At the 2023 Global Cardio-Oncology Summit in Madrid, in a joint session with ASCO and the International Cardio-Oncology Society, Anita Arnold, DO, FACC, MBA, Director, Noninvasive Cardiology, and Director of Cardio-Oncology, Lee Memorial Health Systems, Fort Myers, Florida, discussed the cardiovascular health of women after cancer treatment.1 Also in that joint session, Krishnan Bhaskaran, PhD, Professor of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, UK, shared what we know (and don’t yet know) about potential sex differences regarding the association between a cancer history and cardiovascular disease.2
Heart Health After Cancer Treatment
Dr. Arnold first posed this question: What do female cancer survivors’ worry about? A strong fear of cancer recurrence, concerns about family and finances, changes in body image and sexuality, as well as managing their long-term health needs were among the top choices. However, she noted, “cardiovascular disease is not high on the list of things to be concerned about for most female cancer survivors.”
Anita Arnold, DO, FACC, MBA
Krishnan Bhaskaran, PhD
Yet data from many registries have shown these women should be paying attention to their heart health. For instance, a Canadian population–based study explored cardiovascular mortality following early-stage breast cancer.3 The investigators found that if a woman survived early breast cancer more than 5 years ago and was older than age 66 at around 10 years, cardiovascular mortality exceeded that of breast cancer. And, if they had prior cardiovascular disease, the mortality was higher, added Dr. Arnold.
To learn whether cardiovascular mortality overtakes cancer-specific mortality in cancer survivors—and, if so, when—authors of a retrospective cohort study recently presented their findings.4 The point in years when the cardiovascular disease mortality rate equaled the mortality rate from primary cancer was “anywhere from 4.8 years for bladder cancer to 17.4 years for lung cancer,” stated Dr. Arnold. Breast cancer, she added, “was kind of in the middle at around 12.7 years.”
Next, Dr. Arnold focused on cardioprotective steps that can be taken by cancer survivors. To begin, exercise has been found to yield several health benefits in patients with cancer after therapy. “With moderate to vigorous physical activity, not only do you have a lower risk for all-cause mortality, but cardiovascular diseases and cancer mortality decrease, too,” commented Dr. Arnold.
Furthermore, given the fact that between 20% and 60% of patients with cancer have hyperlipidemia, the role of statin therapy has received recent attention. In the STOP-CA randomized clinical trial, which focused on 300 patients with lymphoma receiving anthracyclines from centers in the United States and Canada, investigators explored whether the use of atorvastatin would result in a reduction in the number of patients who develop cardiac dysfunction.5 They reported atorvastatin treatment had a clinically significant benefit in preserving left ventricular ejection fraction. In addition, Dr. Arnold added, “studies have linked long-term cholesterol-lowering therapy to lower cancer risk and risk of metastatic disease.”
In closing, Dr. Arnold shared some recommendations centering on the need to be aware and aggressively treat all cardiovascular risk factors in cancer survivors. Collaboration among specialists caring for patients with cancer is essential. In addition, patients need to be educated about the benefits of risk factor modification and lifelong assessments. Participation in clinical cardio-oncology trials is also a major issue, she noted, to define and modify best practices in the years ahead. Finally, gaps in research must be addressed, Dr. Arnold, emphasized, as more information is needed to determine whether current therapies for heart failure would be of benefit to patients with cancer and whether women with cancer have a higher incidence of nonobstructive coronary artery disease.
Epidemiologic Perspective
Dr. Bhaskaran provided an epidemiologic status update on the current state of knowledge regarding sex differences regarding the relationship between cancer history and cardiovascular diseases. Many of the conclusions, he noted, are based on findings from studies of patients with cancer and cardiovascular diseases and are not necessarily specific to sex. “We have good epidemiologic data available for breast cancer, but we could do more on other cancers affecting women,” he acknowledged.
In a UK study of the medium- and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers,6 Dr. -Bhaskaran’s group focused on more than 125,000 cancer survivors—52.4% of whom were female—and more than 630,000 matched controls. With a follow-up from 1 year after cancer diagnosis, the risk of venous thromboembolism (VTE) was increased in survivors of 18 of 20 site-specific cancers, he noted. Adjusted hazard ratios ranged from 1.72 in patients with prostate cancer to 9.72 in patients with pancreatic cancer. Although hazard ratios decreased over time, he continued, they remained elevated more than 5 years after cancer diagnosis.
