A recent study in Circulation investigated the mechanisms underlying the negative effects of chemotherapy for breast cancer on heart function.
Cardiovascular complications are the leading cause of morbidity and mortality among cancer survivors. These complications, including impaired heart function, are thought to be caused, in part, by the anti-cancer therapy.
Trastuzumab (Herceptin) and heart dysfunction
For instance, trastuzumab, also known as Herceptin, is a highly effective chemotherapeutic agent used for breast cancer patients that have the human epidermal growth factor receptor 2 (HER2) protein. Trastuzumab, however, has been reported to have the most frequent occurrences of heart dysfunction in patients. It is important, therefore, to investigate the potential negative heart effects of chemotherapy for breast cancer, as well as the effect of other cancer drugs on overall heart health.
In a recent study, published in Circulation, researchers used heart cells from the stem cells of healthy and breast cancer patients to investigate the mechanisms of trastuzumab-induced heart dysfunction. More precisely, they began by isolating and developing cardiac muscle cells from stem cells of 3 healthy participants and 7 breast cancer patients.
Trastuzumab caused cells to contract less vigorously
Administration of trastuzumab caused cells from breast cancer patients to contract less vigorously compared to cells derived from healthy participants. No differences were observed in cell death and in the structure of cellular components responsible for heart contraction.
These results are consistent with clinical findings, where HER+ breast cancer patients experience impaired heart contraction following trastuzumab treatment. The authors believe that heart cells derived and developed from stem cells of breast cancer patients can be used as an effective model to study the effects of chemotherapy on heart cells.
The researchers also conducted further studies which found that trastuzumab acts by disrupting the way the cells consume energy. These findings were validated by further experimentation where metformin, an FDA-approved drug for type 2 diabetes, caused by trastuzumab-weakened cells to contract more vigorously and take up more glucose. In other words, improving the cell’s ability to uptake glucose for energy improved the cell’s contractile force.
Metformin may negate the adverse effects of chemotherapy on the heart
In summary, the authors believe that the current study provides novel insight into the potential mechanisms by which trastuzumab can induce heart toxicity in breast cancer patients. Furthermore, they demonstrated that the use of metformin might be an effective strategy in negating the adverse effects of chemotherapy on the heart.
Furthers studies needed
Moving forward, the authors plan to conduct a prospective study in breast cancer patients using trastuzumab to investigate whether those that also take metformin for diabetes have a reduced number of cardiac side effects, compared to those that do not.
If successful, the authors propose that clinicians will be able to isolate cells from breast cancer patients using trastuzumab and determine the likelihood that they will suffer heart dysfunction. These cells can further be used to test whether the patient would benefit from using metformin or other drugs to reduce the heart toxicity of chemotherapeutics.
Written by Haisam Shah, BSc
Reference: Kitani, T., Ong, S. G., Lam, C. K., Rhee, J. W., Zhang, J. Z., Oikonomopoulos, A., … & Witteles, R. M. (2019). Human Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Breast Cancer Patients. Circulation.