Sex-Specific Cardiovascular Risks of Cancer and Its Therapies

Abstract

In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies.

Gender Differences in Diagnosis, Prevention, and Treatment of Cardiotoxicity in Cardio-Oncology

“…As a therapeutic class, immune checkpoint inhibitors (ICIs) have recently emerged as a promising cancer therapy with increasingly diverse oncologic indications [ 33 ]. While ICI therapy has been a significant advance in the management of many malignancies, we are now aware of multiple immune-related adverse effects of ICIs, including cardiovascular toxicities [ 34 ].…”

“…The most well-known and documented cardiovascular effect of ICI use in humans is ICI myocarditis. ICI use has also been associated with pericarditis, vasculitis, and cardiac arrhythmias [ 33 ]. Given that widespread ICI use is a relatively recent phenomenon, data regarding gender differences in cardiovascular toxicities are limited.…”

“…Given that widespread ICI use is a relatively recent phenomenon, data regarding gender differences in cardiovascular toxicities are limited. Furthermore, the majority of clinical trials include only a small minority of female participants [ 33 , 36 ]. For example, in a meta-analysis of 20 randomized controlled trials with 11,351 participants treated with ICIs, only 33% of participants were women [ 36 ].…”

A Scientific Imperative as Seen Through a Sharpened Lens: Sex, Gender, and the Cardiovascular Condition

“…11 While continuing to expand our recognition of dissimilarities, we need to press forward and more deliberately interrogate mechanisms as well as implications. [11][12][13][14][15][16] Why do we consistently observe these differences and what do they mean for the future of cardiovascular health in females and males, not only as the population ages but also as previously presumed static entities such as atherosclerosis evolve over time-and as new disease types emerge, especially in the setting of new forms of systemic perturbations and stressors. To understand these important differences, we need to include sex-specific studies across all of our work, rather than treating this approach as part of a niche area of expertise.…”

How Common Is Pre-Existing Cardiovascular Disease in Cancer Patients

“…Advances in treatments have extended the life expectancy of patients with cancer through a reduction of cancer-related deaths. Patients with cancer have a significant burden of cardiovascular disease (CVD) due to shared risk factors, 1 similar pathophysiological processes, and adverse cardiovascular effects of chemoradiotherapy and other targeted treatments 2 with significant differences in the types of CVD among different cancer types. 3 Cancer patients have a >2-fold increase in the risk of CVD mortality compared with the general population, 4 with CVD the second most common cause of death after cancer itself.…”