Background

Despite ongoing advancements in medical and surgical care, adults with congenital heart disease (ACHD) continue to experience premature death compared with the general population, even in contemporary cohorts.¹ Malignancy has been shown in multiple studies to be an important cause of death in ACHD. A large cohort study from North Carolina found cancer to be the most common etiology of death in adults with nonsevere CHD and the third most common etiology in those with severe CHD.² These and other data have highlighted cancer in ACHD as a subject area in urgent need of further research and intervention.

Etiology and Epidemiology

Several large population-based studies since the 2010s have consistently shown that cancer incidence among ACHD is approximately twice that of age- and sex-matched control participants.^3,4 Reasons for this are likely multifactorial. Low-dose ionizing radiation from cardiac procedures at a young age has been found to have a dose-dependent relationship to cancer incidence in ACHD in a large Canadian study.⁵ This is likely why specific primary malignancies known to be associated with radiation exposure such as hematologic, breast, and skin appear to predominate in the ACHD population.^3,6 Some genetic syndromes predispose to CHD as well as exponentially increase the risk of malignancy, such as Down syndrome (particularly leukemia) and DiGeorge syndrome.⁷ Specific forms of CHD are also known to increase the risk of specific neoplasms, such as pheochromocytoma and paraganglioma in cyanotic CHD and hepatocellular carcinoma late after Fontan palliation.⁸ Environmental factors such as smoking, obesity, alcohol consumption, occupational exposure, and pollution may have an additive role to play, but this is yet to be studied in patients with ACHD (Figure 1).

Figure 1: Proposed Risk Factors Influencing Incident Cancer in ACHD

This figure was created in BioRender. Venkatesh P. (2025) https://BioRender.com/ek8lbwf.
The risk factors are likely interconnected.
ACHD = adults with congenital heart disease; CHD = congenital heart disease.

Screening

Despite data repeatedly highlighting increased cancer risk, the issue of cancer screening in ACHD is nebulous and largely unresolved. A scientific statement from the American Heart Association calls for age-appropriate cancer screening in ACHD patients.⁸ However, most guideline-mandated screening for the general population at average risk starts at age 40 years or older. Although current breast cancer screening guidelines advocate for earlier screening in patients with prior radiation exposure, most other guidelines do not incorporate this and other risk factors that pertain to ACHD patients.⁹ The result is that many adults with CHD do not qualify for cancer screening—a troubling fact—because these patients are diagnosed with cancer at younger ages compared with those without CHD. A study from an ACHD center in California found that ACHD patients had a mean age of 43.5 years at cancer diagnosis compared with the median age at diagnosis in the United States of 66 years.⁶ The same study showed that only 16% of the ACHD patients had prior cancer screening, and only 10% of the cancers were diagnosed through screening.⁶

Customized screening protocols for malignancy in the ACHD population are therefore urgently warranted, and population-level studies are required to determine the optimal protocols.

Treatment and Outcomes

Two recent studies—a single-center cohort study from California and a population database study from Sweden—are currently the only ones evaluating long-term outcomes after cancer diagnosis in ACHD.^4,6 The former, comprising 68 patients with ACHD and cancer, provided granular data on therapy-related outcomes and cardiovascular events, whereas the latter included pediatric patients as well as a control group of patients with cancer without CHD. Median follow-up after cancer diagnosis was 5 years and 6.3 years, respectively.

Both studies showed that cancer was the overwhelming cause of death in patients with CHD and cancer, and accounted for over two-thirds of deaths.^4,6 Importantly, this finding was not influenced by CHD complexity.⁶ The Swedish study by Karazisi et al. additionally showed that cancer patients with CHD had higher mortality than those without CHD, and that this difference was mainly due to patients with genetic syndromes and prior transplantation.⁴ The single-center study by Venkatesh et al. found that in addition to advanced cancer stage at diagnosis, two cardiovascular variables predicted mortality—history of arrhythmia and baseline diuretic requirement.⁶ This suggests that although cancer-related death predominates in these patients, underlying CHD physiology also influences long-term survival.

