Cardiotoxicity associated with trastuzumab and chemotherapy used for HER2-positive cancers

Breast cancer is the most common cancer in women worldwide, and only lung cancer causes more cancer deaths in women.^1,2 But a better understanding of the disease biology and hallmark advancements in the treatment of breast cancer have resulted in reducing breast cancer deaths.² While the outstanding achievement of novel targeted therapies has improved disease outcomes,² the side effect of impaired cardiac function is an area of current study and a continuing concern for physicians and patients.^3,4

The global burden of breast cancer 

The human, social, and economic costs of breast cancer are staggering. In the United States alone, direct costs in 2010 for breast cancer care were $16.5 billion spent on medications, hospitalizations, and surgical interventions.⁵

Breast cancer survival rates vary greatly worldwide, ranging from over 80% in North America, Sweden, and Japan, to less than 40% in resource-limited countries.¹ Low survival rates in less developed countries may be exacerbated by lack of access to healthcare resources for early detection and diagnosis, resulting in patients presenting with late-stage disease.¹ Patients with early diagnosis of localized disease have a 98% 5-year survival rate, compared with only 24% for those with metastasized disease.⁵

Advancements in testing and treatment

Treatment options today include radiation, lumpectomy, mastectomy, chemotherapy, or a combination of those options.⁵ Chemotherapy for breast cancer includes traditional chemotherapy, hormonal therapy, and targeted therapy.⁵ The death rate from breast cancer has decreased since 1990, as researchers have learned more about the genetic changes in cells that lead to cancer, and newer drugs have been designed that specifically target those changes.^1,5

Researchers have discovered that there are four distinct types of breast cancer, each with its own genetic pattern.⁵ These classifications provide information on how the tumor acts and what kind of treatments may work best in each case. Breast cancers can be classified according to hormone receptors and human epidermal growth factor receptor-2 (HER2) status:⁵ 

• Endocrine receptor (estrogen or progesterone receptor) positive
• HER2-positive
• Triple negative, not positive to receptors for estrogen, progesterone, or HER2
• Triple positive, positive for estrogen receptors, progesterone receptors, and HER2

Approximately 70% of breast cancer tumors express a hormone receptor (estrogen or progesterone), and about 20% demonstrate HER2 overexpression.^3,5 In HER2 positive cancer, the cancer cells have elevated cell surface levels of the HER2/neu growth-promoting protein.⁶ HER2/neu is expressed on both normal and cancer calls; however, cancer cells exhibit gene amplification and/or protein overexpression. Excess HER2/neu levels in breast cancer are associated with more aggressive disease and a poor prognosis without targeted treatment.^3,6

Significant advancements in breast cancer treatment occurred in two hallmark eras: hormonal therapy was introduced in the 1980s as a treatment for estrogen or progesterone positive breast cancer, and trastuzumab was introduced in the 1990s as a targeted therapy in the treatment of HER2- positive breast cancer.⁶ Patients with breast cancer that is tissue-positive are eligible for treatment with HER2-targeted therapies, such as trastuzumab.⁶ 

Trastuzumab is a monoclonal antibody drug that attaches to HER2 and can help slow the growth of cancer cells with too much HER2.⁶ It may also stimulate the immune system to more effectively attack the cancer.⁶ Often used as adjuvant (post-surgical) therapy for HER2-positive cancers to reduce the risk of reoccurrence of the cancer, trastuzumab may be given with chemo at first, and then on its own, usually for a total of a year of treatment.⁶ Trastuzumab may also be started before surgery as neoadjuvant therapy, and is also used to treat HER2-positive advanced breast cancers that return after treatment or continue to grow during treatment.⁶

Trastuzumab and heart failure

A potential side effect of trastuzumab is heart damage that can lead to congestive heart failure.^3,6 This effect can be temporary and can subside when the drug is stopped.⁶ The risk of heart damage is highest when trastuzumab is given with certain chemo drugs, such as the anthracyclines, which are among the most commonly used chemotherapeutic agents.^3,6 Monitoring breast cancer patients for signs of heart failure, effectiveness of aggressive treatments, and reoccurrence of metastasis is key to maintaining quality of life for patients. 

