Cardio-Oncology Investigations Begin to Uncover More Links Between CVD and Breast Cancer

Newer risk factors, prevention measures, and cancer treatments that may cause cardiovascular disease (CVD) are among several facets beyond well-known shared risk factors that are crucial to examine as research on the link between CVD and breast cancer advances. Findings have indicated that patients with CVD may be more likely to be diagnosed with advanced breast cancer and additional data have shown that patients with breast cancer have an increased incidence of CVD events.1,2

A study published in JAMA Network Open evaluated the presence of CVD among patients with stage I or II disease and stage III to IV disease, and propensity score–matched, multivariable-adjusted models revealed that those with locally advanced or metastatic breast cancer at diagnosis had statistically significant increased odds of experiencing prevalent CVD (OR, 1.10; 95% CI, 1.03-1.17; P = .007).1

“Heart disease is the number one killer of women. It is important for oncologists to know that there is a lot of progress in the cardiovascular space and more attention [to] and better understanding [of] unique cardiovascular risk factors for women,” Amy M. Ahnert, MD, director of the Women’s Heart Program at Morristown Medical Center and a cardiologist at Atlantic Health System in New Jersey, said in an interview with OncologyLive. “One of the most significant parts of this [study] is it shows us the importance of having a multidisciplinary, comprehensive approach when we’re looking at patients and trying to understand their illnesses/diseases [as well as] how to treat them and how to prevent [the diseases].”

Additionally, data from the same study showed that, among those with all receptor subtypes, ORs were directionally consistent when locally advanced (OR, 1.09; 95% CI, 1.02-1.17; P = .02) and metastatic (OR, 1.20; 95% CI, 0.94-1.54; P = .15) disease were examined separately.

“There are limitations of this study, because it was a database study, and therefore questions [remain]. What was the type of CVD? CVD is a big umbrella, it’s a very large encompassing term, and there are many different types of CVD—there’s congestive heart failure, coronary artery disease, arrhythmias, [and] valvular heart disease,” Ahnert noted. “When we lump it all [together] in one bucket, that’s a little challenging for me to say, ‘Is it all types? Is it one specific type? Is it CVD that’s been more severe? Is it a CVD that’s been more acute, more recent?’ Being able to track those very specific variables of what type of heart disease it is and looking at the different variables that the patient may have in terms of risk factors and treatments of CVD [is crucial].”

Which Patients With Breast Cancer May Be at a Higher Risk to Develop CVD?

Research has raised the possibility that the link between CVD and breast cancer may apply to patients with hormone receptor–positive and HER2-negative status in particular.1 When the primary analysis population (n = 19,292) of the retrospective, case-control study was stratified by receptor subtype, the association between locally advanced or metastatic breast cancer at diagnosis and prevalent CVD was observed in the hormone receptor–positive population (OR, 1.11; 95% CI, 1.03-1.19; P = .006) but not hormone receptor–negative (OR, 1.02; 95% CI, 0.86-1.21; P = .83).

“Most of this effect appears to be driven by the more indolent types of breast cancer [such as] the hormone receptor–positive, HER2-negative [cancers], the ones that grow more slowly,” Kevin T. Nead, MD, MPhil, study coauthor, said in an interview with OncologyLive. “We are trying to investigate further whether this effect of CVD on cancer might be stronger in the patients who have cancers that tend to stick around for a bit longer before presenting, so there’s more of an opportunity for that CVD to have an effect on the cancer itself.”

Investigators also noted these data should be interpreted with caution as the analysis had insufficient power to show a statistically significant differential association across breast cancer subtypes. However, Nead, who is an assistant professor in the Department of Epidemiology and Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center in Houston, noted that one could theorize that there’s less opportunity for CVD to have an impact in a patient with a faster-developing cancer.

“A slower-growing cancer might [sit] for a bit before it comes to awareness or is picked up on a mammogram,” he explained. “[There] might [be] a longer period of time for the CVD to create that immunosuppressive state and for that cancer to develop a bit more quickly because it’s not being surveilled by the immune system in the same way.”

Additionally, the study authors noted that investigations are needed to confirm these findings; future research should also work to determine interventions to improve patient outcomes, which may include personalized cancer screening.

“If you look at screening recommendations for breast cancer right now—[there’s] the US Preventive [Services] Task Force and the American Cancer Society, for example—it’s not all the same,” Nead said. “There is already variation and uncertainty in what age we should be screening [at and] how frequently we should be screening. Given that uncertainty, it’s reasonable to take into account some of these factors, even if they’re not 100% proven. For a patient who you may be considering screening more frequently or [who is] a younger age, if they have CVD, it’s reasonable to take that into account when you’re trying to decide which guidelines to follow as far as age to start and how frequently to do mammograms.”

