Aromatase Inhibitors and Newly Developed Nonalcoholic Fatty Liver Disease in Postmenopausal Patients with Early Breast Cancer: A Propensity Score-Matched Cohort Study

Abstract

Background Unlike tamoxifen, the relationship between aromatase inhibitor use in postmenopausal patients with breast cancer and nonalcoholic fatty liver disease (NAFLD) has not been delineated. Materials and Methods A retrospective analysis of 253 patients with early breast cancer without baseline NAFLD and treated with nonsteroidal aromatase inhibitors was performed. Among them, 220 patients were matched for sex, age, and menstruation status with healthy patients, and the prevalence of NAFLD was compared. NAFLD was determined by hepatic steatosis index in the absence of other known liver diseases. The presence of significant liver fibrosis in patients with NAFLD was determined noninvasively by AST‐platelet ratio index, FIB‐4 score, and NAFLD fibrosis score (NFS). Results Postmenopausal patients with breast cancer undergoing treatment with aromatase inhibitors had higher prevalence of NAFLD independent of body mass index (BMI) and underlying diabetes mellitus (DM). Although the aromatase inhibitor group showed higher fibrotic burden by NFS, independent of BMI and DM, the proportion of advanced fibrosis did not show statistically significant differences between AI‐treated patients and the healthy patients. Those with abnormal baseline fasting glucose levels are suggested to have increased risk of NAFLD development after aromatase inhibitor treatment. In addition, patients with NAFLD developed after aromatase inhibitor use had significantly lower disease‐free survival than those without NAFLD, although there was no significant difference in overall survival. Conclusion Results of this study suggest that inhibition of estrogen synthesis in postmenopausal women undergoing treatment with aromatase inhibitors could increase the risk of NAFLD, which might have some influence on the prognosis of patients with breast cancer. Implications for Practice Unlike tamoxifen, the role of aromatase inhibitor treatment use in postmenopausal patients with breast cancer in development of fatty liver is not well known. In this propensity‐matched cohort study, postmenopausal patients with breast cancer treated with aromatase inhibitors had increased risk of nonalcoholic fatty liver disease compared with healthy women after menopause, independent of obesity and diabetes mellitus. The results show possible adverse influence of the newly developed fatty liver on breast cancer disease‐free survival and suggest a necessity for further validation. Fatty liver may need to be considered as an adverse event for aromatase inhibitor treatment.

The impact of pre-existed and SERM-induced non-alcoholic fatty liver disease on breast cancer survival: a meta-analysis

“…Totally, 781 relevant studies were extracted from the databases, 41 full-text articles were retrieved for detailed evaluation. Ultimately seven studies with eight cohorts, 3684 patients were enrolled in this meta-analysis [10][11][12][13][15][16][17] . Flowchart of literature selection was shown in Fig.…”

“…Up to now, the correlation between NAFLD and breast cancer prognosis remained contentious. Several studies proved patients with NAFLD had worse prognosis 10,11 , while study by Wu et al suggested NAFLD served as a protective factor towards breast cancer progression 12 . Additionally, given that one of the major ET adverse effect was NAFLD, it remained undetermined that whether NAFLD induced by ET had similar prognostic value as common NAFLD.…”

Sex Differences in the Regulation of Vasopressin and Oxytocin Secretion in Bile Duct-Ligated Rats

“…The decrease in substrates of estradiol synthesis pathway, testosterone and DHEA, and the increase in estradiol suggests the possibility of increased aromatase enzyme activity. Clinical studies show that aromatase inhibitors utilized for treatment of breast cancer induce hepatotoxicity [50, 51]. Aromatase overexpression has been reported in hepatitis and hepatocellular carcinoma, but the role of aromatase in liver disorders remains unclear.…”

Non-alcoholic fatty liver disease through the female lifespan: the role of sex hormones

“…Recovery of NAFLD was noted 1.2 years following treatment withdrawal [89]. Aromatase inhibitors suppress total estrogen synthesis by more than 90% [93]. In a retrospective analysis of 220 postmenopausal women with early breast cancer without baseline NAFLD, who were matched for age and menopausal status with healthy women, treatment with aromatase inhibitors (anastrozole, 1 mg/day or letrozole, 2.5 mg/day) was associated with increased NAFLD rates (diagnosed with the application of non-invasive fatty liver indices) independently of BMI and underlying T2DM (HR 2.98, 95% CI 1.96-4.53) [93].…”