The importance of cardiovascular disease in breast cancer survivors. mini review

doi:10.15406/IJFCM.2022.06.00273

International Journal of

eISSN: 2577-8269

Family & Community Medicine

Mini Review Volume 6 Issue 3

The importance of cardiovascular disease in breast cancer survivors. mini review

Hector Raul Gonzalez-Sanchez,¹ Jose Luis Torres-Cuevas,¹

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Karen María Kortright Maldonado,¹ Guillermo Enrique Chan-Puga,¹ Jose Luis Torres-Escalante²

¹Department of Internal Medicine, Hospital General Dr. Manuel Gea González. Calz. de Tlalpan No. 4800, Sección XVI, Tlalpan, 14080, Mexico City, Mexico
²Department of basic sciences, School of Medicine of the Universidad Autonoma de Yucatan. Av. Itzaes No. 498, Centro, 97000 Mérida, Yucatan, Mexico

Correspondence: Jose Luis Torres-Cuevas, Department of Internal Medicine, Hospital General Dr. Manuel Gea González. Calz. de Tlalpan 4800, Sección XVI, Tlalpan, 14080, Mexico City , Mexico, Tel +529993155606

Received: May 26, 2022 | Published: June 9, 2022

Citation: Gonzalez-Sanchez HR, Torres-Cuevas JL, Kortright-Maldonado KM, et al. The importance of cardiovascular disease in breast cancer survivors. mini review. Int J Fam Commun Med. 2022;6(3):106-108. DOI: 10.15406/IJFCM.2022.06.00273

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Abstract

Objective: Breast cancer (BC) is the most frequent neoplastic disease in women. Recently, cardiovascular disease (CVD) has arisen as a non-cancer related mortality cause between breast cancer survivors. The aim of this paper is to establish the importance of CVD in BC survivors in order to draw attention to this public health problem so new strategies can be implemented in the future.

Methods: A PubMed research of the Mesh terms “Breast Neoplasms” and “Heart Disease Risk Factors” was made. Journals available to the Universidad Nacional Autónoma de México – U.N.A.M. (National Autonomous University of México) were revised. Of 130 articles, 52 were selected and were cited for this review.

Conclusion: Earlier detection rates and advances in breast cancer therapies have improved overall survival in BC patients. CVD is now an important cause of mortality in BC survivors. This might be explained by the conjunction of pre-existing CVD risk factors and cardiovascular injury secondary to cancer therapy.

Keywords: breast cancer, cardiotoxicity, cardiovascular risk, cardiovascular health in women

Introduction

Breast cancer (BC) is the most frequent neoplastic disease in women. It is the result of an unregulated proliferation of abnormal mammary cells, that culminates in a tumor. Without treatment it is highly mortal, but thanks to the understanding of the main pathophysiological and biomolecular alterations involved in the development of BC new therapeutic strategies have improved the overall survival, even if diagnosis is made in advance stages.^1–3

As Knisely et al. brightly exposed, cancer and cardiovascular diseases (CVD) have entered into a ‘clinical overlap’ era.⁴ In the last decade, the paradigm of CVD, the principal cause of death worldwide, has arisen between BC survivors.⁵ This might be explained by shared CVD and BC risk factors, the prothrombotic state of cancer itself, and treatment-associated cardiotoxic effects.^6–7

Given the high prevalence and increasing incidence of CV events in BC survivors, it’s important to train physicians in this knowledge in order to reduce the risk of CV events and improve quality of life for BC survivors.

Breast cancer and cardiovascular disease

BC has an annual world incidence of 2.26 million new cases. It is the second most frequent cause of death by cancer (just after lung cancer), with a mortality of 13.6 per 100,000 patients annually. However, mortality arises up to 74.4 per 100,000 when we evaluate women of 65 years of age or older.⁸

Earlier detection rates and advances in cancer therapies have improved overall survival in BC patients, which results in a growing survivor population that is at increased risk of other non-cancer related mortality causes, specifically CVD.⁹

Lee et al. proposed back in 2007 the “multiple hit hypothesis” in an attempt to explain the increased CVD risk in BC survivors. They affirm that 1.- CVD risk factors at the time of diagnosis, 2.-lifestyle perturbations and 3.- cardiovascular injury directly associated with cancer therapy collectively leave patients with overt or covert CVD. At a minimum, these insults enhance susceptibility to further cardiovascular injury and, ultimately, risk of premature CVD mortality.¹⁰

