16.37 [95% CI,2.97-90.18],NQO1(P = 0.013,OR = 7.70 [95% CI,1.53-38.82] and GSTT1(P = 0.036,OR = 7.59 [95% CI,1.14-50.35])is an independent predictor of radiotherapy toxicity.Somatic mutations such as PIK3 CA and BRCA1 are strongly enriched in patients with severe radiotoxicity.(3)Predicting recurrence after chemoradiotherapy: TTP and OS in 4 patients with KEAP1 mutation were significantly shorter than those in KEAP1 wild type(2.97 months vs 10.83 months,P = 0.05;14.54 months vs 31.83 months,P < 0.01).Seven patients with ROS1 missense mutations showed shorter TTP and OS than ROS1 wild-type patients(4.90 months vs 11.87 months,P < 0.01;19.07 months vs 31.83 months,P = 0.02).Univariate analysis showed that patients with CDKN2 A mutations had significantly longer TTP and OS,whereas patients with ABCB1 missense mutations had shorter TTP and OS than patients with wild-type ABCB1.Multivariate analysis showed that the loss mutation of ZNF703 could be used as an independent predictor of TTP reduction after chemotherapy and radiotherapy.There was a significant association between no genetic mutations and OS.Three of the 31 patients(9.7%)were MSI,showing longer TTP and OS,but there was no significant difference in clinical outcome between MSI and MSS patients.Conclusions : We identified a set of novel potential biomarkers associated with radio-sensitivity and recurrence,through correlating patients' genomic profiles with the development of severe toxicity,disease progression and overall survival after chemo-radiotherapy.Specifically,we found that polymorphisms in genes involved in DNA damage repair and oxidative stress,such as XRCC1,NQO1,and GSTT1,are significantly associated with susceptibility to radiation toxicity.Somatic mutations in PIK3 CA and BRCA1,among others,also increase the likelihood of toxicity development.In addition,mutations in KEAP1 and ROS1,among others,could predict disease progression and/or overall survival following chemo-radiotherapy.Our results suggest that pre-treatment testing for a combination of genetic variants,which act together to confer toxicity or resistance after chemo-radiotherapy,might be clinically useful. |
PDF Full Text Request