Evaluation of Possible Safety and Efficacy of Fenofibrate in the Prophylaxis of Doxorubicin Induced Cardiotoxicity in Breast Cancer Patients

Breast cancer represents the most frequently diagnosed malignancy and the second most common cause of cancer death worldwide (Sung et al., 2021). 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 2020 and forecasted to be approximately 46,000 in 2050 (Ibrahim et al., 2014).

Doxorubicin (DOX) is a cytotoxic agent that is commonly used for treatment of breast cancer. Despite its effectiveness, doxorubicin is associated with cumulative and potential cardiotoxicity (Rawat et al.,2021).

Although the precise mechanisms whereby DOX induces myocardial injury have not been fully elucidated, it is widely accepted that DOX induces cardiac injury via several mechanisms, including activation of nuclear factor- Kabba B (NF-ĸB), the induction of pro-inflammatory cytokines, the generation of free radicals, the promotion of apoptotic cell death, and the suppression of Endothelial progenitor cells (EPC) mobilization and function, which are typical changes observed in DOX-induced cardiotoxcity (Cardinale et al., 2020).

Peroxisome proliferator-activated receptor-α (PPARα) has been proposed as a key lipid metabolism modulator and regulator of inflammation. There are three isotypes of PPAR (α, β and ȣ) which have distinct but overlapping functions. Fenofibrate, an important PPAR- α agonist, is widely used in in the treatment for hypercholesterolemia and hypertriglyceridemia (Kim and Kim, 2020). Many studies demonstrated the pleiotropic effects of fenofibrate on the heart that afford direct myocardial protection in addition to the lipid-lowering effects through improvement of vascular endothelial function, reducing oxidative stress and increasing endothelial nitric oxide synthase (eNOS) activation (Walker et al., 2012; Jen et al., 2016).

In addition recent animal study showed that fenofibrate decreased the transactivation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activated endothelial nitric oxide synthase (eNOS) and increased nitric oxide (NO) bioavailability, which in turn suppressed MMP-2 (matrix 4 metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9), a well-recognized mediator of adverse ventricular fibrosis and subsequent remodeling, which established the role of fenofibrate against DOX-induced cardiotoxicity in mice (Huang et al., 2021). In addition, it is known that DOX- increases circulating N-terminal pro-B-type natriuretic peptide (NT- pro-BNP) and B-type natriuretic peptide (BNP) that were attenuated by fenofibrate (Huang et al., 2021)

Inclusion criteria

• Age ≥ 18 years old.
• Patients with biopsy confirmed diagnosis breast cancer and with stage II and stage III breast cancer according to the American Joint Committee on Cancer (TNM staging system of breast cancer).
• Patients with performance status <2 according to Eastern Cooperative Oncology Group (ECOG) score.
• Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin level ≥ 10 g/dl).
• Patients with adequate liver function (serum bilirubin < 1.2 mg/dl) and adequate renal function (serum creatinine < 1.5 mg/d).

Exclusion criteria

• Patients with prior exposure to anthracyclines in the last 6 months.
• Patients with evidence of metastasis at the initial assessment.
• Concomitant use of antioxidant vitamins (vitamin A, C, E).
• Presence of clinical evidence for severe cardiac illness (angina pectoris, uncontrolled hypertension, arrhythmias and left ventricular ejection fraction <50%).
• Patients with inflammatory diseases (ulcerative colitis, rheumatoid arthritis).
• Patients with conditions associated with oxidative stress (smoking, tuberculosis, comorbid obesity).
• Patients who are candidates for monoclonal antibodies such as Trastuzumab and other targeted therapy (HER2 positive patients).
• Patients with active liver disease (cirrhosis, fatty liver, hepatitis C, etc..).
• Patients with myopathy.
• Patients with renal impairment, including those with end-stage renal disease and those receiving dialysis.
• Pregnant and breast feeding women.
• Known allergy to the fenofibrates.
• Concurrent use of statin, colchicine, ciprofibrate, idelalisib, ivacaftor, aspirin low strength, clopidogrel, warfarin, enzyme inducers (phenytoin, phenobarbitone, carbamazepine,…), enzyme inhibitors (allopurinol, MAOI, SSRI,…), drugs with high plasma protein binding capacity (sulfonamides, valproate, oral hypoglycemic, warfarin,…) in order to avoid potential pharmacodynamics and pharmacokinetic drug interactions.