The cardiac safety of Trastuzumab in the treatment of breast cancer
University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA. Expert Opinion on Drug Safety
(Impact Factor: 2.91).
03/2010; 9(2):335-46. DOI: 10.1517/14740331003627441
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.
Available from: Sunghyun Kim
- "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 "
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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.
Available from: Carmela Salvatore
- "At present, the monoclonal antibody Trastuzumab, targeted against the extracellular domain of erbB-2 receptor, is used in patients with metastatic erbB-2 positive breast cancer with proven benefits . Nevertheless, severe cardiac dysfunction, among significant adverse effects, has been found . Additionally, a relatively large proportion of patients do not benefit from erbB-2 targeted therapy, indicating that other treatments should be investigated for the management of breast tumor in advanced progression. "
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ABSTRACT: Breast cancer is the most common malignancy and the most common cause of cancer death in elderly women. Chemoprevention with dietary compounds and their synthetic analogs has emerged as an attractive strategy to prevent carcinogenic progression to invasive cancer. In this study, we investigated the efficacy of some new synthetic derivatives of berberine, a phytochemical isolated from Barberry and other plants, to induce growth arrest of HER-2/neu overexpressing SK-BR-3 breast cancer cells. Supplementation with berberine or with the synthetic derivatives NAX012, NAX013, NAX014, and NAX035 exerted a dose- and time-dependent inhibition of SK-BR-3 cell viability, with a greater effectiveness of NAX012 and NAX014 compounds with respect to berberine. This cytotoxic effect was related to an increased number of apoptotic cells that reached 71.6% and 68.4% after 72 h treatment with 50 µM of NAX012 and NAX014, respectively, compared with 44.2% of berberine. Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 µM treatments. Furthermore, berberine, NAX012 and NAX014, all reduced both HER-2/neu expression and phosphorylation on tumor cells, the NAX014 compound showing the higher effectiveness. These results provide novel information on the mechanisms involved in the anticancer effects of berberine and demonstrate the greater effectiveness of NAX012 and NAX014 analogs in inducing apoptosis and cellular senescence in HER-2/neu overexpressing tumor cell lines. © 2013 BioFactors, 2013.
Available from: onlinelibrary.wiley.com
- "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? "
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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.
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