Comment on “Association of aspirin and ibuprofen use with endometrial cancer risk in the <scp>PLCO</scp> dataset”

We read with interest the article by Zhao et al., which provides valuable insights into the potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in endometrial cancer prevention.1 We highlight two points for discussion. First, across all four exposure analyses in Table 2—including patterns of NSAID use, aspirin frequency, ibuprofen frequency, and combined use—the hazard ratios and confidence intervals in Model 3 are virtually identical to those in Model 2, with minimal or no change after additional adjustment for cardiovascular disease and diabetes mellitus. Given the high prevalence of these two conditions and their known association with NSAID use, such minimal change is not commonly observed in Cox proportional hazards modeling. This raises concern as to whether the additional covariates were correctly incorporated or whether the reported estimates may inadvertently replicate those from Model 2. Second, the study defines “high-frequency use” as ≥30 pills per month, which—even assuming the lowest tablet strength of 200 mg—corresponds to approximately 200 mg per day. This is far below the high-dose ibuprofen threshold (>2400 mg/day) cited in the Discussion. Because PLCO questionnaires did not capture tablet strength, formulation, or actual dosage, exposure misclassification is unavoidable. The authors cite cardiovascular risks associated with high-dose ibuprofen in the discussion; however, the actual exposure in this study is far below that threshold. Extrapolating cardiovascular risks observed at high-dose ibuprofen to low-dose use constitutes over-interpretation and may lead readers to overestimate the clinical significance of the findings. Clarification on these two points would strengthen confidence in the study's conclusions and their applicability to clinical practice. Shih-Wei Lai: Writing – original draft; writing – review and editing. Kuan-Fu Liao: Conceptualization. The authors declare that they have no conflict of interest.