Cardiotoxicity in Breast Cancer Patients

Breast cancer is a malignant tumor that originates in the cells of the breast tissue. It is the most common cancer in women worldwide, accounting for 24.2% of all cancer cases among women.

According to the latest World Health Organization statistics, there were an estimated 2.3 million new cases of breast cancer in 2020; it is the second leading cause of cancer death in women after lung cancer.

In Egypt, breast cancer is the most common malignancy in women, accounting for 38.8% of cancers in this population, with the estimated number of breast cancer cases nearly 22,700 in 2022 and forecasted to be approximately 46,000 in 2050.

Anthracyclines are well-established and highly effective anti-neoplastic agents, used to treat several adult and pediatric cancers, such as breast cancer, leukemia, lymphomas, sarcomas, and many others.

Anthracycline-induced cardiotoxicity typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic congestive heart failure (CHF).

Acute anthracycline cardiotoxicity - occurs during or immediately after a single dose of an anthracycline. It may manifest as ventricular dysfunction, ECG abnormalities and arrhythmias.

Cardiotoxicity as a result of anthracycline chemotherapy has been linked to increased morbidity and mortality in breast cancer patients.

In a recently published cohort study, 2000 cancer survivors were monitored over 7 years. The authors found that approximately one-third of deaths could be attributed to long-term cardiotoxicity.

The specific mechanisms of anthracycline cardiotoxicity by Oxidative stress, which in the presence of iron, generates reactive oxygen species that cause lipid peroxidation of the cell membrane leading to damage of the cardiomyocytes, inflammation by up-regulating the levels of various inflammatory mediators, including interleukin-1 and tumor necrosis factor-α in the heart, subsequently leading to cardiomyocyte damage, In addition, DOX activated the nod-like receptor pyrin domain containing 3 (NLRP3) in cardiomyocytes, promoting cardiomyocyte apoptosis and down-regulation of sirtuin and adenosine monophosphate-activated protein kinase (AMPK) activity which associated with cardiovascular disease by enhanced apoptosis and increased fibrosis. The cardiomyocyte has always been considered the main cellular target of anthracycline toxic effect in the heart, as their destruction results in the progressive development of cardiac dysfunction.

Since anthracyclines is known to cause cardiotoxicity as a side effect, a baseline echocardiogram (ECHO) is ordered for each patient before initiating anthracycline chemotherapy treatment as a standard of care. Additionally, follow-up ECHOs are conducted after starting the treatment cycles to detect any early signs of cardiotoxicity.

Sodium Glucose co-transport inhibitors (SGLT2i) have demonstrated significant cardioprotective effects beyond their glucose-lowering capabilities. Recent clinical studies have highlighted their ability to reduce cardiovascular events, such as heart failure and myocardial infarction, in diabetic patients.

The cardioprotective benefits are thought to arise from multiple mechanisms, including improved cardiac energy metabolism, reduced blood pressure, and decreased fluid overload. As a result, SGLT2i are emerging as a crucial therapeutic option not only for glycemic control but also for enhancing heart health, marking a promising advancement in the management of cardiovascular risks.

SGLT2i significantly reduces Systolic Blood Pressure (SBP) and arterial stiffness that leads to better oxygen consumption by myocardium and hence lowers the cardiac afterload. It also helps in reducing the body weight slightly. Additionally, dapagliflozin also contributes by lowering the plasma volume by diuresis i.e., the increased excretion of sodium and glucose in urine. Decreasing the inflammation pathway by modulating the activation of NLRP3 inflammasome, thereby attenuating the synthesis of proinflammatory cytokines and reduced levels of tumor necrosis factor-α and interleukins, decreasing oxidative Stress by attenuate the generation of reactive oxygen species and enhance antioxidant mechanisms by inhibiting NADPH oxidase (nicotinamide adenine dinucleotide phosphate hydrogen ) and enhance energy metabolism by up-regulating the expression or activity of AMPK and sirtuins.

In light of the demonstrated cardioprotective effects of SGLT2 inhibitors (SGLT2i) in heart failure patients, these agents have been integrated into standard heart failure clinical guidelines, irrespective of the patient's diabetic status. Considering the well-established cardiotoxicity associated with anthracycline use, a thorough literature review was conducted to explore the potential of SGLT2i as adjunctive therapy to mitigate cardiac toxicity in breast cancer patients undergoing anthracycline-based chemotherapy. However, the search yielded only preclinical evidence, which highlighted the promising role of dapagliflozin. Consequently, this clinical trial aims to evaluate the efficacy of dapagliflozin as adjunctive therapy in breast cancer patients receiving anthracyclines, with a specific focus on preventing or delaying the onset of cardiotoxicity.

Inclusion criteria

• patients with pathologically proved invasive breast carcinoma.
• Patients were indicated for anthracyclines containing adjuvant chemotherapy or new adjuvant anthracyclines.
• Renal function (eGFR > 30 mL/minute per 1.73 m2 )
• LVEF is more than 50 %
• Age ≥ 18 and ≤ 60 years old

Exclusion criteria

• patients with any cardiac condition that contraindicate the use of anthracyclines, like heart failure, arrythmia, stroke and myocardial infarction.
• Previous anthracycline-containing regimens and any cardiotoxic chemotherapy regimens
• pregnant or breastfeeding patients
• patients receiving any other cardiotoxic agents.
• Patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Mediastinal irradiation including heart.
• Refusal to sign the written informed consent.