Frailty

Corresponding Author

Advances in the treatment of breast cancer have improved survival. However, in certain patients, highly effective treatments, such as anthracyclines and HER2-targeted therapies, exert profound and multifaceted perturbations on the cardiovascular system, depleting cardiovascular reserve and accelerating the onset and progression of cardiotoxicity. Cardiotoxicity is associated with diminished quality of life, increased morbidity, and premature mortality. As a result, certain patients are cured of their cancer only to face long-term, treatment-related cardiotoxicity that compromises the quality and length of their survivorship. Despite the recognized impact of cardiotoxicity on noncancer mortality, no definitive pretreatment markers or robust predictive models have been established in clinical practice to identify patients at increased risk for cardiotoxicity, limiting our ability to develop targeted strategies to mitigate or attenuate this risk and, ultimately, improve survivors’ long-term health outcomes.

Most of what we know about pretreatment risk assessment of cardiotoxicity comes from studies of clinical, imaging, or blood-based markers, individually or in combination. However, few studies have explored markers of biological aging, such as frailty.¹ Frailty, a fundamental concept in aging research, is defined as a state of reduced physiological reserve resulting from age-related damage at the molecular, cellular, and organ levels. Unlike chronological age or comorbidities, frailty measures health status at the level of the person as a whole, offering better insight into an individual’s biological or functional age, their physiological reserve, and their capacity to recover and adapt to stressors. In survivors of childhood cancer and older adults with cancer, frailty has also been associated with increased risks for treatment-related toxicity, functional decline, and premature death.^2,3 However, whether frailty could serve as a pretreatment marker of cardiotoxicity in patients with cancer remains largely unexplored.

In a study reported in this issue of JACC: CardioOncology, Yang et al⁴ evaluated the association between pretreatment frailty and cardiotoxicity in a racially and ethnically diverse cohort of more than 2,000 women with breast cancer from the OneFlorida+ clinical research network. Women were diagnosed between 2012 and 2022, underwent surgery within 1 year of diagnosis, and received adjuvant chemotherapy and targeted therapy, including anthracyclines, HER2-targeted therapy, CDK4/6 therapy, and fluoropyrimidines. The primary outcome was a composite of new nonfatal cardiovascular events during adjuvant therapy, including heart failure, cardiomyopathy, and arrhythmias, including atrial fibrillation and atrial flutter, as determined by International Classification of Diseases (ICD) codes. Censoring occurred at 90 days after the last date of adjuvant therapy or at a maximum of 730 days of follow-up. Frailty was measured using a previously validated electronic health record–derived frailty index (eFI), consisting of diagnoses, laboratory test results, and vital signs. Participants were classified as robust, prefrail, or frail. To avoid confounding, diabetes and hypertension were excluded from the eFI but included as covariates in the final analysis.

Overall, 20% of participants experienced nonfatal adverse cardiovascular events during or within the first 90 days after adjuvant therapy. The most frequent adverse event was cardiac arrhythmia, followed by heart failure and cardiomyopathy. After multivariable adjustment, participants who were prefrail (32% of the cohort) or frail (6% of the cohort) had a higher likelihood of experiencing adverse cardiovascular events compared with patients who were robust. An interaction between eFI and race/ethnicity revealed that higher frailty levels were associated with greater cardiotoxicity risks among non-Hispanic White and Black patients but not in other racial/ethnic groups.

We commend the investigators of this study for tackling a new, important area of research at the interface of cancer, aging, and cardiology. This is one of the first and largest studies to evaluate frailty and cardiotoxicity, with a diverse cohort including 23% non-Hispanic Black and 29% Hispanic participants. Notably, 13% lived in nonurban areas, 72% were on Medicaid or uninsured, and 26% resided in areas with high poverty. These demographics, often underrepresented in clinical trials, are a significant strength.

