Exploratory Study Of Different Molecular Markers On The Predictive And Prognostic Value Of Neoadjuvant Chemotherapy In Breast Cancer

Objective:Neoadjuvant chemotherapy(NAC)has become the first-line treatment for locally advanced breast cancer.Peripheral blood inflammatory markers have been.shown to predict the survival prognosis of breast cancer patients undergoing NAC in multiple studies,but the potential value of systemic inflammation response index(SIRI)and systemic immune-inflammation index(SII)as peripheral blood markers reflecting the overall inflammatory and immune status in predicting the efficacy and prognosis of NAC in breast cancer has not been fully investigated.This study aims to explore,for the first time,the potential value of SIRI and SII in predicting the efficacy and prognosis of NAC in breast cancer.Methods:This study retrospectively collected the clinicopathological data of breast cancer patients who underwent neoadjuvant chemotherapy and surgery at the Cancer Hospital of Chinese Academy of Medical Sciences from January 2009 to December 2017.According to the inclusion and exclusion criteria,a total of 257 patients were enrolled in this study.Receiver operating characteristic curve(ROC)was used to determine the optimal cutoff values of SIRI and SII,and the patients were divided into low expression and high expression groups based on these values.The correlations of SIRI and SII with clinicopathological parameters before neoadjuvant chemotherapy and their associations with neoadjuvant chemotherapy efficacy and survival prognosis were analyzed.Results:1)SII was significantly associated with PR expression(p=0.020)and neoadjuvant chemotherapy efficacy(p=0.010).Histological grade(HR=0.516,95%CI:0.298-0.892,p=0.018),Ki-67(HR=2.742,95%CI:1.279-5.878,p=0.010)and SII(HR=0.488,95%CI:0.259-0.922,p=0.027)were independent predictors of pCR in neoadjuvant chemotherapy.2)The low SIRI expression group had a longer mean disease-free survival(DFS)than the high expression group with statistical significance(76.20 vs 54.06 months,p<0.001),and the low SIRI expression group had a longer mean overall survival(OS)than the high expression group with statistical significance(85.82 vs 68.15 months,p=0.001).The low SII expression group had a longer mean DFS than the high expression group with statistical significance(73.51 vs 61.16 months,p=0.005),and the low SII expression group had a longer mean OS than the high expression group without statistical significance(83.34 vs 74.21 months,p=0.619).3)SIRI(HR=2.058,95%CI:1.213-3.493,p=0.007)and clinical T stage(HR=1.400,95%CI:1.048-1.871,p=0.023)were independent prognostic factors for OS in breast cancer patients receiving neoadjuvant chemotherapy,while SIRI(HR=2.746,95%CI:1.5214.955,p<0.0001)and clinical molecular subtype(HR=1.486,95%CI:1.110-1.989,p=0.007)were independent prognostic factors for DFS in breast cancer patients receiving neoadjuvant chemotherapy.Conclusion:This study explored and demonstrated that histological grade,Ki-67 and SII index before neoadjuvant chemotherapy can serve as independent predictive factors for pCR.Patients with low expression of SIRI and SII had prolonged DFS and OS,and SIRI index before neoadjuvant chemotherapy was an independent predictive factor for patient survival prognosis.In clinical practice,SIRI and SII indicators can be combined to develop individualized treatment plans for breast cancer patients receiving neoadjuvant chemotherapy.Objective:The aim of this study is to identify potential genes that can predict the response and prognosis of neoadjuvant chemotherapy in breast cancer by using bioinformatics approaches,and to validate their biological functions and clinical significance in breast cancer by combining cell experiments and clinical samples,providing new biomarkers and molecular targets for guiding the decision-making and optimizing the treatment strategy of neoadjuvant chemotherapy in breast cancer patients.Methods:1)To identify differentially expressed genes associated with neoadjuvant chemotherapy and prognosis,we downloaded and integrated the transcriptomic data,clinical information,and survival data of four datasets(GSE25055,GSE25065,GSE25066,GSE32603)from the GEO database.After selecting STC2 as the study gene,we analyzed its gene expression and prognostic relevance in neoadjuvant breast cancer patients using the GEO datasets,The Cancer Genome Atlas(TCGA)database,and Kaplan-Meier Plotter survival analysis database.We further explored the correlation between STC2 and the sensitivity to common chemotherapy drugs and the clinicopathological characteristics in the TCGA database.2)We measured the expression of STC2 protein in breast cancer cell lines and established stable overexpression cell lines.We then performed basic biological function assays,including cell scratch assay,Transwell assay,MTS assay for cell proliferation,cell plate clone assay,and drug sensitivity assay,to observe the role of STC2 expression in breast cancer cell phenotypes.3)We collected preoperative puncture paraffin sections and clinicopathological data of breast cancer patients who underwent neoadjuvant chemotherapy at the Cancer Hospital of Chinese Academy of Medical Sciences.We performed immunohistochemistry for STC2 on the puncture specimens.We analyzed the correlation