(AF) Hypothesis-Free Screening for Carcinogenic Effects of Drugs

Publication Number: 322

Background: Current methods in pharmacovigilance are based on spontaneous reporting of adverse drug events and are limited by underreporting of delayed adverse events such as cancer. Hypothesis-free screening of adverse effects of drugs using electronic health data could supplement current practices in pharmacovigilance and, ultimately, improve drug safety monitoring.

Objectives: We aimed to establish a setup for hypothesis-free screening of carcinogenic effects of prescriptions drugs using Danish health registries.

Methods: We conducted a series of case-control studies by identifying individuals with incident cancer in Denmark 2001-2018, matching each case with 10 population controls on age, sex, and calendar time. Odds ratios (OR) were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. We included 85 cancer outcomes defined by affected organ/site and histologic subtype, e.g., adenocarcinoma of the lung. We included all prescription drugs available in Denmark and modeled exposure according to individual drugs (ATC level 5) and drug classes (ATC level 4) defining long-term use as 8 or more filled prescriptions up to two years before the index date.

Results: A total of 13,577 drug-cancer associations were examined for individual drugs and 8996 for drug classes. We reviewed 274 drug-cancer pairs where an association with long-term use and a cumulative dose response pattern were present. We classified 65 associations as not readily attributable to bias of which 20 were already established as carcinogens by the International Agency for Research on Cancer. The remaining 45 associations may warrant further study, e.g., the association between long-term use of azathioprine and squamous cell carcinoma of the cervix (OR 2.42, 95% CI 1.56 - 3.7) and nifedipine and meningioma (OR 1.94, 95% CI 1.26 - 2.99).

Conclusions: The present study provides a screening tool for drug carcinogenicity aimed at hypothesis-generation and explorative purposes. We identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation in targeted epidemiological and translational studies.