Certain Conditions and Cancer Treatments Raise the Risk for CVD/Cardiotoxicity

Although it is well known that specific chemotherapy drugs and radiation therapy can result in cardiotoxicity, which has cre

ated the field of cardio-oncology, there are less well-known risk factors also affecting the risk of developing CVD, further supporting the need for multidisciplinary care, according to Ahnert (Figure). Research shows that having high blood pressure during pregnancy increases someone’s risk of developing CVD by 67%, and gestational diabetes raises the risk of CVD later in life by 68%.3 Further, those who had preeclampsia are 75% more likely to die of CVD later in life. Overall, women who experienced hypertensive disorders of pregnancy or gestational diabetes mellitus have a 2- to 3-fold increased risk of having CVD.4

Additionally, the Pathways Heart Study found that with more than a 7-year average follow-up (range, < 1-14 years), women who received anthracyclines and/or trastuzumab (Herceptin) were at high risk for heart failure/cardiomyopathy relative to those without breast cancer; the highest risk was observed among women who received anthracyclines as well as trastuzumab (HR, 3.68; 95% CI, 1.79-7.59).2 Patients with breast cancer (n = 13,642) were matched to women without breast cancer (n = 68,202) in this study, and those who had received prior radiation therapy (HR, 1.38; 95% CI, 1.13-1.69) and an aromatase inhibitor (HR, 1.31; 95% CI, 1.07-1.60) were at high risk of heart failure and/or cardiomyopathy relative to those who did not have breast cancer. The study also noted there were elevated risks for stroke, arrhythmia, cardiac arrest, venous thromboembolic disease, CVD-related death, and death from any cause based on cancer treatment received in those with breast cancer.

“The good news is that we’re starting to understand that these specialties need to interact, but we’ve thought that it’s probably in one direction, that it’s cancer treatments [that] may then cause toxicity to the heart,” Ahnert said. “This is opening up my mind to say maybe it’s a 2-way street. It may not be just linear that breast cancer treatments increase [the] risk of CVD, but maybe CVD also influences breast cancer and breast cancer outcomes. We’re going to need more definitive studies to fully understand [this], but [there] is proof-of-concept that the diseases are related.”

Furthermore, findings from a retrospective cohort study of women diagnosed with first primary unilateral breast cancer (n = 10,211) showed that women who were given anthracyclines and/or trastuzumab had a higher risk for CVD compared with those who had not received chemotherapy (adjusted HR, 1.53; 95% CI, 1.31-1.79).5 Additionally, up to 16% of women younger than 65 years who were treated with anthracyclines and/or trastuzumab developed CVD within 10 years.

Parsing Through Additional Links Between the Diseases and Next Steps

Shared risk factors for breast cancer and CVD, including well-known risk factors such as smoking, poor diet, and lack of exercise, stress the importance of considering additional aspects that may link these diseases.6 A German breast cancer case-control study noted the importance of monitoring and prevention for CVD, which is the leading cause of death worldwide.7 At a median follow-up of 16.1 years, data from the study demonstrated a significant association between CVD and cancer mortality in those at least 65 years of age. Among the 3555 women with primary stage I to III breast cancer or in situ carcinoma and 7334 control individuals who were breast cancer-free at recruitment, CVD was identified as a risk factor for all-cause mortality in patients younger than 65 years (HR, 1.22; 95% CI, 0.96-1.55 and HR, 1.79; 95% CI, 1.43-2.24, respectively) and at least 65 years old (HR, 1.44; 95% CI, 1.20-1.73 and HR, 1.59; 95% CI, 1.37-1.83, respectively). Patients included in the study were 50 to 74 years old.

“Designing a trial where we can be very clear so that we can better prove cause and effect would be one [important future action], and also making sure that the trial is inclusive,” Ahnert said. “That’s the next step and where we’re headed; that’s going to then give us the final chapter in the book of being able to better understand the links, the cause, the 2-way street, and what to do about it.”

Nead noted that as the JAMA Network Open retrospective analysis doesn’t prove causality and is solely in breast cancer,1 “We would like to look at this in some additional cancers, looking at cancers that tend to be more aggressive and that tend to be less aggressive [to] see if we see this difference between more aggressively growing cancers and less aggressively growing cancers. If we see this same pattern in additional cancers, it’s going to give us more confidence that what we’re seeing is the truth, and it’s not some bias or confounding that we couldn’t completely account for.”

“This study reinforces that a heart-healthy lifestyle is benefiting both cardiovascular health and [likely] the risk of being diagnosed with cancer and also potentially how aggressive that cancer is at diagnosis,” Nead added. “At the end of the day, it comes down to prevention and helping people lead a lifestyle that’s going to help keep them from having cancer in the first place. A heart-healthy lifestyle can go a long way. The most common causes of death in the US are CVD and cancer.”

References

1. Angelov I, Haas AM, Brock E, et al. Cardiovascular disease and breast cancer stage at diagnosis. JAMA Netw Open. 2025;8(1):e2452890. doi:10.1001/jamanetworkopen.2024.52890
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: the Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi:10.1200/JCO.21.01736
3. Heart disease & pregnancy. Cleveland Clinic. Updated August 4, 2022. Accessed January 27, 2025. bit.ly/4hzCSUl
4. Quansah DY, Lewis R, Savard K, et al. Cardiovascular disease risk factor interventions in women with prior gestational hypertensive disorders or diabetes in North America: a rapid review. CJC Open. 2023;6(2Part B):153-164. doi:10.1016/j.cjco.2023.12.015
5. Vo JB, Ramin C, Veiga LHS, et al. Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors. J Natl Cancer Inst. 2024;116(8):1384-1394. doi:10.1093/jnci/djae107
6. The link between breast cancer and heart disease. Oregon Health & Science University’s Center for Women’s Health. Accessed January 27, 2025. bit.ly/40PMoNF
7. Möhl A, Behrens S, Flaßkamp F, et al. The impact of cardiovascular disease on all-cause and cancer mortality: results from a 16-year follow-up of a German breast cancer case-control study. Breast Cancer Res. 2023;25:89. doi:10.1186/s13058-023-01680-x