CVD risk factors at the time of diagnosis

Breast cancer and CVD have shared risk factors.^7,11 Risk of death from CVD is even higher in BC survivors with preexisting CVD risk factors at diagnosis, such as diabetes and hypertension, two of the most prevalent comorbidities in the general population.^12,13 The presence of CVD risk factors predicts CVD development regardless of breast cancer.¹⁴

Other well-known risk factors of CVD mortality in BC survivors are older age at diagnosis^15–17 and black ethnic origin.¹⁸ Women diagnosed with breast cancer over the age of 75 have nearly a 23-fold higher risk compared to women diagnosed before 55 years old.¹⁹ Smoking cessation followed BC diagnosis in up to 50% of the patients^20,21 however, quitting after diagnosis did not appear to reduce CVD risk.²²

Lifestyle perturbations

Lifestyle toxicity is a less recognized, but equally as pervasive a consequence of breast cancer diagnosis and therapy.¹⁹ BC patients self-report decreased enjoyment of food and selection of “less healthy food”.²³ Weight gain is commonly reported by women with breast cancer and only 10% return to their pre-diagnosis weight even after up to six years of follow-up.^24,25Being overweight or obese is a significant independent risk factor for CVD.²⁶

BC diagnosis also generates a wide spectrum of psychoaffective and economic disturbances in the patients affected and their family circle.^27–29Stress, depression and anxiety are associated with CVD through behavioral and biological mechanisms. Stress induces physical inactivity, poor diet and smoking habits, as well as triggers inflammation pathways.³⁰

Cardiovascular injury associated to BC therapy

Different breast cancer therapies are closely associated with cardiotoxicity,^15,19 resulting as a paramount cause of morbidity and mortality in BC survivors.^5,31,32

Anthracyclines stand out as frequently employed chemotherapy agents, which generate irreversible and dose-dependent myocardial damage by two different mechanisms: excessive production of reactive oxygen species (ROS) and formation of complexes with the TOP2-beta topoisomerase of cardiomyocytes culminating in the formation of fibrotic tissue, DNA mutations and necrosis.^33–35

Some of the sequelae described following the use of anthracyclines are heart failure, decreased left ventricular ejection fraction (LVEF), and arrhythmias such as atrial fibrillation and ventricular tachycardia.^36–39

Trastuzumab has been proven to effectively decrease mortality, recurrence and incidence of metastatic disease in HER2-positive BC.^32,40,41Trastuzumab-induced cardiotoxicity (TIC) is dose-independent and has been described as an asymptomatic reduction of the LVEF and occasionally as a symptomatic heart failure syndrome.⁵ There is no international consensus on the mechanisms of trastuzumab-induced cardiotoxicity. In vitro studies have proven that trastuzumab blocks the activity of type 1 Neuregulin, a protein that stimulates the sarcomere contractile function and its structure preservation.^42,43 Previously considered a reversible phenomenon after drug discontinuation, new evidence has demonstrated a long-term impairment of cardiopulmonary function and a permanent decrease in LVEF in up to 40% of BC survivors following trastuzumab administration.^44,45 Nonetheless, benefits still overcome the risks and long-term secondary effects.⁴⁶

Radiotherapy (RT) is widely used in BC. By exposure to x-rays, or γ-rays, RT induces DNA fragmentation and diminishes cell proliferation. Cardiotoxic effects of RT aren’t fully understood. However, endothelial injury and increased activity of proinflammatory cytokines, and release of ROS have been described following radiation.⁴⁷ Left-sided tumor is associated with more risk of cardiotoxicity secondary to radiotherapy, mainly because of its heart’s adjacency.^48–51 RT cardiotoxicity is mainly manifested as pericarditis, cardiomyopathy, valve disease, arrhythmias and coronary disease.⁵²

Different cancer treatment options affect in various manners CV structure and function. Alkylating agents may cause LV dysfunction, HF, myocarditis and arrhythmias. Endocrine therapy can cause venous thrombosis, atherosclerosis, dysrhythmias and HF. Cyclin-dependent kinase 4/6 inhibitors have shown QTc prolongation.³¹

Conclusion

At the present day, improved breast cancer survival has resulted in an augmented population of BC survivors at risk of CVD. After a thorough investigation, we couldn’t find guidelines that propose how to systematically evaluate cardiovascular risk and a follow-up protocol in BC survivors. Physicians should be able to recognize CVD risk factors in order to provide assertive strategies to prevent and treat CVD. New studies are necessary to establish evidence-based recommendations to prevent and decrease the risk of new cardiovascular events in BC survivors.