Estradiol exposure and pancreatic cancer risk: convergent evidence from population-based incidence, pharmacovigilance, and tumor biology

Abstract

Aim: To evaluate whether estrogen exposure is associated with pancreatic ductal adenocarcinoma (PDAC) risk and to determine whether estrogen signaling influences tumor biology, integrating population-based incidence, pharmacovigilance, and transcriptomic data. Methods: We conducted a multi-modal analysis using four complementary data sources. Population-based incidence was assessed using Surveillance, Epidemiology, and End Results (SEER) multiple-primary standardized incidence ratio (MP-SIR) methodology among female breast cancer survivors, with latency stratification. Pharmacovigilance disproportionality analysis of estradiol-associated pancreatic cancer reports was performed using OpenVigil access to the Food and Drug Administration Adverse Event Reporting System (FAERS), calculating proportional reporting ratios (PRRs), reporting odds ratios (RORs), and χ2 statistics. A prospective UK Biobank cohort analysis evaluated self-reported ever use of hormone replacement therapy (HRT) and incident registry-confirmed PDAC using a 5-year landmark and multivariable Cox proportional hazards regression. Tumor transcriptomic associations between estrogen receptor 1 (ESR1) signaling and stromal programs were examined in The Cancer Genome Atlas Pancreatic Adenocarcinoma (TCGA-PAAD) using Spearman correlation and nonparametric group comparisons. Results: In SEER, pancreatic cancer incidence among breast cancer survivors was comparable to the general population (SIR 1.03, 95% CI 1.00–1.07), with no elevation in early or late latency periods. In contrast, pharmacovigilance analysis demonstrated a strong inverse association between estradiol exposure and pancreatic cancer reporting (PRR and ROR 0.095; χ2 = 76.674). In the UK Biobank, 265,572 women contributed 705 incident PDAC events after the 5-year landmark. Ever use of HRT was not significantly associated with PDAC after adjustment for age, body mass index, smoking status, type 2 diabetes, and socioeconomic deprivation (HR 1.16, 95% CI 0.99–1.36; p = 0.059). TCGA analyses revealed a significant positive association between ESR1 expression and inflammatory, tumor-restraining cancer-associated fibroblast programs (p < 1 × 10–6). Conclusions: Estrogen exposure was not associated with a statistically significant reduction in PDAC incidence. Pharmacovigilance and transcriptomic findings support a possible tumor-modifying role for estrogen signaling, whereas the UK Biobank results do not demonstrate a protective association between broadly defined HRT use and PDAC incidence.