Venkatesh et al. additionally found a high rate of major adverse cardiovascular and cerebrovascular events (MACCE)—59% over 5 years—but this was most likely mediated by underlying CHD complexity because most of the cohort had either grade II (47%) or grade III (35%) CHD complexity. Baseline diuretic use had a 10-fold increased risk of MACCE in multivariable analysis.⁶ These data underscore the need to optimize cardiovascular status in those with cancer and ACHD.

Finally, the question of tolerability of cancer therapy—particularly systemic pharmacotherapy with potential cardiotoxicity—is raised constantly in the clinical setting, especially in those with pre-existing cardiac disease. Reassuringly, Venkatesh et al. found only a 14% incidence of confirmed or suspected cancer therapy-related cardiac dysfunction. This mostly took the form of symptomatic hypervolemia, and in many cases may have been a consequence of high-volume administration of therapy in the setting of underlying cardiac dysfunction rather than direct cardiotoxicity from therapy. Only one patient with new systemic ventricular dysfunction needed temporary cessation of therapy for 2 weeks, and no patient required permanent cessation.⁶

Conclusions and Future Directions

Malignancy is a major driver of mortality and morbidity in patients with ACHD. The factors influencing cancer risk in this population are complex and likely interconnected. Regardless of the underlying complexity of CHD, most deaths in these patients are due to cancer rather than cardiovascular disease. Thus, prompt diagnosis and therapy are of critical importance, especially because available data suggest good tolerance to cancer therapy even in those with complex CHD. Additional studies evaluating both therapeutic and screening strategies in these patients are crucial to advancing clinical care and improving patient outcomes.

References

1. Müller MJ, Norozi K, Caroline J, et al. Morbidity and mortality in adults with congenital heart defects in the third and fourth life decade. Clin Res Cardiol. 2022;111(8):900-911. doi:10.1007/s00392-022-01989-1
2. Goldstein SA, D'Ottavio A, Spears T, et al. Causes of death and cardiovascular comorbidities in adults with congenital heart disease. J Am Heart Assoc. 2020;9(14):e016400. doi:10.1161/JAHA.119.016400
3. Mandalenakis Z, Karazisi C, Skoglund K, et al. Risk of cancer among children and young adults with congenital heart disease compared with healthy controls. JAMA Netw Open. 2019;2(7):e196762. Published 2019 Jul 3. doi:10.1001/jamanetworkopen.2019.6762
4. Karazisi C, Dellborg M, Mellgren K, et al. Outcomes after cancer diagnosis in children and adult patients with congenital heart disease in Sweden: a registry-based cohort study. BMJ Open. 2024;14(4):e083237. Published 2024 Apr 17. doi:10.1136/bmjopen-2023-083237
5. Cohen S, Liu A, Gurvitz M, et al. Exposure to low-dose ionizing radiation from cardiac procedures and malignancy risk in adults with congenital heart disease. Circulation. 2018;137(13):1334-1345. doi:10.1161/CIRCULATIONAHA.117.029138
6. Venkatesh P, Yan KL, Bravo-Jaimes K, Yang EH, Lluri G. Outcomes of malignancy in adults with congenital heart disease: a single center experience. Cardiooncology. 2022;8(1):20. Published 2022 Nov 23. doi:10.1186/s40959-022-00144-z
7. Wahrmann S, Kainulainen L, Kytö V, Lempainen J. Childhood manifestations of 22q11.2 deletion syndrome: a Finnish nationwide register-based cohort study. Acta Paediatr. 2023;112(6):1312-1318. doi:10.1111/apa.16737
8. Lui GK, Saidi A, Bhatt AB, et al. Diagnosis and management of noncardiac complications in adults with congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2017;136(20):e348-e392. doi:10.1161/CIR.0000000000000535
9. Oeffinger KC, Fontham ET, Etzioni R, et al. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society [published correction appears in JAMA. 2016 Apr 5;315(13):1406. doi: 10.1001/jama.2016.3404.]. JAMA. 2015;314(15):1599-1614. doi:10.1001/jama.2015.12783