Adjuvant endocrine therapy (ET), which consists of selective estrogen receptive modulators (SERMs) such as tamoxifen or toremifene and aromatase inhibitors (AIs; e.g., anastrozole, letrozole, and exemestane), is the standard of care in the management of breast cancer (BC), especially for patients with estrogen-positive/progesterone-positive (ER+/PR+) BC. Prolonged estrogen deprivation has been associated with the development of dyslipidemia. However, questions remain regarding the differences in the dyslipidemic potential of the various endocrine therapies.
Investigators conducted a large-scale, real-world, retrospective study to investigate the effects of various endocrine therapies on blood lipid changes over a 6-year period. Female patients receiving ET between January 1, 2013, and December 31, 2021, at Peking Union Medical College Hospital were retrospectively enrolled in this study. Patients were included if they met the following criteria: female aged >18 years; had stage I-III BC; BC was hormone receptor–positive (HR+); and received ET with either anastrozole, letrozole, exemestane or toremifene for at least 6 months; tamoxifen was not studied. Male patients, those who had received multiple forms of ET or had switched agents, those who had dyslipidemia or were on a lipid-lowering agent prior to initiation of ET, and those who had received ET during neoadjuvant therapy or before a BC diagnosis were excluded from analysis. Lipid levels were measured at baseline, and at 6, 12, 18, 24, 36, 48, 60, and 72 months after initiation of ET. Dyslipidemia was defined as having any of the following: total cholesterol (TC) >5.2 mmol/L (201.1 mg/dL); triglycerides (TGs) >1.7 mmol/L (150.58 mg/dL); LDL-cholesterol (LDL-C) >3.4 mmol/L (131.48 mg/dL); and HDL-cholesterol (HDL-C) < 1.0 mmol/L (38.67 mg/dL).
A total of 2,756 patients were included in the study, including 1,201 patients on an AI (mean age: 55.61 years; 723 received anastrozole, 298 received letrozole, and 180 received exemestane) and 1,555 patients on toremifene (mean age: 42.2 years; P <.001). There was a statistically significant difference in mean age between the groups, with more younger patients receiving the SERM. Baseline TG levels were 0.95 mmol/L (84.15 mg/dL) in the AI group and 0.81 mmol/L (71.74 mg/dL) in the toremifene group (P <.001); this difference in TG levels was statistically significant. The TC and TG levels were significantly higher at 6 months in both treatment groups compared with baseline (P <.05), and a trend persisted through the follow-up period. Whereas LDL-C increased significantly in the AI group (P <.05), however, there was no significant increase in the toremifene despite a slight upward trend.
There was an inverse relationship between AI use and HDL-C, but there was an opposite trend in the toremifene group, with HDL-C levels being significantly higher in those treated with the SERM throughout the study period (P <.05). All lipid components increased over time in both groups, but the increase in lipid levels was less significant in the toremifene compared with the AI group. Age was correlated with TC and TG levels, and BMI was associated with TG and LDL-C levels. LDL-C levels were significantly higher in the AI group compared with the toremifene group, especially during 18 to 36 months of therapy.
Whereas AIs significantly affected lipid levels in both premenopausal and postmenopausal women, there was an increasing trend in TC, TG, and LDL-C level elevations in the premenopausal AI-treated group compared with the postmenopausal AI group, and this was more evident over time. TC and LDL-C levels in the premenopausal AI group were lower within 1.5 years after starting the ET, however, compared with the postmenopausal AI group (P <.05).
When examining individual agents, TC, TG, and LDL-C levels were significantly higher than baseline at 3 years in those taking anastrozole and letrozole (P <.05), but there were no significant changes in TC and TG levels in the exemestane group. Whereas the initial decrease in HDL-C levels seen in the anastrozole and letrozole during the first 6 months flattened, however, there was a significant decrease compared with baseline in HDL-C levels in the exemestane group over the course of 4 years (P <.05).
The authors concluded that the main differences between the AIs on lipid levels was that TG levels in the exemestane group were lower within 3 years than in either the anastrozole or letrozole groups (P <.05), and TC was also lower in the former group compared with the latter groups between 12 to 48 months of initiating treatment (P <.05). However, HDL-C levels were lower in the exemestane compared with the anastrozole group from the first year onward.
When examining for the development of dyslipidemia, there was a higher proportion of lipid disorders in the AI group compared with the toremifene group over the course of 5 years (P <.01). Dyslipidemia was more common in postmenopausal than premenopausal women 1 year after initiation of ET therapy. Among the patients on AIs, those who received exemestane had a lower proportion of dyslipidemia compared with either anastrozole or letrozole (P <.05).
A look at the prescribing information (PI) for the four ET agents used in this study revealed that that the data are mixed for anastrozole and its effects on TC, LDL-C, and HDL-C, with one study showing an increase in TC and other studies showing no difference in lipid parameters. The PI recommends that women with early BC on anastrozole should be managed using standard lipid-lowering guidelines. The PI for letrozole contains a warning/precaution recommending to monitor TC, as this AI has been associated with the development of hypercholesterolemia, including Grade 3 or 4 disease. Additionally, its use has been associated with a >1.5 increase of the upper limit of normal for TC. Lipid-lowering medication was instituted in 29% of letrozole-treated patients compared with 20% of those receiving tamoxifen.
The prescribing information for exemestane indicates that HDL-C decreases 6% to 9% but that there is no effect on TC, LDL-C, and TG. Toremifene prescribing information does not address any drug-related lipid changes.
This paper provides pharmacists with valuable insight into real-world data on the relative lipid-altering effects of ET therapy in women with early-stage BC. Pharmacists should take proactive measures to monitor these lipid changes and recommend lipid-lowering therapy as necessary.
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