Importance of the field: Trastuzumab has become a mainstay in the treatment of women with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer in the metastatic and adjuvant settings. Although trastuzumab is generally well tolerated, cardiac toxicity has emerged as a rare but potentially serious complication that limits its use in some patients. It is critically important to understand the nature of this cardiac risk when counseling patients, especially as new anti-HER2 agents are developed and tested in combination with trastuzumab. Areas covered in this review: This review describes the incidence, risk factors and natural history of trastuzumab-associated cardiac toxicity reported in updated efficacy and cardiac safety analyses of metastatic and adjuvant trastuzumab clinical trials. Mechanisms of trastuzumab-associated cardiotoxicity are proposed and compared to what is known about anthracycline-induced cardiotoxicity. The existing cardiac safety data for lapatinib and other newer HER2-targeted therapies are also discussed, both as single agents and in combination with trastuzumab. What the reader will gain: The reader will gain a comprehensive understanding of the existing cardiac safety data for trastuzumab including the notable differences in trial design and study populations between each of the major adjuvant trials. Readers will become familiar with the risk factors associated with trastuzumab-induced cardiotoxicity as well as with the natural history of its course. Take home message: The majority of trastuzumab-related cardiac events observed have been asymptomatic declines in left ventricular ejection fraction. The incidence of severe congestive heart failure and cardiac death observed in the large adjuvant trastuzumab trials ranges from 0.6 to 4%. Both symptomatic and asymptomatic events are largely reversible and manageable; however, little is known about the significance of asymptomatic left ventricular ejection fraction decline and longer cardiac follow-up is needed. Close cardiac monitoring must be performed for all patients receiving anti-HER2 agents currently in the clinic or in development.
"Nowadays, breast cancer therapy is selected based on the HER-2 expression level. Thus, reliable laboratory data in detecting HER2 status is essential for selection of a correct therapeutic method to treat breast cancer avoiding latent side effect particularly in women who do not exhibit amplification and overexpression of HER2 (Chien et al., 2010). The most commonly used assays in the clinical setting for detecting HER2 status are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, both of which are approved assays for HER2 detection by the United States Food and Drug Administration "
[Show abstract][Hide abstract] ABSTRACT: Breast cancer patients who have a positive result for HER2 overexpression are commonly treated with Herceptin, a HER2-targeted therapy. In the present study, the BrightGen HER2 RT-qDx (Syantra, Calgary, Canada), which is based on a one-tube nested RT-qPCR method that detects HER2 mRNA overexpression, was clinically evaluated in a total of 237 formalin-fixed paraffin-embedded (FFPE) tissue samples from breast cancer patients. Among the 38 HER2 positive samples, which were determined via IHC/FISH methods, 13 samples out of 16 (81.3%) that were IHC2 +/FISH + and 22 samples out of 22 (100%) that were IHC3 + have been decided positive for HER2 expression via the RT-qPCR method. The true positivity and false positivity results for the RT-qPCR were 92% (35/38) and 2% (1/65), respectively. The concordance between RT-qPCR and IHC results and RT-qPCR and IHC/FISH was 87.2% and 92.1%, respectively. Conclusively, the BrightGen HER2 RT-qDx may be a reliable and convenient method that can supplement traditional IHC and FISH methods for efficient use of trastuzumab.
"As already noted, this is part of the limitation of routine preclinical studies to accurately predict the human adverse effects of immunomodulatory drugs. It is also not surprising that studies in normal animals fail to detect some of the more serious adverse events seen in humans related to an interaction with a concurrent treatment, such as the increased risk of cardiac dysfunction in patients receiving trastuzumab following treatment with doxorubicin and cyclophosphamide (Chien and Rugo, 2010). So what can we learn in order to design more efficient and successful drug development programs? "
[Show abstract][Hide abstract] ABSTRACT: To improve drug development outcomes, it is important to review when preclinical pharmacodynamic and safety models have successfully predicted human responses and when they have not. In a recent issue of the BJP, Bugelski and Martin examined the concordance between preclinical and human data for biopharmaceuticals targeted to cell-surface proteins. The cases are interesting and several trends emerge. The pharmacodynamics of biopharmaceuticals in non-human primates is largely predictive; the use of surrogates in rodents may be similarly predictive, allowing for more conservative use of non-human primates. While overall concordance of preclinical toxicology data and clinical safety was poor, this is largely a reflection of the immunomodulatory biology of the majority of the biopharmaceuticals evaluated. The examples show that adverse effects in animals that were the result of direct and/or exaggerated pharmacology were modelled well, but that specific infections or other indirect outcomes of immunomodulation, along with cytokine-related events, were not modelled well in preclinical studies.
British Journal of Pharmacology 02/2012; 166(5):1600-2. DOI:10.1111/j.1476-5381.2012.01916.x · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OPThe benefits of exercise in patients with chronic disease have been studied extensively over the last half century. In contrast, investigation of the role of exercise following a diagnosis of cancer has received comparably less attention. In this article, we review the efficacy of exercise training in specific areas across the cancer survivorship continuum [i.e., pre-surgery, post-surgery during adjuvant therapy, following the completion of primary adjuvant therapy (survivorship), and palliation], with a view toward future research. The current evidence base provides strong but preliminary evidence that exercise training is a well-tolerated and safe adjunct therapy that can mitigate several common treatment-related side-effects among cancer patients with early disease both during and following adjuvant therapy although many questions remain unanswered. Preliminary evidence in this area supports that exercise therapy may be an important consideration in multidisciplinary management of patients following a cancer diagnosis.
Current Treatment Options in Oncology 06/2010; 11(1-2):45-58. DOI:10.1007/s11864-010-0121-5 · 3.24 Impact Factor
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