Frontiers in Aging · Oct 30, 2026
Divergent Aging-Related Clinical Trajectories Associated with Aromatase Inhibitors and Tamoxifen in Older Breast Cancer Survivors
By Ohad Regev, S. Matzri, E. Izkhakov et al.
Purpose To compare longitudinal changes in body weight, serum protein measures, and metabolic parameters between women with breast cancer treated with tamoxifen versus aromatase inhibitors, with particular interest in older women. Methods We analyzed 4,987 women aged ≥50 years with estrogen receptor–positive breast cancer prescribed AI or tamoxifen. Propensity score matching on six covariates (chemotherapy exposure, age, BMI, prior fracture, diabetes and statin use) yielded 3,738 matched patients (AI: 2,492; tamoxifen: 1,246). Linear mixed-effects models with a random intercept per patient assessed longitudinal changes in albumin, total protein, weight, blood pressure, and lipid levels over up to 5 years. The 17 outcomes assessed in the full matched cohort formed the primary analysis family and were adjusted for multiplicity using the Benjamini-Hochberg procedure; age-stratified analyses were exploratory. Results AI therapy was associated with significantly greater declines in albumin (β=+0.27 g/L per year, tamoxifen relative to AI; p=0.010) and total protein (β=+0.44 g/L per year, p=0.004), corresponding to approximately 0.8–1.3 g/L greater decline over 3 years, and a significantly greater rate of weight loss (β=+0.41 kg per year, p<0.001) compared with tamoxifen. After Benjamini-Hochberg adjustment within the primary family of 17 outcomes, the weight (q=0.001) and total protein (q=0.030) differences remained significant, while the albumin difference was of borderline significance (q=0.058). tamoxifen therapy was associated with an increased rate of LDL cholesterol rise overall (β=2.17 mg/dL per year, p=0.034; q=0.143), and, in exploratory age-stratified analyses, with increased systolic blood pressure in women aged 50–59 years (β=1.61 mmHg per year, p=0.046) and increased LDL cholesterol in women aged 60–69 years (β=5.32 mg/dL per year, p=0.010). Conclusions AI therapy was associated with a greater rate of weight loss over time, with directionally consistent declines in nutritional biomarkers, whereas tamoxifen therapy was associated with less favorable metabolic changes in exploratory age-stratified analyses. Long-term follow-up of older breast cancer survivors should therefore include assessment of frailty-related and metabolic parameters in addition to bone health.