Abstract A013: Clonal hematopoiesis as biomarker for 10-year risk of coronary heart disease in men with prostate cancer
Authors: Himbert Caroline , Chan Irenaeus C. C. , Ma Yuan , Mukamal Kenneth J , Mucci Lorelei A , Kantoff Philip W , Bolton Kelly L , Stopsack Konrad H 
Published: February 2025

Background: Men with prostate cancer have a high risk for cardiovascular disease (CVD), including coronary heart and cerebrovascular disease, following cancer diagnosis. Clonal hematopoiesis (CH) is associated with coronary heart disease (CHD) in the general population. We hypothesized that a higher burden of CH among men with non-metastatic prostate cancer is associated with an increased risk of CHD. Methods: This is a nested case-cohort study among men diagnosed with non-metastatic prostate cancer and free of CVD at cancer diagnosis within the prospective Health Professionals Follow-up Study. Men had to be free from prostate cancer and CVD at blood draw and at cancer diagnosis to be included. Men diagnosed with prostate cancer were followed for incident CHD events, defined as fatal and non-fatal myocardial infarction, coronary artery bypass graft surgery, and percutaneous coronary intervention infarction, over up to 10 years after cancer diagnosis. DNA was sequenced for putative CH driver mutations in the 9 most common CH-defining genes with a custom targeted panel (VariantPlex, Invitae, Inc.) at ultra-high depth (mean, 19,664X). CH variant calling used a novel ensemble calling approach, ArCH, validated with in-silico tumor dilutions and blinded technical replicates, which had high accuracy for variant allele frequency (VAFs) as low as 0.1%. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were computed using proportional hazard regression models with Prentice case-cohort weights. Results: In a sample of 562 men with prostate cancer and free from CVD at cancer diagnosis, men had a median age at cancer diagnosis of 70 years and 48% were never smokers. 95% were diagnosed with stage I and II, and 70% had a Gleason score of ≤3+4. The median time between blood draw and cancer diagnosis was 7 years (interquartile range (IQR): 3, 12). There were 116 events over 10 years of follow-up after cancer diagnosis. 59% of men had no CH or very small clones (VAF ≤0.5%), 25% had VAFs 0.5-2%, 12% had VAFs 2-10%, and 3% had VAFs ≥10%. 61% of men had variants in epigenetic modifier genes (DNMT3A, TET2, ASXL1), and 3% had variants in DNA repair genes (PPM1D, TP53, CHEK2). CH ≥10% VAF was associated with an increased risk of CHD events following cancer diagnosis compared to no CH or very small clones after adjusting for age at blood draw and at cancer diagnosis (VAF ≤0.5%) (HR 2.94, 95% CI 1.04-8.33). After further adjustment for smoking status at blood draw the association was essentially unchanged (HR 2.90, 95% CI 1.02-8.23). The association between CH and CHD risk tended to become stronger with increasing VAFs compared to VAFs ≤0.5% (VAF 0.5-2%: HR 0.92, 95% CI 0.46-1.82; VAF 2-10%: HR 1.20, 95% CI 0.57-2.52). Results for epigenetic modifiers and DNA repair genes were not individually statistically significant. Conclusions: Results from this prospective cohort suggest that a higher burden of CH is associated with CHD and may be a potential biomarker for CHD risk among men with prostate cancer.

Citation Format: Caroline Himbert, Irenaeus C. C. Chan, Yuan Ma, Kenneth J Mukamal, Lorelei A Mucci, Philip W Kantoff, Kelly L Bolton, Konrad H Stopsack. Clonal hematopoiesis as biomarker for 10-year risk of coronary heart disease in men with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A013.