Analysis Of Clinical And Pathology Factor Of Endocrine Resistance In Breast Cancer And The Difference Of LMTK3 Expression Level

Background:Breast cancer is the most malignant tumor in china even in the world.The mortality of breast cancer keep the first place all the time.Data from national cancer cencer shows that in china,The highest incidence of malignant tumors is breast cancer.And it have the trend growth to augment year by year.The diagnostic and treatment technique has improved recent years,but the mortality still not effectly controls.The most important reason that resulted in the deaths of patients with breast cancer is tumor metastasis and recurrence.Endocrine resistance is one of the main reason for breast cancer metastasis and recurrence.More than 80%of breast cancer patients express estrogen receptor.Endocrine therapy is necessary for those patients.The use of endocrine therapy medicine can effectively extend the disease-free survival and overall survival period of patients with breast cancer.But there are 30-40%of estrogen receptor-positive breast cancer patients suffer endocrine resistance during or after endocrine therapy.The symptoms of endocrine resistance is recurrence、metastasis or the original metastases progress.Some of the mechanism of endocrine resustance is clear.According to a study in 2011,The most effective to adjust ER activity is LMTK3,It works by reducing the activity of protein kinase c(PKC),phosphorylated AKT,affect PKC/AKT pathway,The pathways regulating tumor cell proliferation and survival,it’s active anomalies can not only cause the malignant cell transformation,but also affect tumor cell migration,adhesion,tumor angiogenesis and the degradation of extracellular matrix,etc.Studies have shown that LMTK3 expression level in tissues of patients with breast cancer have Significant correlation with degree of tumor malignant、DFS、OS and endocrine treatment effect.According to the produces time of breast cancer endocrine resistance,resistance can be divided into primary resistance and secondary resistance.Patients with primary resistance were those relapsing during or within 6 months of stopping endocrine treatment or progressing within 6 months of starting endocrine treatment in the metastatic setting.Patients with secondary resistance were those relapsing 6 month after stopping endocrine treatment or responding for6 months to endocrine treatment in the metastatic setting.At present the association of primary and secondary resistance is unclear,our study explores the predictors of endocrine resistance of breast cancer through collecting clinical features,pathological type,transfer information and other related materials of women who suffers breast cancer.LMTK3 is closely related to breast cancer endocrine resistance,but the difference of LMTK3 expression in primary and secondary resistance is unclear.We explored the difference of LMTK3 expression level in each group through immunohistochemical detection,to guide the prognosis of patients with hormone receptor-positive breast cancer.Objects:1.Explore the predictors related to primary and secondary resistance in breast cancer;2.Explore LMTK3 expression differences in different resistant group,guide the prognosis of patients with breast cancer.3.Analysis the clinical and pathological index differences between LMTK3 positive group and negative group to explore the influence factors of LMTK3 expression.4.Compare the DFS and OS between LMTK3 positive group and negative group,guide the prognosis of patients with breast cancer.Methods:Collect the female patients of breast cancer with recurrence or metastasis in The Second Hospital of Shandong University during 2004.01-2016.06 as resistance group,and female patients of breast cancer since 2006.01-2009.08 no recurrence and metastasis until now as control group.Collect patients’ onset age,side,body weight,menarche age,menopausal status,lactation time,family history,history of chronic histologic classification,tumor TNM stage,tumor diameter,tumor histologic classification for data analysis.Extract 47 patients’ tumor tissues for LMTK3、ER、PR、HER-2、Ki67 immunohistochemical detection after formalin fixed,paraffin embedding.Use Kaplan-Meier method and Log-rank test to analyze the prognostic value of LMTK3 positive and negative group.We use SPSS 17.0 for statistical analysis.Results:1.Characteristics of patients:We select 72 female breast cancer patients that are treated in the Second Hospital of Shandong University from 2004.01-2016.06,21(29.17%)cases of them with primary endocrine resistance among them,15(20.83%)cases of them with secondary endocrine resistance,36(50.00%)cases of them without any resistance.2.Analysis of factors affecting endocrine resistance:2.1.1 analysis of influence factors between resistant group and control groupCompared with no resistance group,onset age is smaller in resistant group(t=-2.791,P=0.007),and the rate of oncet age ≤50 is higher.(χ2 =6.854,P=0.009).Menarche age 14 years of age or less ratio is higher(χ2 =5.672,P=0.017),HER-2 positive rate is higher(χ2=4.417,P=0.045),Ki67 expression>14%rate is higher(χ2=9.873,P=0.002).Luminal B molecular subtype is more than Luminal A(χ2=9.873,P=0.002),LMTK3 positive rate is higher(χ2 =7.685,p=0.006).There’s no difference between the onset side,birth and lactation time,menopausal status,family history,chronic disease,tumor length to diameter,weight value,histological grading,TNM staging.ER、PR expression(p>0.05).2.1.2 analysis of influence factors between primary and secondary resistance groupCompared with secondary resistance group,lactation time is longer in primary resistance group(t=1.568,p=0.049),Ki67 expression>14%rate is higher(χ2=5.487,P-0.032).Luminal B molecular subtype is more than Luminal A(χ2 =5.487,P=0.032),LMTK3 positive rate is higher(χ2 =5.445,p=0.038).There’s no difference between the onset side,birth time,menarche age,menopausal status,family history,chronic disease,tumor length to diameter,weight value,histological grading,TNM staging,ER、PR、HER-2 expression(p>0.05).2.2 multivariate analysisKi67>14%(OR=5.461,95%CI:1.346-22.152)and LMTK3 positive(OR=5.602,95%CI:1.017-16.959)can be dependent predictive indicators of endocrine resistance through binary Logistic regression analysis.3.Analysis of influence factors between LMTK3 positive group and negative groupCompared with LMTK3 negative group,Menarche age 14 years of age or less ratio of positive group is higher(χ2 =6.421,P=0.011),Ki67 expression>14%rate is higher(χ2 =4.182,P=0.041).Luminal B molecular subtype is more than Luminal A(χ2 =4.664,P=0.031).There’s no difference between the onset age,onset side,birth and lactation time,menopausal status,family history,chronic disease,tumor length to diameter,weight value,histological grading,TNM staging,ER、PR、HER-2 expression(p>0.05).4.Analysis of survival of LMTK3 positive and negative patientsCompared with LMTK3 negative group,the DFS of positive group is shorter(χ2=10.388,P=0.0001);There is no difference on OS between two groups(χ2=0.801,P=0.371).Conclusion:1.In patients with hormone receptor-positive breast cancer who accepted endocrine therapy,onset age<50,Ki67>14%,menarche age<14,HER-2 positive,LMTK3 positive,Luminal B molecular subtype have higher endocrine resistance rate;2.In patients who suffered endocrine resistance,longer lactation time,Ki67>14%.LMTK3 positive expression and Luminal B molecular subtype have higher primary resistance rate,it means the recurrence or metastasis may happen earlier.3.Ki67>14%and LMTK3 positive expressioncan be dependent predictive indicators of endocrine resistance.4.Compared with LMTK3 express negative group.the menarche age is small in positive group,and the menarche age<14 ratio is higher,Ki67>14%ratio is higher,Luminal B type patients is more than Luminal A.5.Compared with LMTK3 negative group,the DFS of positive group is shorter;There is no difference on OS between two groups.