INTRODUCTION
Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States, and a growing public health concern.1 While a variety of prevention strategies exist for high-risk groups such as organ transplant recipients, few systemic agents have been evaluated for NMSC prevention in the general population.1 Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has demonstrated antitumor effects through antiangiogenic and proapoptotic mechanisms, and studies in high-risk patients found that celecoxib significantly reduced the incidence of NMSC.2 In addition, the mammalian target of rapamycin (mTOR) inhibitor, sirolimus, inhibits keratinocyte proliferation, angiogenesis, and oncogenic signaling, with randomized controlled trials in organ transplant populations demonstrating sirolimus's association with significant reduction in NMSC incidence.3 Similarly, retinoids have also been studied as chemopreventive agents, with trials demonstrating acitretin decreases risk for squamous cell carcinoma (SCC) in high-risk populations.4 This large-scale retrospective cohort study evaluated the real-world impact of celecoxib, sirolimus, and acitretin use on the risk of NMSC development and related procedural interventions in the general population.
MATERIALS AND METHODS
Within the TriNetX Research Network, we queried codes from the 10th revision of the International Classification of Diseases (ICD-10), Current Procedural Terminology (CPT), and RxNorm from August 1, 2015 to August 1, 2025. Three individual studies were conducted of adults (greater than or equal to 18) with greater than or equal to 2 documented encounters for celecoxib (RxNorm: 140587), sirolimus (RxNorm: 35202), or acitretin (RxNorm: 16818) use were included and compared with a cohort without study medication exposure after propensity score matching (PSM). PSM was performed 1:1 on patient characteristics documented prior to study medication initiation, including demographics, comorbidities, and immunosuppressive medications/conditions (Table 1). Patients with inherited or acquired risk factors for NMSC, organ transplantation, previous or current systemic malignancy, exposure to multiple study medications or documentation of the target outcomes prior to study medication initiation were excluded. Primary outcomes included risk of NMSC development. Secondary outcomes included risk of Mohs micrographic surgery (MMS) (CPT: 17311-17315) and excision of malignant skin lesions (CPT: 1003243). Outcomes were evaluated using risk ratios (RR) and 95% confidence intervals (CI) at 5- and 10-year follow-up, with significance defined as P-value <0.05.
RESULTS
After PSM, the celecoxib, sirolimus, and acitretin cohorts included 15,415, 2,288, and 5,915 patients per group, respectively (Table 2). Celecoxib use was associated with a significantly lower risk of developing NMSC at both 5 years (RR 0.83; P<0.001) and 10 years (RR 0.77; P<0.001), as well as reduced risk of MMS at 5 years (RR 0.81; P=0.0002) and 10 years (RR 0.77; P<0.001), and lower risk of excision for malignant skin lesions at 5 years (RR 0.73; P<0.001) and 10 years (RR 0.75; P<0.001). Similarly, sirolimus exposure was associated with a reduced risk of NMSC at 5 years (RR 0.49; P=0.018), with this protective effect persisting at 10 years (RR 0.49; P=0.01); however, less than or equal to 10 MMS and excision events were reported at both time points, and exact counts were suppressed by TriNetX privacy policies, precluding statistical analysis of these outcomes. Acitretin use was also associated with a significantly lower risk of NMSC at 5 years (RR 0.58; P<0.0001) and 10 years (RR 0.66; P<0.0001), along with markedly reduced risk of MMS at 5 years (RR 0.27; P<0.0001) and 10 years (RR 0.31; P<0.0001), and lower risk of excision for malignant skin lesions at 5 years (RR 0.35; P<0.0001) and 10 years (RR 0.41; P<0.0001).
