The total study population consisted of 569 patients. Median age at BC diagnosis differed significantly between patients who did not receive ET (46.7, interquartile range (IQR) 43.7-49.4), tamoxifen only (45.9, IQR: 43.0-48.4), AI only (46.2, IQR: 43.2-49.0) or both tamoxifen and AI (47.4, IQR: 44.5-49.5). Menopausal status at BC diagnosis did not differ between these groups. Patients with a more recent diagnosis more often received tamoxifen only, compared to patients diagnosed in earlier years. Cardiovascular risk factors at BC diagnosis were equally distributed among groups (Table 1).
Almost all patients who had received ET had estrogen receptor positive and/or progesterone receptor positive BC (99.1%). The prevalence of human epidermal growth factor receptor 2 (HER2)-positive disease was unknown in 17.5% of patients, and was relatively high (40.4%) among patients who had received treatment with an AI only. Patients who had received ET in general had higher risk disease (higher TNM-stage, higher tumor grade) compared to those not treated with ET. Patients who had received ET more often underwent mastectomy (versus lumpectomy) than patients who had not received ET. Approximately 75% of patients treated with ET had also received chemotherapy, whereas only 28% of the no ET-group had received chemotherapy. The vast majority of chemotherapy regimens contained anthracyclines. Table 2 summarizes breast cancer and treatment characteristics.
Endocrine therapy exposure
Forty percent of patients had used an AI, either alone (n=47, 8.2%) or sequentially with tamoxifen (n=184, 32.3%), and median duration of AI use was 3.0 years (IQR 2.0 – 5.0). Forty-seven percent of patients (n=272) had received tamoxifen with a median duration of use of 3.0 years (IQR 2.3 – 5.0). In the group of patients with low AI exposure (no ET or AI ratio <0.40), 250 patients had used no ET and 132 had only/predominantly used tamoxifen. The median duration of AI use in this group was 0.0 years (IQR 0.0 – 0.0 years). Sixty-nine patients had received an AI and tamoxifen in approximately equal duration (intermediate AI exposure: 0.40≤ AI ratio ≤0.60); median absolute AI duration in this group was 2.6 years (IQR 2.0 - 3.1 years). The third group (high AI exposure: AI ratio >0.60) consisted of 90 patients and median absolute duration of AI use in this group was 5.0 years (IQR 4.8 – 6.9 years) (Figure 1).
cIMT did not differ between AI ratio groups; median cIMT was 0.63 mm (IQR 0.56 – 0.71 mm) among patients with low AI exposure, 0.66 mm (IQR 0.59 – 0.75 mm) among patients with intermediate AI exposure and 0.64 mm (IQR 0.59 – 0.73 mm) among patients with high AI exposure (Table 3 and Figure 2a). Each year increase in age at study visit was associated with an increase in cIMT of 0.01 mm (95% confidence interval (CI) 0.01 - 0.01). Overweight and obese patients had higher cIMT (0.02 mm (95% CI 0.00 – 0.04) and 0.04 mm (95% CI 0.02 – 0.06) respectively) than patients with a BMI <25 kg/m2. In UMCG-patients, cIMT was 0.12 mm (95% CI: 0.10 – 0.14) higher than in NKI-AVL-patients. Although AI ratio in itself was not significantly associated with cIMT, we did observe a significant interaction between institute and AI ratio. UMCG-patients with intermediate AI exposure had a 0.02 mm (95% CI -0.07 – 0.03) lower cIMT than NKI-AVL-patients, and UMCG-patients with high AI exposure had a 0.05 mm (95% CI -0.10 – -0.01) lower cIMT than NKI-AVL-patients.
Fifty patients had a cIMT above their institute specific 90th percentile cut-off. Only age at study visit (odds ratio (OR) 1.2, 95% CI 1.12-1.34) was associated with a cIMT value above the institute specific cut-off (Table 4).
AI ratio was associated with AGEs on a continuous scale neither in univariable analysis nor after adjusting for potential confounders in multivariable analysis (Table 3). Median AGEs was 2.13 AU (IQR: 1.90 – 2.40 AU) among patients with low AI exposure, 2.20 AU (IQR: 1.90 – 2.51 AU) among patients with intermediate AI exposure and 2.11 AU (IQR: 1.90 – 2.43 AU) among patients with high AI exposure (Figure 2b). AGEs increased by 0.02 AU (95% CI 0.01 – 0.02) per year increase in age at study visit, and patients with a history of endocrine disease (compared to those without endocrine disease history) and current smokers (compared to never smokers) had higher AGEs (0.15 AU (95% CI 0.01 – 0.29) and 0.37 AU (95% CI 0.29 – 0.46), respectively). In UMCG-patients, AGEs were 0.11 AU (95% CI 0.04 – 0.18) higher than in NKI-AVL patients. Overweight patients had lower AGEs (-0.09 AU, 95% CI -0.16 - -0.01) than those with a BMI <25 kg/m2.
In all, 91 patients had elevated AGEs based on age-specific reference values. Patients with a history of endocrine disease (OR 2.35, 95% CI 1.10 – 5.03) and those who currently smoked (OR 3.75, 95% CI 2.17 – 6.47) had elevated AGEs in this analysis (Table 4).
At study visit, 195 (34.2%) patients had dyslipidemia. In univariable logistic regression analysis, women with intermediate AI exposure had higher odds of dyslipidemia at study visit than women with low AI exposure. This association was not present in the group with high AI exposure. After adjusting for confounders in multivariable analysis, the association between intermediate AI exposure and dyslipidemia disappeared (Table 4). Older age at study visit (OR 1.08, 95% CI 1.03 – 1.13) and higher BMI (compared to BMI <25; OR 1.50, 95% CI 0.99 – 2.27 for BMI ≥25 and <30 kg/m2, OR 1.86, 95% CI 1.12 – 3.09 for BMI ≥30 kg/m2) were associated with higher odds of dyslipidemia
Combined endpoint: cIMT, AGEs and/or dyslipidemia
Of the 569 study participants, 260 (45.7%) had elevated cIMT, elevated AGEs and/or dyslipidemia at study visit. In a multivariable logistic regression model, intermediate AI exposure was associated with higher odds of the combined endpoint (OR 2.06, 95% CI 1.17 – 3.62) than low AI exposure. High AI exposure, however, was not associated with higher odds of the combined endpoint than low AI exposure (OR 1.32, 95% CI 0.80 - 2.16). Factors that were significantly associated with higher odds for the combined endpoint in the multivariable model were older age at study visit (OR 1.07, 95% CI 1.02 – 1.13), a higher BMI (OR 1.53, 95% CI 1.02 – 2.30 for BMI ≥25 and <30 kg/m2; OR 1.55, 95% CI 0.92 – 2.60 for BMI ≥30 kg/m2), and current smoking (compared to never smokers; OR 2.43, 95% CI 1.54 – 3.84) (Table 4).
For all outcomes, sensitivity analyses with absolute AI duration, a different AI ratio categorization or long AI use (≥5 years versus <5 years) provided similar results (Supplementary Data).