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. 2023 Sep:7:e2300208.
doi: 10.1200/PO.23.00208.

Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study

Jamila Mammadova  1 , Christelle Colin-Leitzinger  2 , Diep Nguyen  3 , Rahul Mhaskar  3 , Shridar Ganesan  4 , Yi-Han Tang  2 , Mingxiang Teng  5 , Roohi Ismail-Khan  6 , Nancy Gillis  2   7
Affiliations

Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study

Jamila Mammadova et al. JCO Precis Oncol. 2023 Sep.

Abstract

Purpose: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC).

Methods: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA.

Results: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC.

Conclusion: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
(A) Oncoplot of CH mutations in cases (n = 7 of 25) and controls (n = 6 of 75). Each column represents a patient, and each row represents a gene of interest. Colored cells indicate the presence of a mutation in that gene and patient. Types of mutations are classified according to colors as shown in the legend on the bottom. (B) Prevalence of CH in cases and controls. (C) Boxplot of variant allele frequency of CH mutations in cases and controls, depicted as median and range. *P < .05. CH, clonal hematopoiesis; MB, mutation burden; ns, not significant.
FIG 2.
FIG 2.
Forest plot for associations with doxorubicin-induced cardiotoxicity in the multivariable logistic regression model. Values represent odds ratios with 95% CIs. Statistically significant variables are shown in red. OR, odds ratio.
FIG 3.
FIG 3.
Kaplan-Meier curve for overall survival. The graph shows the overall survival in months in cases who had DIC (red) and controls who did not (blue). DIC, doxorubicin-induced cardiotoxicity; OS, overall survival.
See this image and copyright information in PMC

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