Human epidermal growth factor antagonists and cardiotoxicity-A short review of the problem and preventative measures.

The Human Epidermal growth factor Receptor 2 (HER2) is a potent mediator of cellular growth and proliferation. It plays an important role in cardiac development and maintaining the physiologic function of an adult heart. Amplification of the HER2 gene, and the corresponding overexpression of the HER2 receptor, occurs in roughly 20% of breast tumors and is associated with a poor outcome. Molecular targeting of the HER2 receptor with the humanized monoclonal antibody, Trastuzumab has improved disease-free and overall survival in patients with both metastatic and early HER2-positive breast cancer. Although trastuzumab is devoid of the classical toxicities associated with chemotherapy, one of the major concerns noted is the occurrence of symptomatic and asymptomatic cardiotoxicity (decline in left-ventricular-ejection-fraction (LVEF). Additionally, newer HER2 therapies such as Lapatinib, Pertuzumab and Ado-trastuzumab (TDM1) are either approved or are being evaluated in clinical trials for cancer therapy. Targeted therapies against HER2 have led to revolutionary strides in breast cancer research and treatment. With the concern of cardiotoxicity caused by these agents, new treatment strategies for preventing cardiac side effects need to be developed. In this review, we discuss the proposed mechanisms of HER 2 antagonist-induced cardiotoxicity and the ways to prevent it.

Identification of a serum-detectable metabolomic fingerprint potentially correlated with the presence of micrometastatic disease in early breast cancer patients at varying risks of disease relapse by traditional prognostic methods.

BACKGROUND: Prognostic tools in early breast cancer are inadequate. The evolving field of metabolomics may allow more accurate identification of patients with residual micrometastases. PATIENTS AND METHODS: Forty-four early breast cancer patients with pre- and postoperative serum samples had metabolomic assessment by nuclear magnetic resonance. Fifty-one metastatic patients served as control. Differential clustering was identified and used to calculate individual early patient 'metabolomic risk', calculated as inverse distance of each early patient from the metastatic cluster barycenter. Metabolomic risk was compared with Adjuvantionline 10-year mortality assessment. RESULTS: Innate serum metabolomic differences exist between early and metastatic patients. Preoperative patients were identified with 75% sensitivity, 69% specificity and 72% predictive accuracy. Comparison with Adjuvantionline revealed discordance. Of 21 patients assessed as high risk by Adjuvantionline, 10 (48%) and 6 (29%) were at high risk by metabolomics in pre- and postoperative settings, respectively. Of 23 low-risk patients by Adjuvantionline, 11 (48%) preoperative and 20 (87%) postoperative patients were at low risk by metabolomics. CONCLUSIONS: This study identifies metabolomic discrimination between early and metastatic breast cancer. Micrometastatic disease may account for metabolomic misclassification of some early patients as metastatic. Metabolomics identifies more patients as low relapse risk compared with Adjuvantionline. Further exploration of this metabolomic fingerprint is warranted.

New strategies to identify molecular markers predicting chemotherapy activity and toxicity in breast cancer.

Despite significant improvements in the treatment and outcomes of early-stage breast cancer, the quest continues to find biological and molecular markers that would enable earlier diagnosis or better prediction of treatment efficacy and toxicity. Metabolomics--the latest and one of the most exciting of the 'omic' sciences--has shown early promise as a non-invasive diagnostic aid in ovarian cancer, and may allow the detection of subtle metabolic changes that could have diagnostic, prognostic or predictive value in breast cancer. Routine monitoring of circulating tumour cells (CTCs) has also been advocated as a novel means of detecting breast cancer progression earlier, and identifying alterations in tumour cells that might signal the need for therapy changes. Ongoing studies should help to answer important questions relating to the use of metabolomics and CTC evaluation as new strategies to monitor cancer progression and identify markers of chemotherapy activity and toxicity.