Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues

Abstract

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.

Trastuzumab and lapatinib differ in effects on calcium cycling and HER2 expression in human embryonic stem cell-derived cardiomyocytes

“…The mechanisms by which these agents affect calcium handling are not known. They may include doi: 10.7243/2052-4358-1-10 interference with downstream effector pathways, including PI3K/Akt, Ras/MEK/ERK and Src/FAK [1,2,7,22], and effects on function or expression of proteins involved in calcium release and uptake, such as RyR or SERCA2a.…”

“…These agents have revolutionized breast cancer treatment [1,2]. Addition of trastuzumab to anthracycline-or taxane-based chemotherapy significantly improves response rate, time to progression, and survival in HER2-positive metastatic disease.…”

I Diretriz Brasileira de Cardio-Oncologia da Sociedade Brasileira de Cardiologia

“…Fatores de risco propostos para IC relacionada ao bevacizumabe incluem idade acima de 65 anos e história prévia de evento trombótico arterial 161 . Essa toxicidade não parece ser dose-relacionada.…”

“…Uma redução no processo de regeneração das células endoteliais durante o tratamento anti-VEGF tem sido proposto como mecanismo de cardiotoxicidade. Isso permitiria a exposição de colágeno subendotelial, que ativaria o fator tecidual, aumentando o risco de eventos trombóticos 161 . O bevacizumabe está associado com a ocorrência de tromboembolismo arterial em 8,5% dos casos, e tromboembolismo venoso em 5% a 15,1% 161 .…”

“…Está indicado na segunda linha de tratamento do carcinoma de células renais e no carcinoma hepatocelular 161 . O sorafenibe induz síndrome coronariana aguda em 2,9% dos pacientes, incluindo infarto agudo do miocárdio.…”