between high or low expression of STC2 and the clinicopathological characteristics of patients.We performed univariate and multivariate analyses to determine whether STC2 expression can predict the efficacy and survival prognosis of neoadjuvant chemotherapy.Results:1)We performed differential gene analysis of NAC response-related genes in GSE25055,GSE25065,and GSE25066 datasets and obtained 46 genes by intersecting these genes.We extracted 29 prognosis-related genes from the GSE32603 dataset and intersected them with the 46 NAC response differential genes,resulting in the gene STC2.By analyzing the correlation between STC2 expression and prognosis in GEO datasets,TCGA database and KM Plotter survival analysis database,we found that high expression of STC2 significantly improved the survival outcome of patients.We performed STC2 single-gene analysis in TCGA database and found that high expression of STC2 reduced the sensitivity to paclitaxel,doxorubicin and tamoxifen drugs,and STC2 was significantly associated with ER,PR,HER2 and molecular subtype factors(p<0.001).2)STC2 protein was highly expressed in T-47D and MCF-7 cells,but not expressed in MDA-MB-231 cells.We constructed a stable overexpression cell line of STC2 in MDAMB-231 cells(231-STC2-OE).Cell scratch assay and Transwell assay results indicated that STC2 overexpression could reduce the migration ability of breast cancer cells;MTS assay for cell proliferation and plate clone assay suggested that STC2 overexpression reduced the proliferation ability of breast cancer cells;STC2 overexpression could reduce the sensitivity of breast cancer cells to paclitaxel.3)We performed immunohistochemistry for STC2 on preoperative puncture specimens from breast cancer patients who underwent neoadjuvant chemotherapy at the Cancer Hospital of Chinese Academy of Medical Sciences.The results showed that STC2 expression was significantly correlated with ER(p=0.002),PR(p=0.004),HER2(p=0.037),Ki-67(p=0.001),molecular subtype(p<0.0001);STC2 expression was not an independent predictive factor for neoadjuvant chemotherapy efficacy;high expression of STC2 had better OS(p=0.036)and DFS(p=0.032)than low expression of STC2;T stage(HR=1.704,95%CI:1.074-2.703,p=0.024)and STC2 expression(HR=0.270,95%CI:0.102-0.714,p=0.008)were independent prognostic factors for DFS in neoadjuvant breast cancer patients.Conclusions:STC2 gene can be used to predict the efficacy of neoadjuvant chemotherapy and the prognosis of breast cancer in public databases.Higher expression of STC2 is associated with better prognosis,but reduced sensitivity to chemotherapy drugs.In breast cancer cells,overexpression of STC2 protein decreases the migration and proliferation abilities of breast cancer cells,as well as their sensitivity to paclitaxel.In clinical specimens,higher expression of STC2 protein in preoperative biopsy samples of breast cancer is associated with better survival prognosis,and STC2 can serve as an independent predictor of DFS in neoadjuvant chemotherapy patients with breast cancer.Objective:Patients with residual cancer after neoadjuvant chemotherapy may face higher risks of distant metastasis and poorer prognosis compared to those who achieve pathological complete response.Effective prognostic indicators and treatment methods for these patients have not been fully investigated.This study aims to explore the potential prognostic value of Plakoglobin in patients with residual cancer after neoadjuvant chemotherapy for breast cancer,in order to provide personalized treatment guidance for this patient population.Methods:We collected the clinicopathological data of breast cancer patients who underwent NAC and surgery at the Cancer Hospital of Chinese Academy of Medical Sciences from January 2009 to December 2017.According to the inclusion and exclusion criteria,174 patients were enrolled in this study.We analyzed the protein expression of plakoglobin in the postoperative residual tumor specimens by immunohistochemistry.We evaluated the correlation between plakoglobin expression and clinicopathological characteristics,and used the Kaplan-Meier method to assess the relationship between plakoglobin expression and patient prognosis.In addition,we used univariate and multivariate Cox proportional hazards regression models to identify the independent prognostic factors for survival of these patients.Results:The patients were divided into two groups according to their plakoglobin protein expression level,the low plakoglobin expression group had longer mean DFS and OS times than the high expression group(59.46 vs.36.58 months,p=0.050;71.68 vs.47.26 months,p=0.001).The results of univariate and multivariate Cox regression analysis showed that Ki-67 was an independent predictor of DFS for the patients(HR=2.228,95%CI:1.3163.773,p=0.003),while plakoglobin was an independent predictor of OS for these patients(HR=2.438,95%CI:1.256-4.735,p=0.008).Conclusions:Plakoglobin expression level was negatively correlated with OS and DFS of patients who still had residual cancer lesions after NAC,and plakoglobin was an independent prognostic factor for OS of these patients.This suggests that plakoglobin is a potentially valuable clinical marker that can guide the selection of subsequent treatment regimens and maximize the therapeutic effect for these patients.