Can We Mitigate Coronary Heart Disease Risk in Patients with Cancer?

PURPOSE OF REVIEW: The review focuses on the shared risk factors observed between coronary heart disease and cancer, cancer therapeutics causing coronary heart disease, and potential strategies to mitigate atherosclerosis in patients with cancer. RECENT FINDINGS: The pathophysiology behind how traditional cardiovascular risk factors also contribute to cancer development and mortality is increasingly recognized. In addition, newer cancer therapies, such as immune checkpoint inhibitors, cause increased inflammation leading to increased cardiovascular events. Traditional coronary heart disease risk factors such as obesity, hypertension, diabetes, and hyperlipidemia also contribute to cancer development and worse cancer outcomes. Cancer therapeutics can also lead to atherosclerotic events in addition to the shared risk factors present at the time of cancer diagnosis. Understanding the pathophysiology, using multidisciplinary care teams, and developing machine learning algorithms for individualized patient care will help to mitigate the risk of coronary heart disease in patients with cancer.

Radiation-Induced Cardiovascular Disease: Mechanisms, Prevention, and Treatment.

PURPOSE OF REVIEW: Despite the advancements of modern radiotherapy, radiation-induced cardiovascular disease (RICVD) remains a common cause of morbidity and mortality among cancer survivors. RECENT FINDINGS: Proposed pathogenetic mechanisms of RICVD include endothelial cell damage with accelerated atherosclerosis, pro-thrombotic alterations in the coagulation pathway as well as inflammation and fibrosis of the myocardial, pericardial, valvular, and conduction tissues. Prevention of RICVD can be achieved by minimizing the exposure of the cardiovascular system to radiation, by treatment of underlying cardiovascular risk factors and cardiovascular disease, and possibly by prophylactic pharmacotherapy post exposure. Herein we summarize current knowledge on the mechanisms underlying the pathogenesis of RICVD and propose prevention and treatment strategies.

Kinase Inhibitors and Atrial Fibrillation: Mechanisms of Action and Clinical Implications.

Recent advances have significantly expanded the options of available therapeutics for cancer treatment, including novel targeted cancer therapies. Within this broad category of targeted therapies is the class of kinase inhibitors (KIs), which target kinases that have undergone aberrant activation in cancerous cells. Although KIs have shown a benefit in treating various forms of malignancy, they have also been shown to cause a wide array of cardiovascular toxicities, with cardiac arrhythmias, in particular atrial fibrillation (AF), being 1 of the predominant side effects. The occurrence of AF in patients undergoing cancer treatment can complicate the treatment approach and poses unique clinical challenges. The association of KIs and AF has led to new research aimed at trying to elucidate the underlying mechanisms. Furthermore, there are unique considerations to treating KI-induced AF because of the anticoagulant properties of some KIs as well as drug-drug interactions with KIs and some cardiovascular medications. Here, we review the current literature pertaining to KI-induced AF.

Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.

The insulin-like growth factor receptor (IGF-IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF-IR is over-expressed and hyper-phosphorylated. Additionally, microarray analysis has shown that IGF-I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF-IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF-I action in breast cancer cells. We show that genes regulated by IGF-I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF-I to regulate gene expression. IGF-I treatment of MCF7 cells increased the half-life of FOXA1 protein and this increase in half-life appeared to be dependent on canonical IGF-I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF-I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF-I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF-I regulation of gene expression and IGF-I-mediated biological responses.

Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth.

Although estrogen receptor alpha (ERα) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERα. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERα and IGF-IR signaling may require co-targeting of both pathways.

Outcomes by Class of Anticoagulant Use for Nonvalvular Atrial Fibrillation in Patients With Active Cancer.

Background: The choice of anticoagulant agent for patients with nonvalvular atrial fibrillation (NVAF) in the setting of active cancer has not been well studied. Objectives: The aim of this study was to compare the rates of cerebrovascular accident (CVA), gastrointestinal bleeding (GIB), and intracranial hemorrhage (ICH) in patients treated with direct oral anticoagulant agents (DOACs) compared with warfarin for NVAF in patients with active cancer. Methods: This was a retrospective electronic medical record review of eligible patients treated at a cancer hospital. The outcome events were CVA; GIB; ICH; the composite of GIB, CVA, or ICH; and overall mortality. Propensity score matching (1:1) was conducted to select comparable patients receiving warfarin vs DOACs. Fine-Gray models were fitted for each outcome event. Results: The study cohort included 1,133 patients (mean age 72 ± 8.8 years, 42% women), of whom 74% received DOACs (57% received apixaban). After propensity score matching, 195 patients were included in each anticoagulant agent group. When comparing warfarin with DOACs, there were similar risks for CVA (subdistribution HR: 0.738; 95% CI: 0.334-1.629); ICH (subdistribution HR: 0.295; 95% CI: 0.032-2.709); GIB (subdistribution HR: 1.819; 95% CI: 0.774-4.277); and the composite of GIB, CVA, or ICH (subdistribution HR: 1.151; 95% CI: 0.645-2.054). Conclusions: Patients with active cancer had similar risks for CVA, ICH, and GIB when treated with DOACs compared with warfarin for NVAF.