The Association Between Gene Expression Profiling Scores and Malignancy in Adult Heart Transplant Recipients

Malignancy is a common morbidity following heart transplantation (HTx), with an incidence of 15.3% (1). The immunosuppressive therapy used to prevent allograft rejection after HTx increases the risk of malignancy by inhibiting the immune defense mechanisms, thereby allowing unchecked proliferation of oncogenic viruses and malignancies associated with these viruses (2). Gene expression profiling (GEP; AlloMap) is a non-invasive blood test used to identify HTx patients at increased risk for moderate/severe acute cellular rejection by assessing immune quiescence in the transplant recipient (3). We hypothesize lower Allomap scores >1 year posttransplant will be associated with higher rates of malignancy following HTx. The goal of this study was to determine whether GEP reflects immune activity and may provide insight into long-term cancer risk.

We conducted a retrospective, single-center cohort study of adult HTx recipients with longitudinal AlloMap surveillance ≥365 days posttransplant. Patients with pre-transplant malignancy, CMV viremia, or clinically significant cardiac allograft vasculopathy were excluded. Malignancy was defined as the first invasive cancer diagnosed after transplantation. AlloMap scores were modeled as a time-varying cumulative mean using start-stop Cox proportional hazards models. Sensitivity analyses included time-varying last-observation-carried-forward (LOCF) AlloMap values and patient-level mean scores. Models were adjusted for demographic factors, CMV serostatus, rejection history, and maintenance immunosuppression.

Among 104 recipients, 29 (27.9%) developed invasive malignancy at a median of 35 months posttransplant. Higher cumulative mean AlloMap scores were independently associated with a lower risk of posttransplant malignancy (hazard ratio per 5-unit increase, 0.95; 95% CI, 0.91-0.99). Restricted cubic spline analyses demonstrated an approximately linear association without evidence of a threshold effect. In contrast, AlloMap modeled as a time-varying LOCF variable or as a patient-level mean was not significantly associated with malignancy risk. Rates of treated rejection and antibody-mediated rejection did not differ between patients with and without malignancy. Cutaneous squamous cell carcinoma was the most common malignancy observed.

Longitudinal cumulative AlloMap monitoring, but not isolated or short-term measurements, was associated with posttransplant malignancy risk, supporting the concept that sustained low immune activity over time, reflected by lower cumulative AlloMap scores, may identify patients at increased oncologic risk after heart transplantation. These findings suggest a potential role for longitudinal immune profiling in malignancy risk stratification and warrant validation in larger multicenter studies incorporating complementary immune biomarkers.