Correlation Of Spatial Distribution Of Brain Metastases From Lung Cancer With Gene Mutation Types

Background and Objective:Lung cancer has the second highest incidence(11.4%)and the highest mortality rate among all malignant tumors.Brain metastasis is one of the distant metastatic sites most closely related to the prognosis of lung cancer patients.Currently,its treatment methods mainly include surgery,chemotherapy,radiotherapy,targeted therapy and immunotherapy,etc.However,these treatments can only temporarily delay the development of the disease,but not prolong the survival of patients,so it is essential for lung cancer patients to prevent the occurrence of brain metastasis.Studies have reported that prophylactic whole-brain irradiation(PCI)can prolong the time to brain metastasis in non-small cell lung cancer,but indiscriminate whole-brain irradiation can damage many unnecessary brain regions,which can produce various complications,while precise prophylactic brain irradiation requires predicting the metastasis-prone brain regions before the patient develops brain metastasis.Genetic mutations play an important role in the development of lung cancer brain metastases,and it has been found that mutations in different loci of EGFR lead to significantly higher metastasis rates in specific brain domains,while studies on the correlation between other gene mutation types,such as ALK and KRAS,and brain metastasis regions have not been reported.In this study,we tried to find the correlation between different mutation types and brain metastasis regions,and to predict the brain metastasis-prone regions for lung cancer patients before the occurrence of brain metastasis,so as to provide a reference for early preventive intervention.Meanwhile,this study also counted the clinical characteristics,spatial distribution of brain metastasis sites and distribution of gene mutation types in driver gene-positive lung cancer patients to provide guidance for clinical management of driver gene-positive lung cancer patients with brain metastasis.Research methods:This retrospective study included 321 patients with brain metastases from lung cancer who were positive for driver genes.The patients’ medical records were reviewed to record their age,pathological type,gender,gene mutation type,smoking status,alcohol consumption status,KPS score,brain metastasis site,and other metastasis sites.The brain metastasis sites were also divided into right and left frontal lobe,right and left parietal lobe,right and left temporal lobe,right and left occipital lobe,right and left insula,right and left basal nucleus,right and left thalamus,cerebellum,brainstem,other(pituitary gland,cingulate gyrus)and unclassified areas.All enrolled mutation types included EGFR,TP53,ALK,KRAS,MET,ERBB2/HER-2,ROS1,BRAF,PTEN,PIK3CA,CDKN2A,MLH1,NF1,RB1.The clinical characteristics,mutation site distribution,and brain metastasis site distribution of lung cancer brain metastasis patients were counted,and the The correlation between different gene mutation types and brain metastasis sites in patients with metastasis.In this study,the data of count data were expressed as percentages,and the data between groups(the relationship between brain metastasis sites and genes in lung cancer patients)were compared using the chi-square test or Fisher’s exact probability method.P<0.05 was considered a statistically significant difference.Study results:1.Clinical characteristics of patients with brain metastases from lung cancer:the most common type of genetic variant of brain metastases from lung cancer included in this study was EGFR(256 cases;79.75%),followed by TP53(44 cases;13.71%).The pathological type of patients was predominantly adenocarcinoma,with 307 cases(95.64%).Only 83(25.86%)of the included patients were smokers,while 95(29.60%)were alcohol drinkers.A total of 122(38.00%)of the included patients had CNS symptoms and 196(61.06%)had KPS scores greater than or equal to 70.The highest percentage of metastatic areas outside of brain metastases was the lung itself(60.44%),followed by bone(56.70%).The median time to the development of brain metastases was 17.0 months in a total of 93 patients who used targeted therapy before the first appearance of brain metastases and 8.0 months in a total of 228 patients who did not use targeted therapy.2.Distribution of lung cancer brain metastasis sites:among all lung cancer brain metastasis patients with gene mutation.106 cases(33.02%)in the right frontal lobe,91 cases(28.35%)in the left frontal lobe,98 cases(30.53%)in the cerebellum,and 82 cases(25.55%)in the right parietal lobe accounted for a relatively high proportion of metastasis sites.The highest incidence of metastasis was found in the right frontal lobe,left frontal lobe,cerebellum,and right parietal lobe compared with other metastasis sites(P<0.05).3.Distribution of gene mutation loci:256(79.75%)EGFR mutations were included in the study,followed by 44(13.71%)TP53 mutations,25(7.79%)ALK mutations,20(6.23%)KRAS mutations,8(2.49%)MET and HER-2 mutations each,and 4(1.25%)ROS1 mutations,BRAF and PTEN mutations were both in 2 cases(0.62%),and PIK3CA,CDKN2A,MLH1,NF1,and RB1 mutations were in 1 case each(0.31%).The most frequent co-mutations were EGFR and EGFR co-mutations and EGFR and TP53 co-mutations,with 38 and 29 cases,respectively.4.Correlation between different mutation types and brain metastasis sites:EGFR mutated lung cancer had the highest incidence of metastasis in the right frontal lobe(32.42%;83/256),cerebellum(30.10%;77/256),left frontal lobe(28.52%;73/256),right parietal lobe(27.34%;70/256),left parietal lobe(19.53%;50/256)The highest incidence of metastasis was found in the left frontal lobe(40.91%;18/44)and right parietal lobe(38.64%;17/44)in TP53 mutant lung cancer,which was statistically different compared to other regions.(The incidence of metastasis was highest in the cerebellum(32.00%;8/25),left parietal lobe(32.00%;8/25),and left parietal lobe(32.00%;8/25),with statistical differences compared with other regions.metastasis was highest in the cerebellum,left parietal lobe,right parietal lobe,and right temporal lobe(30.00%;6/20),with statistical differences compared with other regions.5.The incidence of left frontal metastases was higher in patients with TP53/EGFR co-mutations than in patients with EGFR mutations and TP53 wild-type(P=0.016).left frontal,left basal ganglia,and right parietal metastases were higher in TP53 mutations than in TP53 wild-type patients(P<0.05).left frontal,left basal ganglia,and right parietal metastases were higher in TP53 mutations than in TP53 wild-type patients(P<0.05).The incidence of left frontal,left basal ganglia,and right parietal metastases was higher in TP53 mutant than in TP53 wild-type patients(P<0.05).Conclusion:This analysis is the first to reveal the relationship between gene mutation status and the spatial distribution of brain metastases of lung cancer.