Immunosuppressive regimens and skin cancer risk in solid-organ transplant recipients

Background Solid organ transplant recipients (SOTRs) are at increased risk of developing skin cancer due to chronic immunosuppressive (IS) therapy. Calcineurin inhibitors (CNIs), particularly tacrolimus and cyclosporine, are associated with elevated skin cancer risk. MTOR inhibitors (MTORIs) are considered protective, but real-life evidence of their effectiveness, especially when combined with reduced-dose CNIs, is limited. Understanding the impact of current IS regimens on skin cancer risk is essential for improving patient outcomes. Objective To evaluate the relative risk of different IS drugs and regimens on skin cancer development in SOTRs. Methods We conducted a prospective observational study at Vall d’Hebron University Hospital, Barcelona, Spain, from 2011 to 2021. The study included 1,055 SOTRs from a mixed-organ cohort, with a combined follow-up of 3,336 person-years. Real-life IS drug regimens were recorded during scheduled posttransplant screenings or dermatological follow-ups. Cox proportional hazards models with shared frailty were used to assess skin cancer risk, accounting for multiple events and adjusting for time-varying drug exposure. Results Skin cancer occurred in 12.4% of patients. A total of 450 skin cancer events were registered, including 317 squamous cell carcinomas (71%), 118 basal cell carcinomas (26%), and 15 melanomas (3%). MTORI-based regimens were associated with significantly lower skin cancer rates (Hazard Ratio [HR], 0.66; 95% CI, 0.47-0.92; p = .01). Everolimus appeared more protective than sirolimus (HR, 0.38; 95% CI, 0.21-0.69; p = .001). Reduced-dose CNI combined with MTORI was linked to a 37% reduction in skin cancer rates in high-risk patients (HR, 0.63; 95% CI, 0.42-0.93; p = .02) and a 32% reduction in patients with posttransplant events (HR, 0.68; 95% CI, 0.47-0.98; p = .04). The reduction was mainly driven by decreased squamous cell carcinoma incidence. Conclusions MTORI-based regimens, particularly with reduced-dose tacrolimus, appear to offer a safer and more effective alternative to CNI-heavy regimens for skin cancer prevention in SOTRs. Real-life data support the integration of MTORIs into immunosuppressive strategies to reduce skin cancer risk, particularly for high-risk patients and those with prior skin malignancies.