Differential Causal Effects of Common Analgesics on Breast Cancer Risk and Survival: Evidence from Mendelian Randomization

Zhan Peng,* Zhuobin Liu, Guangye Wang* Department of Spinal Surgery, Shenzhen Baoan District People’s Hospital, the Second Affiliated Hospital of Shenzhen University, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhan Peng, Department of Spinal Surgery, Shenzhen Baoan District People’s Hospital, No. 118, Longjing Two Road, Xinan Street, Shenzhen, 518101, People’s Republic of China, Email [email protected] Guangye Wang, Department of Spinal Surgery, Shenzhen Baoan District People’s Hospital, No. 118, Longjing Two Road, Xinan Street, Shenzhen, 518101, People’s Republic of China, Email [email protected]: The causal effects of widely used analgesics—paracetamol(acetaminophen), aspirin (acetylsalicylic acid), and ibuprofen—on breast cancer risk and survival remain uncertain. This Mendelian randomization (MR) study investigated their causal relationships with breast cancer incidence, mortality, and estrogen receptor (ER)-subtype heterogeneity.Methods: Using two-sample MR, genetic instruments for analgesic use were derived from UK Biobank GWAS (N=457,547). Outcome data included breast cancer incidence (122,977 cases/105,974 controls), ER-subtypes (ER+: 69,501 cases; ER−: 21,468 cases), and survival statistics. Inverse-variance weighted (IVW) analyses were primary, supplemented by MR-Egger, weighted median/mode, and sensitivity analyses (MR-PRESSO, leave-one-out). Bidirectional MR assessed reverse causation.Results: Genetically predicted paracetamol use increased overall breast cancer risk (IVW OR=3.26, 95% CI:1.60– 6.63, pFDR=0.005) and ER+ subtype risk (OR=3.65, 1.79– 7.45, pFDR=0.003). Aspirin use showed no association with incidence but improved overall survival (HR=0.0036, 0.0001– 0.1218, pFDR=0.016). Ibuprofen demonstrated no significant associations with risk or survival. Subtype-specific survival analyses were null. No reverse causation was detected (all p > 0.05). Sensitivity analyses confirmed robustness, with minimal pleiotropy (MR-Egger intercept p > 0.05) and consistent effects after outlier correction.Conclusion: This MR study links a genetic predisposition to paracetamol use with increased breast cancer risk (especially ER+), and to aspirin use with improved survival. These divergent findings point to drug-specific mechanisms, warranting caution with long-term paracetamol use and further study of aspirin’s therapeutic potential. Clinical decisions should balance analgesic benefits against these potential cancer-related outcomes. Keywords: breast cancer, paracetamol, aspirin, ibuprofen, Mendelian randomization, nonsteroidal anti-inflammatory drugs, pharmacoepidemiology