Diagnosis and Prediction of Subclinical Cardiac Dysfunction Induced by Therapy With Taxanes in Patients With Breast Cancer

Scientific context and motivation. Breast cancer represents the most frequent form of neoplasia in women worldwide, comprising 16% off all neoplasias. A report of the World Health Organization showed that 1 from 6 cancers is determined by breast cancer and this form of neoplasm causes around 550,000 deaths/year, respective 1.6% of all annual deaths in the world. The incidence of breast cancer is increasing, over 1.1 million of women being newly diagnosed with cancer every year. Although considered a pathology specific to developed countries, recently it was established that developing countries, such as Romania, include over 69% of all breast cancers. Therefore, breast cancer is currently a major public health and economical issue and research on new therapies, as well as monitoring their safety use, should be a priority.

Many studies showed that, due to new chemotherapy, breast cancer can be considered a curable disease. And indeed, use of a multidisciplinary approach - surgery, radiotherapy, chemotherapy - has conducted to a significant reduction in the mortality. As a consequence of increased life expectancy, it becomes essential that specific oncologic therapies should be safe.

Taxanes, inhibitors of cellular mitosis (paclitaxel and docetaxel), relatively new drugs, are extremely potent and widely used in different therapeutic regimes. Their single use or the association with classical chemotherapy, have been proved to increase significantly rate of cure in breast cancer, as well as to reduce recurrences. However, the applicability of these drugs on medium or long term is limited by the risk of cardiotoxicity.

Cardiotoxicity is one of the most important adverse reactions of taxanes, leading to an important increase of morbidity and mortality. Cardiotoxicity can appear early or late in the course of the disease, and may vary from subclinical myocardial dysfunction to irreversible heart failure or even death. Recent research has showed that cardiac dysfunction induced by taxanes may increase exponentially with the cumulative dose used; meanwhile, it may be augmented by other associated cytotoxic drugs. Data on the susceptibility of patients to develop cardiotoxicity are scarce. Some studies suggest that patients without known cardiovascular history may develop symptomatic heart failure in direct connection to the cumulative dose received, affirmation which has led to the use of reduced doses of chemotherapy and, therefore, to a reduction in their efficiency. But also under these circumstances, there is a risk of cardiotoxicity induced by taxanes therapy, risk which cannot be foreseen by the cumulative dose. Moreover, the cardiac alteration is very frequently subclinical and it can appear early (during therapy), late (during the first year after therapy) or very late (more than one year after finishing therapy). Consequently, early diagnosis of subclinical cardiac dysfunction in patients with breast cancer treated with taxanes, as well as the establishment of prediction models for irreversible heart failure is essential in the management of such patients.

Currently, recommendations of diagnosis of cardiac dysfunction induced by taxanes are to use functional and structural parameters of conventional echocardiography, such as left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVSF), as well as diameters and volumes of the heart chambers. However, sometime, these conventional measurements allow only the late diagnosis of cardiac dysfunction, which might be already irreversible. Therefore, description of new and simple parameters, able to diagnose more subtle, subclinical changes of cardiac function becomes mandatory.