Durham, NC - Trastuzumab (Herceptin, Genentech) appears to have a greater potential for causing cardiovascular damage in women being treated for breast cancer as compared with the newer agent lapatinib (Tykerb, GlaxoSmithKline), and now researchers may have identified the underlying mechanisms responsible for this difference. According to preliminary data, published online June 7, 2007 in Proceedings of the National Academy of Science, lapatinib but not trastuzumab initiates a metabolic stress response in human cardiomyocytes that protects against cell death.

"Trastuzumab remains an effective therapy for some women with HER2-positive breast cancer," said first author Dr Neil Spector (Duke University, Durham, NC). "Physicians should not be discontinuing trastuzumab therapy based on the findings from this preclinical study alone. There are other reasons why physicians should consider lapatinib, especially in women who are progressing clinically on trastuzumab."

Trastuzumab is a humanized anti-HER2 monoclonal antibody used to treat breast cancers that overexpress human epidermal growth factor receptor (EGFR) HER2. Other HER2-targeted therapies, including lapatinib, vary in their mechanisms of action and do not seem to cause the same risk for adverse cardiac-related events. Lapatinib is a small-molecule inhibitor of the HER2 and EGFR tyrosine kinase, the researchers explain in their paper, and studies have shown it to be clinically effective in patients with HER2-overexpressing breast cancers who have been heavily pretreated. The drug was recently approved for use in women who have not responded to trastuzumab therapy, but lapatinib also appears to incur less of a risk for cardiomyopathy as compared with trastuzumab.

"If the clinical safety of lapatinib with regard to reduced incidence of heart dysfunction continues to hold true, then physicians might want to consider lapatinib as an option for women who are at risk for or have preexisting heart disease," Spector said. "The indication for lapatinib is currently in combination with capecitabine for patients with HER2-positive tumors that have progressed on prior trastuzumab therapy, so treating women 'up-front' with lapatinib would be off label at this time."

To gain better insight into the apparent cardiac-sparing effects of HER2 kinase inhibitors such as lapatinib, Spector and colleagues evaluated and compared the actions of both drugs in experiments involving human cell lines and rats. Cancer patients frequently are observed to have elevated levels of proinflammatory cytokines such as TNF-, especially in those receiving chemotherapy. Higher levels of these cytokines are potentially a contributing factor to the cardiotoxic effects of trastuzumab, the researchers explain.

The team also tested the experimental compound GW2974, a small and potent molecule HER2/EGFR tyrosine kinase inhibitor that has a profile similar to that of lapatinib. They found that both GW2974 and lapatinib activated AMP-activated protein kinase (AMPK), which in turn stimulates a metabolic stress response in human cardiac cells that appears to offer protection against TNF--induced cell death. This reaction was not seen with trastuzumab.

The researchers also observed that in rats, GW2974 induced the oxidation of fatty acids, caused changes in lipid content, and protected myocardial cells from apoptosis. In vitro studies showed that GW2974 modulated the activity of various genes associated with calcium/ion channels and fatty-acid metabolism, in that it appeared to stimulate calcium-dependent fatty-acid oxidation that resulted in downstream events that conserve energy in the cells.

The activation of AMPK and its consequential effects on metabolic pathways and energy production in human cardiac myocytes may explain the apparent reduced risk for cardiotoxicity associated with certain HER2 small-molecule tyrosine kinase inhibitors, as compared with trastuzumab, write the researchers.

"GW2974 shares many of the same drug characteristics and inhibitory properties as lapatinib, so I would expect these results will extrapolate to lapatinib," explained Spector. "Furthermore, we know from the current database that lapatinib appears thus far to have less cardiotoxicity associated with its use compared with trastuzumab. There are potentially other explanations for these observations, such as the use of strict LVEF parameters for patients who have been entered in lapatinib clinical trials. So the apparent reduced risk of cardiotoxicity associated with lapatinib is likely to be multifactorial."

Clinical trials are currently investigating the combination of lapatinib with trastuzumab, and they will also examine the effect of combined therapy on the potential cardiac toxicity associated with trastuzumab. A phase 1 trial already has investigated the pharmacokinetics and safety of the combination.

"It was a small typical phase 1 trial, so it would be inappropriate to comment on cardiac safety from such a small study," said Spector. "Our preclinical data indicates that GW2974 protects cardiac myocytes from the effects of trastuzumab. The large phase 2 trial combining trastuzumab and lapatinib should be completed soon, and hopefully we will hear about the efficacy and safety data either at the San Antonio Breast Cancer Symposium later this year or at next year's American Society for Clinical Oncology annual meeting. I have heard exciting anecdotal reports on efficacy from some investigators."

As GW2974 and lapatinib appear to have a protective effect on cardiac cells, screening HER2 and other tyrosine kinase inhibitors therapies that activate rather than inhibit AMPK might be able to identify novel targeted approaches that protect myocardium from apoptosis induced by proinflammatory cytokines or other stresses such as acute ischemic injury, write the investigators, and it warrants further investigation.