Prognostic Role of Hedgehog Signaling Pathway Markers in Pancreatic Carcinogenesis

Background: Proton pump inhibitors (PPIs) cause hypergastrinemia, which has been linked to gastrointestinal malignancies in experimental models.In spite of this highly suggestive mechanism, epidemiologic study results have been mixed, with no study capturing the increase in PPI prescriptions in recent years.We evaluated the association between PPI use and both pancreatic cancer risk and survival after diagnosis.Elucidating these associations could advance our understanding of the role of gastrin in pancreatic cancer and help inform discussions between patients and providers starting PPIs.Methods: We conducted a nested case-control study and a retrospective cohort study in The Health Improvement Network (THIN), a medical records database representative of the UK population.In the case-control study, each patient with incident pancreatic cancer was matched with up to four controls based on age, sex, practice site and both duration and calendar time of follow-up using incidence density sampling.The odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer risk associated with PPI use were estimated using multivariable conditional logistic regression.The retrospective cohort study compared the survival of pancreatic cancer patients according to their PPI exposure at the time of diagnosis.The effect of PPI use on pancreatic cancer survival was assessed using a multivariable Cox regression analysis.Results:The case-control study included 4,113 cases and 16,072 matched controls, with cases more likely to use PPIs (53% vs. 26% current users), be obese, smoke, use alcohol and have diabetes.The duration of PPI use was significantly shorter in cases compared to controls (2.47 years vs. 4.14 years, OR 0.85, 95% CI 0.83-0.87).Adjusting for diabetes, smoking, alcohol use and BMI, all PPI users (both former and active users) had a higher risk of pancreatic cancer than non-users (Table 1).Only short-term, active users had a modest decrease in survival (Table 2).Conclusions: Our findings are the first population-level study in accordance with the compelling link between hypergastrinemia and pancreatic cancer seen in in vitro and animal models.The increase in pancreatic cancer risk seen in individuals recently started on PPIs (OR 10.42,, coupled with the significantly shorter duration of PPI use in cases compared to controls likely represents reverse causation, with PPIs initiated due to symptoms from pancreatic cancer.However, even in the case of reverse causality, a new PPI prescription may indicate an individual at higher risk for pancreatic cancer.The elevated OR in all patients taking PPIs, even >24 months before pancreatic cancer diagnosis, argues against reverse causality as the main explanation for our results.Our data suggests that PPIs themselves do increase the risk of pancreatic cancer.Table 1.PPI exposure and pancreatic cancer risk