Non-alcoholic Fatty Liver Decreases The Risk Of Liver Metastasis In Patients With Breast Cancer

BackgroundBreast cancer(BC)is the most common cancer type and the leading cause of cancer-related deaths in women worldwide.BC preferentially metastasizes to specific organs and tissues,with the liver representing the third most frequent metastatic site following the bone and lung.Moreover,patients with breast cancer liver metastasis(BCLM)have a poor prognosis,with median survival times of approximately 14 months and 5-year survival rates of only 5.5-8.5%.This challenging reality demands a better understanding of this lethal disease and a search for methods of prevention.Non-alcoholic fatty liver disease(NAFLD)is a very common liver disease worldwide,occurring in 10-24%of the general population,and is significantly associated with obesity and age.In addition,NAFLD is commonly encountered in many cancer patients,especially in BC patients,in clinical oncology practice.NAFLD in patients with breast cancer may be associated with the malignancy itself or with tamoxifen administration.NAFLD can progress to non-alcoholic steatohepatitis,which refers to a fatty liver with hepatitis.Given the current NAFLD epidemic,it is important to clarify the association between liver metastasis and hepatic steatosis,which is considered a major area of interest regarding the development of BCLM.However,very few reports have studied the relationship between NAFLD and the hepatic metastasis of BC.Ayse et al reported that hepatic metastases were more frequent in metastatic BC patients with NAFLD,but the samples were too small.However,it has been demonstrated that patients with fatty liver had lower incidences of liver metastases in gastrointestinal tumors.Whether patients with BCLM could be affected by NAFLD remains to be determined,the result of which would be of great significance for future clinical practice.Thus,we designed this two-center cohort study to observe whether liver metastasis in patients with non-metastatic BC could be affected by NAFLD.MethodsPatients who underwent treatment for BC at two affiliated hospitals of Southern Medical University,between January 1,2005 and December 31,2015,were retrospectively reviewed.BC patients were divided into the study and control groups based on the presence of NAFLD,examined by abdominal ultrasound.The follow-up duration was calculated from the day of pathological biopsy to the day of liver metastasis,or to the last liver imaging.Liver metastasis-free survival(LMS)and distant metastasis-free survival(DMS)were calculated using the Kaplan-Meier method,multivariable analysis was performed using a Cox proportional hazards regression model.To overcome biases owing to the different distribution of covariables among patients between the study and control groups,propensity score analysis was performed.The following covariables were matched for age,T classification,N classification,pathological type,her-2 status,ER or PR status,ALT or AST level,hepatitis virus status,diabetes mellitus,BMI,endocrinotherapy and radiotherapy.A p value<0.05 was used to determine statistical significance and all p values were based on 2-sided tests.ResultsIn total,1230 female BC patients(609 in Zhujinag Hospital and 621 in Nanfang Hospital)were included during the study period,and 372(30.2%)patients were diagnosed with NAFLD(at the time of diagnosis BC or before).Thus,three hundred seventy-two patients(30.2%)with NAFLD were included in the study group,and 858 patients(69.8%)were included in the control group.The monitored endpoint was assessed liver MFS.Distant organ metastasis was observed in 275(22.4%)of 1230 patients.There were 56 liver metastasis,65 bone metastasis,51 lung metastasis,28 others metastasis,and 75 multiple organ metastasis.In patients with multiple organ metastases,67 had liver metastasis.Thus,a total of 123 patients(10.0%)had hepatic metastasis.The liver metastasis were observed in 27(7.3%)patients in the study group and 96(11.2%)in the control group,and the difference in the frequency of liver metastasis between groups was significant(P=0.035).The cumulative liver LMS rate was significantly higher in the study group than in the control group(hazard ratio 0.61;95%confidence interval 0.40-0.94;P=0.024).On multivariate analysis,NAFLD was an independent protective factor for local liver metastasis(HR 0.55;0.35-0.86;P=0.008).When NAFLD and endocrinotherapy were analyzed together,the 5-year liver MFS(87.3 vs.71.8%,P=0.002)was significantly greater for patients with NAFLD and endocrinotherapy,compared with those without.After one-to-one matching of the study group(344)with the control group(344),liver LMS remained significantly better in the study group(HR 0.42;0.26-0.69;P = 0.001).The cumulative liver DMS rate was not significantly higher in the study group than in the control group(HR 0.83;0.64-1.08;P=0.157).On multivariate analysis,NAFLD was not a protective factor for local liver metastasis(HR 0.77;0.59-1.02;P=0.065).After one-to-one matching of the study group(344)with the control group(344),liver DMS remained similar between the study and control groups(HR 0.76;0.56-1.04;P=0.086).ConclusionIn this study,we found that NAFLD decreased the liver metastasis rate and was an independent protective factor for liver metastasis in BC patients.Also we demonstrated that NAFLD did not play a role in the distant metastasis and was not an independent risk factor for distant metastasis in BC patients.Considering the existing studies investigating the relationship between NAFLD and BC mainly regarded NAFLD as a risk factor in BC patients,our study provided the opposite results in clinical oncology practice.Additionally,further histological studies would be helpful in confirming the crosstalk between NAFLD and hepatic tissue that is responsible for the reduction of liver metastasis.