Rick Whitehead and Dr. Kim L. O’Neill, Microbiology
In 1998, approximately 10 million women reached the age of 50 years, at a rate of 5,000 women per day. Based on the age incidence data for breast cancer, this means that, within the next ten years, 296,000 women will be affected annually with breast cancer. Because of the tremendous growth in newly diagnosed breast cancer patients, new strategies will be required to treat this “baby boomer” explosion.
Recent work with the growth receptor Her-2 may be one of those strategies. The human epidermal growth factor receptor 2 protein (Her-2) encodes a 185-kDa tyrosine kinase receptor that is over-expressed in approximately 30% of women with breast cancer. Her-2 overexpression is predictive of decreased life expectancy and poor patient prognosis. As its prognostic and predictive significance has grown it has become a standard laboratory test for all breast cancer patients. The majority of research on Her-2 has occurred over the last 5 years, and many answers have been uncovered regarding its role in breast cancer.
In 1999 the drug Herceptin (Trastazumab, Genentech, Inc. San Francisco, CA) was approved for use as an anti-Her-2 cancer therapy drug. Herceptin is a humanized monoclonal antibody that targets the Her-2 receptors that are over-expressed on breast epithelial cells. Although the nature of its response is not fully known, it is thought that Herceptin is a mediator of antibodydependent cellular cytotoxicity, although various studies have linked it as a mediator of DNA damage. Ultimately, it inhibits proliferation of human cells that overexpress Her-2.
Clinical trials showed that Herceptin was most effective when given in combination with paclitaxel or anthracycline and cyclophosphamide. However, in the patient group receiving Herceptin with anthracycline and cyclophosphamide 28% (n=143) of the patients experienced some form of cardiac dysfunction. Level III or IV cardiac dysfunction, which includes cardiac failure, mural thrombosis, and death, was seen in 19% of the patients. Anthracycline and cyclophosphamide alone (without Herceptin) yielded 7% (n=135) cardiac dysfunction. Physicians have been warned to complete a thorough cardiac workup before prescribing Herceptin.
Surgeons and physicians are uncertain why Herceptin has high cardiotoxicity. Some have hypothesized that Herceptin may bind to receptors in the cardiac cells of the heart, especially since fetal myocardial cells express Her-2 receptors and the adult myocardium expresses Her-3 receptors. However, Herceptin has not been shown to localize to the heart in animal models. Further, monkeys treated with Herceptin at doses 10-times greater than those given to humans showed no increased cardiac toxicity. Immuno-histochemical studies of myocardial cells showed no Her-2 protein expression in myocardial tissue.1
One proposed explanation for the increased cardiotoxicity is an observational artifact brought on by increased surveillance and misread cardiac symptoms. This is inaccurate for many reasons. First, the trials would have been uniform in cardiac dysfunction; they were not. Second, the observed incidence of cardiac dysfunction in patients with previous or concurrent doxorubicin is comparable to previously reported research on doxorubicin-based therapy.
While the activation mechanism is unclear, recent research has identified myocyte survival pathways that have been shown in animal models to prevent the onset of cardiomyopathy and associated heart failure.2 These pathways are stimulated by biomechanical stress, of which the Her-2 binding may be one form. In fact, gene targeting of these signaling components leads to cardiac myocyte apoptosis. Two results follow: cell death via apoptosis or compensatory hypertrophy via the hypertrophic signaling pathway. Thus, it is felt that Her-2 may increase the likelihood of mycardial cells following the apoptotic pathway and leading to greater cardiotoxicity. However, it should be understood that the mechanisms of cardiac failure and cardiotoxicity are not clear, so these findings are merely hypotheses.
Although Herceptin has been approved for the treatment of breast cancer, there is still some doubt about its efficacy and safety when used in combination with other chemotherapies. Further clinical trials must be done before physicians are warranted to prescribe Herceptin to all patients with Her-2 positive breast cancer. A thorough cardiac workup should be accomplished and evaluated closely. In addition, patients with increased risk for cardiac dysfunction must be monitored during each Herceptin cycle.3
References
- “Cardiac toxicity of trastuzumab (Herceptin): Implications for the design of adjuvant trials.” Seminars in Oncology. 28(1), Suppl 3 (February). 2001:20-27.
- “Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity.” Seminars in Oncology. 27(6), Suppl II (December). 2000:9-19.
- Acknowledgements: Thanks to Dr. Kim L. O’Neill for mentoring. Also, thanks to Dr. Charles E. Cox and the Comprehensive Breast Clinic of the H. Lee Moffitt Cancer Center at the University of South Florida.