Clonal hematopoiesis association with cardiac function and mortality in patients with solid tumors.
Authors: Regan Jessica A. , Green Michelle , Kao Chester , Powers Eric , Neff Jadee , Strickler John H. , McKinney Matthew Stuart , Shah Svati H. , Zhang Tian 
Published: June 2021

10586

Background: Clonal hematopoiesis (CH) is the presence of expanded somatic clones in hematopoietic cells and is associated with higher overall mortality (OM). Studies suggest atherosclerotic cardiovascular disease may drive mortality, but the detailed mechanisms remain unclear. CH mutations can be detected in solid tumor sequencing, often confounding genomic tumor analysis. We evaluated the association of CH in solid tumor next-generation sequencing (NGS) with echocardiographic findings and OM. Methods: Sequential adult patients treated at the Duke Cancer Institute with solid tumor NGS analysis by FoundationOne were captured retrospectively. CH mutations present at a variant allele fraction ≥2% across 57 genes previously associated with hematologic malignancies were included. Patients with echocardiograms between 2 years before NGS testing and up to 5 years afterward were analyzed. Association between CH mutations with cardiomyopathy (CM, left ventricular ejection fraction < 45%) and global longitudinal strain (GLS) was determined using logistic and linear regression, respectively. In a subset of patients with detailed cancer diagnosis date and clinical follow-up, Cox proportional hazard models were used to associate CH mutations with OM, with or without TP53/ KRAS (included in most CH analyses but highly prevalent in solid tumors). Analyses were adjusted for age, gender and race. Results: Of 3029 patients with NGS testing, 2212 (73.0%) carried at least one CH related mutation, the majority of which were in TP53/ KRAS. When excluding TP53/ KRAS, CH mutations were observed in 806 of 3029 (26.6%) patients. CH mutations were associated with age (est 2.1, 95% CI 1.1-3.2, p < 0.001). Excluding TP53/ KRAS strengthened the association between CH and age (est 2.8, 95% CI 1.8-3.9, p < 0.001). Echocardiogram data were available in 828 patients, of whom 48 (5.8%) had CM. CH mutations were not associated with CM (OR 1.3, 95% CI 0.6-2.6, p = 0.5), however when excluding TP53 and KRAS, CH mutations were associated with lower odds of (OR 0.4, 95% CI 0.1-0.9, p = 0.03). GLS was available in 423 patients and was not associated with CH mutations (p = 0.8 with TP53/ KRAS; p = 0.4 without TP53/ KRAS as CH). In 222 patients with clinical information, OM did not differ between the CH vs no CH cohorts (HR 0.8, 95% CI 0.6 = 1.2, p = 0.3 inclusive of TP53/KRAS). When excluding TP53/ KRAS mutations, in this population of patients with cancer, non- TP53/ KRAS CH was associated with less OM (HR 0.6, 95% CI 0.4-0.9, p = 0.01). Conclusions: In this patient population with cancer, CH mutations did not associate with higher CM. In contrast to prior studies, CH detected in solid tumor does not associate with OM in this population. CH mutations confound tumor sequencing and these findings support the value of paired tumor-blood sequencing to determine true CH. Consensus around CH variants should be undertaken in future studies.