Abstract B111: Risk of pancreatitis and autoimmune hepatitis among patients with breast cancer receiving 5-years of aromatase inhibitor therapy vs. tamoxifen

Abstract Introduction Aromatase inhibitors (anastrozole, letrozole, exemestane) are widely used to treat estrogen receptor–positive breast cancer in postmenopausal women. While effective in reducing recurrence, a few case reports suggest a possible link between AI therapy, pancreatitis and autoimmune conditions. These include antiphospholipid syndrome, Sjögren syndrome, systemic sclerosis, subacute cutaneous lupus, and inflammatory myopathies that improved after discontinuation. One population-based study also noted an increased risk of rheumatoid arthritis. This study explores a possible connection between prolonged AI use and pancreatitis and autoimmune hepatitis. Methods We conducted a retrospective cohort study using deidentified data from the TriNetX platform, which compiles electronic health records from 143 healthcare systems across 18 countries. Postmenopausal women with hormone-sensitive breast cancer were divided into two groups: Cohort A (n = 120,699) received five years of AI therapy, while Cohort B (n = 120,939) received tamoxifen. Patients with a prior history of pancreatitis, hepatitis, or liver disease were excluded. The cohorts were propensity score matched to control for baseline differences. Results The risk of acute pancreatitis was higher among Cohort A (0.67%, 809 of 120,939) compared to theCohort B (0.437%, 528 of 120,699), (p < 0.0001, Odds Ratio 1.53, 95% CI 1.37–1.71). The risk of autoimmune hepatitis was slightly higher among Cohort A (0.067%, 82 of 121,685) than Cohort B (0.051%, 62 of 121,665), but this difference did not reach statistical significance (p = 0.0957, Odds Ratio 1.32, 95% CI 0.95–1.84). Conclusion Our findings reveal a significant association between prolonged aromatase inhibitor therapy and an increased risk of acute pancreatitis. Aromatase inhibitors reduce systemic estrogen levels, which may impair immune tolerance and shift the inflammatory balance toward autoimmunity. Estrogen is known to modulate both innate and adaptive immune responses, and its depletion may unmask or exacerbate subclinical autoimmune processes targeting the pancreas. Additionally, given estrogen’s role in lipid metabolism, AI therapy may contribute to dyslipidemia, a known risk factor for pancreatitis. Patients receiving AI therapy may benefit from screening and treatment of their pre-existing lipid and immune disorders. Although the observed increase in autoimmune hepatitis did not reach statistical significance, the trend may support the broader hypothesis that prolonged estrogen suppression can influence systemic immune function. Citation Format: Yohannes Haile, Allen Seylani. Risk of pancreatitis and autoimmune hepatitis among patients with breast cancer receiving 5-years of aromatase inhibitor therapy vs. tamoxifen [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B111.