Research On Prognostic Factors And Treatment Methods Of Special Types Of Breast Cancer

Background and Objective:The prognosis of triple negative breast cancer(TNBC)has become the worst due to the large heterogeneity and lack of any other treatment except chemotherapy.At present,in addition to clinicopathological factors,there is no accurate marker to predict the prognosis of TNBC,neither for potential target guiding the treatment for specific types of TNBC.The purpose of this study is to explore the potential prognostic marker and therapeutic targets based on the genetic mutation data and immune parametersv through the combination with the prognosis.Methods:Seventy-five TNBC patients were enrolled in this study.We analyzed the data through next generation sequencing(NGS)which included the germline mutation,somatic mutation,tumor mutation burden(TMB)and microsatellite instability(MSI).Wilcoxon rank sum test and Pearson chi square test were used to analyze and compare the differences among different groups of factors.Kaplan Meier method was used to draw the survival curve and explore the influence of different factors on survival.Cox multivariate analysis was used to determine the independent prognostic factors affecting disease free survival(DFS)and overall survival(OS).To explore the mechanism of independent prognostic factors affecting prognosis in genetic pathway,DAVID bioinformatics was used to analyze genetic enrichment analysis.Results:In this study,27 germline mutations were found,including 26 homologous recombination repair(HRR)pathway genetic mutations and 1 mismatch repair genetic mutation.We also found 480 somatic mutations among which 110 copy number variations(CNV)were found.There was no statistical difference in DFS(P=0.0624)of TNBC with or without germline HRR mutation.So was for the patients with or without BRCA1/2 mutation in DFS(P=0.15).The median value of TMB in this study was determined to be 4.1 Muts/Mb.According to this,74 TNBC patients were divided into two groups,TMB-low(TMB-1)and TMB-high(TMB-h).Survival analysis showed that DFS in TMB-1 group was worse than that in TMB-h group in 5 years(P=0.0457).In this study,3 cases of MSI-low and 72 cases of microsatellite stability(MSS)were detected,but no MSI-high was found.The somatic mutations with high frequency were found in this study including TP53(91%),MYC(14%),PIK3CA(11%),MCL1(11%),EPHA3(9%),GATA3(9%),FAT3(8%),RB1(8%),CCND2(6%),CCNE1(5%).In this study,we analyzed the impact on prognosis of TNBC with somatic mutations in high frequency.We found that gains of copy number in CCNE1 induced worse DFS in 5 years(P<0.0001).Cox multivariate regression analysis showed that tumor size(T),lymphovascular invasion(LVI)and CCNE1 copy number gain were the independent risk factors for DFS(T,HR=2.01(95%CI 1.05-3.87),P=0.036;LVI,HR=2.81(95%CI 1.1-7.17),P=0.031;CCNE1,HR=13.48(95%CI 2.62-69.23),P=0.002).It was found that 4 cases with CCNE1 copy number gain were TMB-1 group.We also found that CCNE1 copy number gain was mutually exclusive with BRCA1/2 mutation.Further analysis of genetic enrichment in somatic mutations confirmed that CCNE1 copy number gain made the impact on prognosis through regulation of transcription involved in G1/S phase of mitotic cell cycle.Conclusions:Neither HRR mutation nor BRCA1/2 mutation had impact on the prognosis of TNBC.The TNBC patients with TMB? 4.1Muts/Mb had survival advantages compared to those with TMB<4.1Muts/Mb,which may be due to th reason that CCNE1 as a specific somatic mutation site for TMB-1 group.MSI-H may be not suitable for targeting immunotherapy for TNBC such as PD-1 or PD-L1.Tumor size,lymphovascular invasion(LVI)and CCNE1 copy number gain were independent risk factors for TNBC.The CCNE1 copy gain was mutually exclusive with BRCA1/2 mutation.CCNE1 may be the potential therapeutic target for CDK4/6 inhibitor(pabocillin)or bortezomib(proteasome inhibitor).Purpose:BRCA 1/2 germline mutations are associated with a high risk of breast cancer,which may preclude breast cancer patients with BRCA1/2 germline mutations from breast-conserving surgery(BCS).It is debatable whether BCS can be a rational option for Chinese breast cancer patients with BRCA1/2 germline mutations.This study was intended to explore whether BCS can be a safe and rational option for Chinese breast cancer patients with BRA 1/2 germline mutation.Methods:We retrospectively evaluated the effects of different types of surgery on breast cancer prognosis among Chinese germline BRCA1/2 mutation carriers.Among 1120 consecutive Chinese women with primary invasive breast cancer,531 underwent next generation testing to confirm BRCA1/2 mutation status.Fifty-six patients with BRCA1/2 germline mutation were selected and divided into two groups(BCS and mastectomy).Chi-square test,log-rank test,and Cox regression analysis were used to analyze the association between different surgical management and cases' clinicopathological factors and survival.Results:Fifteen(26.8%)patients received BCS,while 73.2%received mastectomy.Patients who received mastectomy demonstrated significantly more advanced TNM stage(p=0.000),more often had positive nodes(p=0.001),higher number of positive lymph nodes(p=0.008),and more frequently had lymphovascular invasion(p=0.025).The median follow-up time was 20.5 months.There were significant differences in the rate of local recurrence between the BCS(13.3%)and mastectomy(0.0%)groups(p=0.006);however,the patients who received BCS had a similar disease-free survival(DFS)and overall survival(OS)as those who received mastectomy(p=0.126 and 0.865,respectively).After adjustment of all clinicopathological factors,no factor was found to be a significant risk factor for survival.After adjustment for clinical-pathological characteristics,patients who received BCT had a similar breast cancer disease-free survival,overall survival and recurrence free survival compared with patients who received mastectomy[HRDFS=6.4,confidence interval(CI):0.4-115.8,P=0.21;HROS=0.18,confidence interval(CI):0.01-32.1,P=0.52;HRRFS=0.002,CI 0.001-18.9,P=0.95,respectively).Conclusions:Thus,BCS might be a safe and rational option for Chinese breast cancer patients with BRCA1/2 germline mutations.However,TNM stage,number of positive lymph nodes,and lymphovascular invasion might be taken into consideration when choosing surgical management.