Asnani et al studied cardiotoxicity from breast cancer agents in a case-control study. Anthracyclines and trastuzumab are effective medications used to treat breast cancer, but their use is limited at times due to the severe side effect of cardiotoxicity, which is dose-dependent. About 10% to 20% of patients who have been treated with these agents experience cardiotoxicity within a couple of years after finishing treatment. When an anthracycline and trastuzumab are combined, the risk of cardiotoxicity increases greatly.
Trastuzumab cardiotoxicity is due to direct inhibition of HER2 signaling in cardiomyocytes. Other researchers have looked at how cardiotoxicity develops, including oxidative stress, iron accumulation, and direct cardiomyocyte injury. In this study, the scientists examined mitochondrial dysfunction and employed metabolite profiling. Using this approach, they profiled early changes in circulating intermediary metabolites that can be impaired and are associated with developing cardiotoxicity. This might help identify the mechanisms behind cardiotoxicity.
This study included 81 patients who were older than age 18 years, were diagnosed with HER2-positive breast cancer, and were going to receive treatment with anthracyclines, taxanes, and trastuzumab at MD Anderson Cancer Center, Massachusetts General Hospital, and McGill University. The regimen utilized was a first-line treatment option with standard dosages of doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks for four cycles followed by paclitaxel 80 mg/m2, and trastuzumab 2 mg/kg every week for 12 weeks, followed by trastuzumab 6 mg/kg every 3 weeks for 1 year. Anyone with a left ventricular ejection fraction (LVEF) <50% before chemotherapy was excluded. Of the 81 patients, 26 developed cardiotoxicity, which was defined by a decline in LVEF of >10% to a value <55% compared with baseline. Metabolic profiling was done using 71 metabolites.
Baseline characteristics were similar in both groups of patients. Cardiotoxicity appeared in two of 19 patients at 3 months and eight patients at 6 months. The remaining 11 patients developed cardiotoxicity at 9 months or later. From the metabolic profiling, it was noted that changes in citric acid cycle, purine, and pyrimidine metabolites differentiated patients who developed cardiotoxicity from those who did not. However, not all of the changes were statistically significant. Metabolic changes in these three areas were more pronounced in five of the 19 patients who developed signs of heart failure from cardiotoxicity.
The researchers also compared patients’ metabolite levels at 3 months to baseline values. It was found that patients without cardiotoxicity had increased levels of citric acid and those with cardiotoxicity had decreased citric acid levels. Also, patients with cardiotoxicity had an increase in purine metabolites, inosine, hypoxanthine and pyrimidine metabolites, pseudouridine, and orotic acid.
Based on findings of increased purine and pyrimidine metabolites in patients who developed cardiotoxicity, more studies need to be done to look at the role of the citric acid cycle in the pathogenesis of cardiotoxicity. This can help identify patients early and pinpoint risk factors to help provide methods of prevention and cardioprotection in patients receiving chemotherapy.
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