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A look at CV effects of novel cancer therapies
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During the past decade, an explosion of novel cancer therapies has led to a significant increase in cancer survivorship. However, CVD is a leading cause of morbidity and mortality in patients with cancer treated with therapies as well as cancer survivors, which number 15.5 million Americans today. Several factors contribute to this, including CV and cardiometabolic toxicities from cancer treatments themselves.
Most cardiologists are familiar with the CVD profiles associated with traditional therapeutic strategies such as anthracyclines and radiation therapy. However, several novel therapies have been developed, including targeted tyrosine kinase inhibitors (TKIs), multitargeted TKIs, hormonal deprivation therapy, immunomodulatory drugs, proteasome inhibitors and immune checkpoint inhibitors. These agents have their own unique CVD profiles. Cardiologists will benefit from knowledge of the specific cardiac effects of these agents.
Here, we provide a brief overview of the cardiac toxicities associated with novel cancer therapies. Future articles within this series will provide detailed and mechanistic-based information for each novel therapeutic class.
Targeted TKIs
HER2 antagonists
A subset of breast cancer overexpresses a kinase receptor and growth factor called HER2 (also called erB2). Inhibition of HER2, by disrupting intracellular tyrosine kinase signaling essential for cell growth and survival, is a new therapy for this subset of breast cancers. Trastuzumab (Herceptin, Genentech) was the first drug in this class. Cardiomyopathy is a well-recognized side effect of HER2 inhibitors, specifically leading to an asymptomatic decrease in left ventricular ejection fraction with a smaller subset of patients developing clinical HF. Patients treated with HER2 inhibitors need to undergo serial cardiac monitoring during treatment.
VEGF inhibitors
VEGF promotes angiogenesis, cell survival and cell proliferation. Inhibition of VEGF receptor has proved an effective therapy for numerous cancer types. There are now at least 12 new FDA-approved drugs in this class, with many more under investigation. Bevacizumab (Avastin, Genentech) was the first approved drug in this class and is a monoclonal antibody against VEGF that is administered intravenously. The majority of these drugs, however, are small molecular inhibitors that are taken orally. VEGF inhibitors can result in CV complications, including hypertension, proteinuria, HF, thrombosis and hemorrhage. Of these, hypertension is the most common, occurring in at least one-quarter of the patients. Cardiomyopathy is less common, occurring in about 10% to 15%. Various algorithms have been developed to treat these cardiac complications, including the hypertension.
Multitargeted TKIs
Multitargeted TKIs are small-molecule inhibitors that can block multiple tyrosine kinases. Depending on the kinase target, the CV toxicities of these drugs can be different. In some cancer types, TKIs have made a huge impact. For example, in chronic myeloid leukemia (CML) TKI therapy has increased 5-year survival rate to greater than 90%. Pulmonary hypertension, arrhythmias and vascular events have been associated with these agents. In CML, for example, dasatinib (Sprycel, Bristol-Myers Squibb/Otsuka Pharmaceuticals) is associated with pulmonary hypertension and pericardial (and pleural) effusions; nilotinib and dasatinib are associated with increased vascular events, including coronary, cerebral and peripheral events.
Hormonal deprivation therapy
Androgen deprivation therapy (ADT) is used to block activation of the androgen receptor in prostate cancer cells, which require androgen hormones (such as testosterone) to grow. Up to 50% of patients with prostate cancer receive ADT during treatment. Traditional therapies in this class affect the pituitary — so-called gonadotropin-releasing hormone receptor agonists, like leuprolide (Lupron, AbbVie) — while newer classes of drugs work via adrenals and directly on the androgen receptor. ADT has been associated with aberrations in metabolic profile, including worsening insulin resistance, LDL, triglyceride levels and increased body fat composition. In 2010, the American Heart Association released a statement recommending assessment of risk factors for metabolic and cardiac disease during treatment with ADT.
Immunomodulatory drugs and proteasome inhibitors
Immunomodulatory drugs and proteasome inhibitors have revolutionized treatment of certain cancer types such as multiple myeloma. Both classes of drugs work by affecting protein degradation in the cellular machinery; however, both are associated with CVD. Immunomodulatory drugs (eg, lenalidomide [Revlimid, Celgene]) can lead to venous and arterial thrombosis, necessitating prophylaxis in high-risk patients. Proteasome inhibitors such as carfilzomib (Kyprolis, Amgen) can cause a number of CVDs, including cardiomyopathy, arrhythmia, hypertension and thrombosis.
Immune checkpoint inhibitors
Arguably, the fastest-emerging group of cancer therapies is immunotherapies. One group of such therapies, so-called immune checkpoint inhibitors, harness the immune system to attack the cancer cells and have proved effective in a number of different cancer types, including lung cancer and melanoma. However, recent reports suggest a small subset of patients treated with immunotherapies can have myocarditis. The FDA will be hosting a 1-day symposium on Dec. 1, bringing together world experts in this area given the fulminant nature of this side effect.
Personalized cardio-oncology
The diversity of novel cancer therapies and their unique CVD profiles suggest that a personalized approach must be incorporated into patient care. This has resulted in the new field of cardio-oncology. Multiple cardiology centers now have cardio-oncology physician groups to specifically address CVD in patients with cancer with considerations for the cancer type, cancer therapies and therapy-associated CVD profiles.
- For more information:
- Wendy Bottinor, MD, is a cardio-oncology fellow in the division of cardio-oncology at Vanderbilt University Medical Center. She can be reached at wendy.bottinor@vanderbilt.edu.
Disclosure: Bottinor reports no relevant financial disclosures.
This is a new column that will appear regularly in Cardiology Today. The authors will address the growing attention on the intersection between cardiology and oncology care.