Grant Number:	1R01CA292523-01A1 Interpret this number
Primary Investigator:	Bittermann, Therese
Organization:	University Of Pennsylvania
Project Title:	The Role of Immunosuppression and Environmental Exposures on Incident and Subsequent Keratinocyte Carcinoma Risk After Solid Organ Transplant
Fiscal Year:	2025

PROJECT SUMMARY Keratinocyte carcinomas (KCs), which include squamous cell and basal cell carcinomas of the skin, are the most common type of cancer in the U.S. with over 5 million new cases annually. The immune system plays a pivotal role in KC development and progression via immunological surveillance. Immunocompromised solid organ transplant recipients face an exponentially increased risk of KC, with significantly higher risks of KC-related morbidity and, in some cases, mortality. The more aggressive tumor biology in the setting of immunosuppression of solid organ transplant recipients also serves as a model for other diseases where immunosuppression is the mainstay of therapy (e.g., rheumatologic diseases, immune-mediated gastrointestinal disease). Yet, due to limited data on the factors influencing this relationship, there remains no risk-individualized approach to KC screening, surveillance and management in transplant recipients. This critical unmet need represents a missed opportunity to reduce incident and recurrent KC and achieve superior skin cancer-related outcomes in this high- risk population. Although exposure to ultraviolet (UV) rays from sunlight and skin type have been extensively studied as the major cause of KC in the non-transplant setting, they are not included in existing skin cancer risk scores for solid organ transplant recipients. Key limitations of existing skin cancer risk prediction models for solid organ transplant recipients also include a lack of immunosuppression treatment variables. Together, these have led to a lack of evidence-based guidelines for KC surveillance and management, contributing to suboptimal KC- related outcomes in organ transplant recipients with preventable morbidity and possibly even mortality. Addressing these knowledge gaps would lead to more accurate KC risk stratification in the immunosuppressed population and for an individualized approach to treatment decision-making that considers the necessary balance of immunosuppression to prevent rejection with skin cancer treatment options. We will leverage a pre- existing data source of linked national transplant registry data and data from the Veterans Health Administration (VA), along with a prospective multi-center cohort study of a diverse population of kidney and liver transplant recipients to develop two clinically-useful sets of deliverables with the potential to change practice: (i) validated prediction models to standardize KC screening and surveillance in a high-risk population and (ii) a Markov simulation model to enhance immunosuppression-related decision-making for patients who experience post- transplant KC. To achieve these objectives, we will: a) derive and internally validate a model that includes immunosuppression treatment variables to predict incident and subsequent KC in a retrospective cohort of kidney and liver transplant recipients in the VA; b) externally validate and refine these models in a prospective diverse multi-center cohort of kidney and liver transplant recipients, capturing detailed data on UV exposure, skin type, and photosensitivity; and c) construct a Markov simulation model to guide immunosuppression-related management strategies for incident and subsequent KC.





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