Increased risks for heart failure or cardiomyopathy were reported in those with hematologic malignancies, as well as in patients with esophageal, lung, kidney, and ovarian cancers. In addition, elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were observed for many cancers. “We saw large increased risks of VTE for almost all cancers including breast, cervical, uterine, and ovarian,” said Dr. Bhaskaran. Of interest, patients with breast cancer seemed to have better coronary artery disease outcomes than cancer-free controls. “We don’t think breast cancer is protecting anyone, but there’s probably some residual confounding,” he stated. However, that was not the case for patients with ovarian cancer, where there was a signal of a harmful relationship.
Finally, as for heart failure, there appeared to be a different pattern. “We see a slightly increased risk for breast cancer survivors compared with controls [in terms of heart failure],” according to Dr. -Bhaskaran, “and the same for ovarian cancer survivors.” The UK study also showed no “strong pattern” of a sex difference in either direction in terms of the relative risks for men and women with other cancers, he explained. Similar findings were reported this past year by Canadian researchers in a population-based cohort study.7
Dr. Bhaskaran then turned to sex-specific issues related to toxicities associated with cancer treatment. The most well-known cardiotoxicity related to cancer treatment is that linked to anthracyclines, which have been found to increase the risk of reduced left ventricular ejection fraction and subsequent clinical heart failure.6However, to determine whether women are particularly vulnerable to anthracycline toxicity, “we need to go outside of breast cancer, where we have some comparison,” Dr. Bhaskaran said.
Single-center study data from Massachusetts suggested that male sex was a risk factor in adults with cancer who received anthracyclines.8 These investigators reported a hazard ratio of 1.9 for symptomatic heart failure and cardiac death. However, he added, an opposite pattern has emerged in survivors of childhood cancer who were given anthracyclines, where the risk for clinical cardiotoxicity was higher in females.
In another study of sex-specific cardiovascular risks of cancer and its therapies by Wilcox et al,9 relative to male patients, the risk of anthracycline-induced cardiotoxicity was higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females.
As for the risks associated with endocrine therapies for cancer, “a few studies have found a higher risk for cardiovascular diseases in people getting aromatase inhibitors compared with tamoxifen,” noted Dr. Bhaskaran. However, another analysis of this group “changed the picture a little bit,” he said. “We still saw a higher risk of cardiovascular diseases in aromatase inhibitor users vs users of tamoxifen, but when we zoomed out to bring in the unexposed group, it looks like the aromatase inhibitor users have similar risks as those not receiving these drugs. And tamoxifen use was associated with a lower risk and seems to be somewhat protective here,” he said.
In the Wilcox study,9 the use of hormone therapies such as gonadotropin-releasing hormone modulators, androgen receptors, selective estrogen receptor modulators, and aromatase inhibitors was linked to cardiotoxicity, “but sex-based differences have not yet been elucidated,” said Dr. Bhaskaran. As for immunotherapy, he added, there is limited evaluation of sex-based differences, although some studies suggest females may be at increased risk for immune checkpoint inhibitor–related myocarditis.
DISCLOSURE: Dr. Arnold reported no conflicts of interest. Dr. Bhaskaran has received funding from Wellcome, the British Heart Foundation, and the Medical Research Council.
REFERENCES
1. Arnold A: Women’s cardiovascular health after cancer. 2023 Global Cardio-Oncology Summit. Presented September 29, 2023.
2. Bhaskaran K: Epidemiology of cancer and cardiovascular diseases in women. 2023 Global Cardio-Oncology Summit. Presented September 29, 2023.
3. Abdel-Qadir H, et al: A population-based study of cardiovascular mortality following early-stage breast cancer. JAMA Cardiol 2:88-93, 2017.
4. Strongman H, et al: Does cardiovascular mortality overtake cancer mortality during cancer survivorship? JACC CardioOncol 4:113-123, 2022.
5. Neilan TG, et al: Atorvastatin for anthracycline-associated cardiac dysfunction. JAMA 330:528-536, 2023.
6. Strongman H, et al: Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers. Lancet 394:1041-1054, 2019.
7. Paterson DI, et al: Incident cardiovascular disease among adults with cancer. JACC CardioOncol 4:85-94, 2022.
8. Wang L, et al: Major cardiac events and the value of echocardiographic evaluation in patients receiving anthracycline-based chemotherapy. Am J Cardiol 116:442-445, 2015.
9. Wilcox NS, et al: Sex-specific cardiovascular risks of cancer and its therapies. Circ Res 130:632-651, 2022.