Serum HER2/neu, the cleaved extracellular domain of the HER2/neu oncoprotein, circulates in the bloodstream, and its functions include driving cell growth. An automated, FDA-cleared, serum HER2/neu assay is available to be used in the quantitative determination of the HER2/neu protein in human serum.⁷

Serum HER2/neu levels can be used to monitor metastatic breast cancer patients whose status determined by tissue testing is either HER2/neu positive or HER2/neu negative, and as an aid in monitoring metastatic breast cancer patients treated with chemotherapy, hormonal therapy, radiotherapy, and HER2/neu-targeted therapies.^8-11 If a baseline level is greater than 15 ng/ml, the patient can be monitored on a regular basis using serum HER2/ neu. If the baseline is less than 15 ng/ml, it may be useful to test periodically to monitor for levels that increase to greater than 15 ng/ml.^7,8,10,11 

While the clinical utility of the measurement of HER2/neu in serum as a prognostic indicator of early recurrence and in the management of patients on immunotherapy has not been fully established, increasing serum HER2/neu levels are associated with disease progression, and decreasing levels are associated with response to therapy.^8-12 Ali et al. demonstrated that a lack of a significant (> 20%) decrease in levels was associated with lower overall survival, shorter duration of response, shorter time to progression, and lower response rates.⁸ Additional studies demonstrated better survival in patients whose levels remained less than 15 ng/ml (median survival 48 months), compared to patients whose levels exceeded 15 ng/ml consistently or at any point in the observation period.^9,13 Serum HER2/neu values should be used in conjunction with information available from clinical and other diagnostic procedures in the management of breast cancer.

The specter of cardiotoxicity

With advancements in cancer treatments and the general aging of the population, the number of patients with oncological and cardiological comorbidities is increasing. In the U.S. alone, more than 2.2 million women are now breast cancer survivors.¹⁴ It would be tragic indeed to survive breast cancer only to face heart failure as a latent impact of anticancer treatments. 

Cardiac events may occur during or shortly after cancer treatment, within days or weeks, or may not be apparent for months and sometimes years after completion of chemotherapy and radiotherapy. A recent population-based, eight-year retrospective cohort study by Bowles et al. of 12,500 women diagnosed with incident, invasive breast cancer demonstrated that the overall risk of incident heart failure and/or cardiomyopathy (HF/CM) was statistically significantly increased among women who used anthracycline alone compared with no chemotherapy, but the overall risk of incident HF/CM was even greater among women who used trastuzumab.³ Compared with women who received no chemotherapy, the study’s hazard ratios suggest a fourfold increase in the risk of HF/CM among women who received trastuzumab alone, and a sevenfold increase in the risk of HF/CM for those who received anthracycline plus trastuzumab.³ Major symptoms of heart failure are shortness of breath, leg swelling, and severe fatigue.⁶

Because of a concern that clinical symptoms and left ventricular dysfunction may signal that cardiac damage has already occurred, researchers continue to investigate whether cardiac biomarkers can serve as early warning of cardiac impact from anticancer treatments. While there is not a clear, consistent recommendation, currently, the measurement of cardiac biomarkers troponin I and troponin T, B-type natriuretic peptide (BNP), and N-terminal pro-BNP are becoming more widely used in the U.S. in an effort to detect cardiac toxicity among patients actively receiving cancer therapy, as well as short-term survivors.⁴ More research is needed as there are many variations in the techniques to measure each parameter, and the optimal timing of measurement and interpretation in relation to chemotherapy have not been established.⁴ All cancer patients who are treated with potentially cardiotoxic chemotherapy represent a high-risk group for the development of heart failure.⁴ 

The emerging need to spare the heart while combating cancer has given rise to the new clinical specialty of cardioncology. The International CardiOncology Society (ICOS http://www.cardioncology.com) is a non-profit professional society founded to promote training, research, and study in the fields of cardiology and oncology as associated comorbidities, to understand the cardiovascular implications of oncology treatments, and to eliminate cardiac diseases as a barrier to optimal cancer therapy for the millions of cancer patients.