Study: Aromatase Inhibitor Adherence Linked to Higher Metabolic Risk, Lower Mortality

Five-year adherence to aromatase inhibitors among postmenopausal women with early-stage HR-positive breast cancer raises the 10-year cumulative incidence of hypertension, dyslipidemia, and diabetes, according to a prospective cohort study published in JNCI Cancer Spectrum.

Cardiometabolic Risks Following Aromatase Inhibitor Therapy

Prolonged adjuvant endocrine therapy alters lipid metabolism, glucose control, and blood vessel function in cancer survivors. Researchers at Kaiser Permanente Northern California investigated these long-term consequences by analyzing 8,365 postmenopausal women with a median age of 64 years who initiated therapy with an aromatase inhibitor or tamoxifen between 2005 and 2013. The study evaluated patients with stage I to III HR-positive breast cancer using annual prescription dispensing data, defining adherence as a proportion of days covered exceeding 80%.

Among the cohort, 42.7% of patients maintained adherence to endocrine therapy for five years or longer. Another 12.3% adhered for three to four years, 12.9% for one to two years, and 12.8% remained non-adherent. Using sequentially doubly estimation with Super Learner algorithms, the investigators estimated counterfactual 10-year cumulative incidence under six adherence duration strategies while adjusting for demographic, clinical, lifestyle, and tumor characteristics.

Aromatase Inhibitors Increase Metabolic Risks More than Tamoxifen

Five-year adherence to aromatase inhibitors produced distinct metabolic alterations. The data showed a higher 10-year cumulative incidence of hypertension at 9.37%, dyslipidemia at 6.84%, and diabetes at 3.29% compared with non-adherent women. Tamoxifen adherence demonstrated an association only with a higher cumulative incidence of hypertension at 9.38%. When researchers directly compared adherent users, aromatase inhibitor use was tied to a 9.86% higher absolute 10-year cumulative incidence of dyslipidemia than tamoxifen use.

Conversely, five-year adherence to either endocrine therapy yielded survival benefits. Adherent patients experienced a lower 10-year cumulative incidence of all-cause death at 10.7%, breast cancer-specific death at 5.37%, and cardiovascular disease death at 2.89% relative to non-adherence. The study authors, led by Jorge R. Ledesma from the Kaiser Permanente Northern California Division of Research, suggested that adherent patients likely maintained deeper engagement with the healthcare system, which permitted earlier identification and management of emerging risk factors.

Screening and Healthy Habits Mitigate Cardiometabolic Risks

“Although long-term [adjuvant endocrine therapy] adherence was associated with increased cardiometabolic risk, these findings underscore opportunities to optimize overall patient health by maintaining therapy while proactively managing potentials risks,” the study authors wrote.

Drawing on prior evidence demonstrating the value of diet and exercise for breast cancer survivors, the investigators noted that routine cardiometabolic screening combined with adherence to American Cancer Society recommendations for healthy eating and physical activity could mitigate downstream risks. The research received financial support from the National Cancer Institute. Study limitations included potential residual confounding from unmeasured lifestyle factors, possible exposure misclassification stemming from pharmacy dispensing records, and the use of clinical algorithms rather than direct physiological biomarkers to measure outcomes.

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