Association and causality between breast cancer subtypes and papillary thyroid carcinoma: evidence from a clinical cohort and Mendelian randomization

OBJECTIVES: To systematically evaluate the clinical phenotypic associations and genetic causal architecture between breast cancer (BC) and papillary thyroid carcinoma (PTC). MATERIAL AND METHODS: We conducted a single-center retrospective case-control study, involving 44 patients with dual primary BC-PTC, age-matched (1:2) with a pure BC cohort (n = 88) and a pure PTC cohort (n = 88). The study applied multivariable logistic regression to identify independent predictors for the occurrence of secondary PTC. To clarify whether a genetic causal link exists between specific BC subtypes and PTC risk, we subsequently conducted a bidirectional two-sample Mendelian randomization analysis. RESULTS: Clinical analysis demonstrated that patients in the BC-PTC group were characterized by smaller breast tumor diameters, a significantly higher prevalence of ER/PR positive, and elevated serum estradiol levels compared to the pure BC group. Multivariable regression identified low HER2 expression as an independent risk factor for secondary PTC (OR = 3.59, 95% CI: 1.31-9.86), while PR positive emerged as a potent protective factor (OR = 0.11, 95% CI: 0.02-0.69). Compared to the pure PTC cohort, the BC-PTC group exhibited more indolent PTC features, including smaller tumor sizes and lower metastatic prevalence. Genetically, MR analysis corroborated a unidirectional causal effect of ER-positive BC on increased PTC risk (IVW OR = 1.32, 95% CI: 1.13-1.55), whereas reverse MR analysis yielded null findings across all BC subtypes. CONCLUSIONS: Patients with secondary PTC post-BC exhibit a distinct clustering of hormone receptor-related phenotypes. HER2-low expression and PR status represent critical biomarkers for risk stratification in BC survivors. Genetic evidence supports a unidirectional causal link from ER-positive BC to PTC. These findings suggest that thyroid surveillance should be tailored based on BC molecular subtypes, although prospective multicenter studies are essential to further delineate the impact of surveillance bias.