S140 Lower Incidence of Pancreatic Cancer in Patients on HER2-Targeted Therapy: Potential Implications in Pancreatic Cancer Prevention

Introduction: Pancreatic cancer (PC) incidence and mortality have been rising steadily in the United States since 1995. Despite ongoing advances, no effective preventive agents exist. Human epidermal growth factor receptor 2 (HER2) positivity is reported in 2-15% of PCs and is linked to poorer prognosis. HER2-targeted agents improve outcomes in other HER2-positive cancers, including breast and gastric cancers. However, their preventive effect on PC has not been investigated. We aimed to assess the incidence of pancreatic cancer in patients receiving HER2-targeted therapies for non-pancreatic malignancies. Methods: Data was obtained from the TriNetX Global Collaborative Network, including 143 healthcare organizations. Patients aged 18 to 90 years with diagnosis of breast, colon, rectal, biliary, endometrial, gastric, esophageal, salivary gland, oral cavity, bladder, ovarian cancer, and non-small cell carcinoma were included. Cohort 1 comprised patients who received HER2-targeted agents (trastuzumab, pertuzumab, margetuximab, neratinib, lapatinib, tucatinib, trastuzumab deruxtecan); Cohort 2 included patients with a cancer diagnosis but no exposure to HER2-targeted agents. Patients with prior PC were excluded. Propensity score matching (1:1) was performed based on demographics and comorbidities (diabetes mellitus, obesity, alcoholic liver disease, chronic pancreatitis, and nicotine dependence), and use of gastrointestinal medications. The primary outcome was PC incidence after the index event across a 20-year observation window. Results: After matching, 54,338 patients were included in each cohort. The incidence of PC was lower in the HER2-targeted group compared to the control group (276 vs 329). Risk analysis showed a statistically significant lower risk in the HER2 cohort (Risk Difference -0.1%, P = 0.025; odds ratio 0.833, 95% CI: 0.710–0.978). Kaplan-Meier analysis confirmed this finding, with a hazard ratio of 0.768 (95% CI: 0.654–0.901, P = 0.042). Patients in the HER2 group also had fewer instances of PC events (mean 9.4 vs 17.2, P < 0.001). Conclusion: In a large, matched cohort analysis, HER2-targeted therapy was associated with a significantly lower incidence of PC in patients with non-pancreatic malignancies. These findings raised the possibility of a preventive effect, potentially through suppression of HER2-driven pathways in occult pancreatic lesions. Further studies are warranted to explore this hypothesis and define the role of HER2 inhibition in PC prevention.