This study has important implications. First, pretreatment frailty status may serve as a marker of cardiotoxicity risk in patients undergoing adjuvant systematic treatments for early-stage breast cancer. One possible mechanism to explain this finding is that cardiotoxic treatments accelerate biological aging, making patients with higher markers of biological aging (eg, frailty) more susceptible to age-related adverse events of cancer treatment (eg, accelerated onset and progression of cardiotoxicity).⁵ Increasing evidence suggests that adjuvant systemic treatments, such as anthracyclines, accelerate biological aging.^6,7 Preclinical studies in mice indicate that doxorubicin-induced cellular senescence, a process in which cells stop dividing but remain metabolically active, contributes to inflammation, tissue damage, and cardiac dysfunction.⁸ Removing senescent cells in these models reversed inflammation and cardiac dysfunction. Patients who are frail prior to treatment may have a greater burden of senescent cells, rendering them more vulnerable to accelerated aging and cardiotoxicity.⁹ Additional research at the intersection of cancer, aging, and cardiovascular comorbidity is needed to elucidate these mechanisms and inform biology-driven, precision strategies for risk assessment and intervention.

Second, this study underscores the potential benefit of incorporating biological aging markers such as frailty in the clinic. Geriatric assessment (GA) is now guideline recommended for the routine evaluation and management of older adults receiving systemic therapy, given GA’s ability to inform treatment decisions, reduce chemotherapy-related toxicity, and improve quality of life.¹⁰ Although this study did not include a traditional GA, many of the variables used in the eFI are also in the GA and, thus, extend current literature by demonstrating that these tools may help clinicians tailor treatments by balancing the benefits of aggressive cancer therapies with their cardiovascular risks. Beyond improving treatment decision making, identifying prefrail and frail patients might also allow more enhanced cardiovascular monitoring (eg, increased serial cardiac imaging or blood-based cardiac biomarkers) during and after treatment, as well as testing of preventive cardioprotective interventions. However, further independent validation is critical before these results are incorporated into practice.

Third, the investigators observed variations in the relationship between frailty and cardiotoxicity risk across racial and ethnic groups, suggesting that frailty alone may not fully capture the complexity of risk factors influencing cardiotoxicity in diverse populations. These findings highlight the potential interplay among biological, social, and environmental determinants of health, which may vary across racial and ethnic groups. For example, differences in access to health care, socioeconomic status, and the prevalence of comorbidities could influence both baseline frailty and cardiovascular outcomes.¹¹ Additionally, genetic factors and varying responses to systemic therapies may also contribute to these disparities.¹² Future research is needed to better understand the interaction between frailty and race/ethnicity and to identify additional risk factors that may enhance precision in cardiotoxicity risk assessment. Such efforts will be critical to developing equitable, personalized strategies for mitigating cardiotoxicity risk.

Although the findings of this study are innovative and significant, we believe that at this time, they should be interpreted with caution and as hypothesis generating. The reliance on ICD codes to define the primary outcome of cardiovascular is an important limitation. Previous research has shown that ICD codes may lack specificity compared with adjudication by cardiologists.¹³ Natural language processing could enhance the accuracy of outcome assessments. Additionally, cardiomyopathy and heart failure may present beyond the 90-day follow-up window used in this study, particularly for anthracycline-related toxicities.¹⁴ This is important because, in a recently published single-center, retrospective analysis, frailty was not an independent risk factor for anthracycline-associated heart failure.¹ Additional research with longer follow-up is needed. Indeed, these findings highlight an urgent need for future studies to validate frailty as a predictive marker, explore its implementation in diverse clinical settings, and address health disparities that may influence outcomes.

In conclusion, this study underscores the potential value of integrating frailty assessments into the care of patients with early-stage breast cancer to enhance precision in cardiotoxicity risk stratification. By bridging science across intersecting fields, we can better understand the interplay between cancer treatments, biological aging, and cardiovascular health. As the population of cancer survivors grows, multidisciplinary approaches that incorporate markers of biological aging will be essential to advancing equitable, personalized care and improving long-term health outcomes for all patients with cancer and survivors.

Funding Support and Author Disclosures

Dr Sedrak is supported in part by grants K76AG074918, R21CA277660, and R01CA280088. Dr Asnani is supported in part by grant R01HL163172. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any other funders. Dr Sedrak has received research funding to the institution from Eli Lilly, Novartis, Seattle Genetics, and Pfizer Foundation (outside the submitted work). Dr Asnani is a member of the board of directors of Corventum; receives patent royalties from Mass General Brigham; and serves as the principal investigator of a sponsored research agreement with Genentech (all unrelated to the present work).