Long‐Term Follow‐Up of Chemotherapy‐Associated Biological Aging in Women With Early Breast Cancer

ABSTRACT Background p16 INK4a ( p16 ), a robust marker of cell senescence, rises rapidly and dramatically after adjuvant chemotherapy for breast cancer. We measured p16 in peripheral blood T cells of 119 women with stage I–III breast cancer, 75 with previous adjuvant chemotherapy and 44 randomly selected women who had never received chemotherapy. p16 was measured at least 3 years (mean, 6 years) following diagnosis. Aims This study aims to assess the expression of p16 after long‐term follow‐up and define the trajectory of the p16 increase in a subset of patients with baseline, 6‐month post‐chemotherapy, and long‐term follow‐up data. Methods and Results All patients were treated in accordance with national guidelines, and 53% of the chemotherapy‐treated patients received anthracycline regimens. After a mean follow‐up of 6 years from the end of treatment, chemotherapy‐treated patients demonstrated p16 levels corresponding to approximate age‐equivalent increase of ∼14 years compared to 2.1 years in non‐chemotherapy‐treated patients. When compared to community‐dwelling adults, p16 expression increased markedly at 6 months post‐chemotherapy, particularly among anthracycline‐treated patients (corresponding to larger age‐equivalent deviation: median 21.5 years vs. median 15.4 years). At long‐term follow‐up, both anthracycline and non‐anthracycline‐treated patients showed elevated but converging p16 levels (age‐equivalent median of 18.1 years vs. median 17.2 years), indicating an improvement in p16 levels over time in anthracycline‐treated patients. Age‐equivalent values are reported as an interpretive aid derived from population‐level p16 –age relationship and are not intended to represent literal biological age or clock‐based aging. Conclusion Early breast cancer patients treated with chemotherapy exhibited a marked increase in p16 expression shortly after treatment completion that persists for years after treatment. The long‐term impact of these changes remains uncertain but raises the possibility that chemotherapy‐related cellular senescence could contribute to an increased risk of age‐related comorbidities over time.