RISK OF HEART FAILURE WITH TRASTUZUMAB

Clinical trials have already shown that breast cancer patients who receive treatment with anthracyclines and trastuzumab (Herceptin, Genentech/Roche) are at increased risk for heart failure and cardiomyopathy.

Now, an observational cohort study conducted in a "real-world" setting suggests that this risk might be much higher.

The study, led by Erin J. Aiello Bowles, MPH, from the Group Health Research Institute in Seattle, Washington, was published online August 31 in the Journal of the National Cancer Institute.

This study adds to the understanding of the association between trastuzumab and heart failure, writes Ann M. Geiger, MPH, PhD, from Wake Forest School of Medicine in Winston-Salem, North Carolina, in an accompanying editorial. In this study, the median follow-up time is a year longer than that of previous clinical trials, and the incidence of heart failure appears to increase with longer follow-up.

"These results provide additional evidence that heightened risk of heart failure is a long-term effect of previous trastuzumab use rather than a short-term increase associated with current or recent use," she writes.

"This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials," Dr. Geiger notes.

Real-World Community Setting

"Clinical trials have shown that anthracyclines and trastuzumab are not only effective at improving survival, but are also associated with an increased risk of heart failure. However, these studies typically exclude older women and women with chronic diseases, so we really don't know what the real-world estimate of heart failure risk associated with these drugs is," Bowles told Medscape Medical News.

"Our goal was to describe not only the population of women with breast cancer who do and who do not receive these drugs, but also to estimate the risk of heart failure associated with these drugs in a real-world community practice," she said.

In this population-based retrospective study, Bowles and her colleagues from the Cancer Research Network analyzed data from 12,500 women diagnosed with incident invasive breast cancer from January 1, 1999 to December 31, 2007.

The women were patients for at least 12 months before their diagnosis at 6 health maintenance organizations in different areas of the United States.

The risk for heart failure and cardiomyopathy with anthracycline alone, trastuzumab alone, anthracycline followed by trastuzumab, and other chemotherapy was compared with no chemotherapy.

Among the women in the analysis, 5807 (46.5%) received no chemotherapy, 3697 (29.6%) received anthracycline-based chemotherapy alone, 112 (0.9%) received trastuzumab-based therapy without anthracycline, 442 (3.5%) received anthracycline plus trastuzumab, and 2442 (19.5%) received other chemotherapy.

The mean age of the population was 60 years (range, 22 to 99 years), 85.8% were white, and the median follow-up time was 4.4 years (interquartile range, 2.6 to 6.9 years).

The researchers found that women who received anthracycline or anthracycline plus trastuzumab were younger. Of the women who received anthracycline alone, 86.4% were younger than 65 years, as were 89.6% of the women who received both anthracycline and trastuzumab.

Younger women were also diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy than women who received other chemotherapy or no chemotherapy.

The small proportion of women who received trastuzumab without anthracycline were older (more than 65 years) and had more comorbidities.

The researchers also found that the risk for heart failure was higher among women who received anthracycline alone than among those who received no chemotherapy, and that the magnitude of that risk was similar to what has been reported in clinical trials.

For that population, the risk for heart failure or cardiomyopathy was higher than among those who received no anthracycline (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11 to 1.76). The increased risk was similar to that seen with other chemotherapy (adjusted HR, 1.49; 95% CI, 1.25 to 1.77).

However, the risk for heart failure associated with trastuzumab following anthracycline was much higher than has been reported in clinical trials (adjusted HR, 4.12; 95% CI, 2.30 to 7.42)

Overall, for anthracycline, the cumulative incidence at 5 years was 4.3%. But for the women who received anthracycline and then trastuzumab, the 5-year cumulative incidence was 20.1%.

"It is a lot bigger than what has been reported from the clinical trials," said Bowles. "But keep in mind that this is a much broader population that we looked at. We have a lot more older women who are already at an increased risk for heart failure, so that is going to drive up our results."

Bowles said this study can be generalized to other women, whereas the results from clinical trials are only applicable to the populations in those trials.

"We know clinical trials are very well done, they're very controlled and have great internal validity because they control any kind of confounding for age and other characteristics, but their generalizability to people who many not be included in those trials is really limited," she explained.

"Our results are much more generalizable, but at the expense of the internal validity. But we did our best to control for age, comorbidities, and any other things that we thought would affect the results. I think our study provides a nice complement to clinical trials," she said.

Long-term Follow-up

In her editorial, Dr. Geiger notes that the results of this study add to the evidence that anthracycline and trastuzumab (in particular) increases the risk for heart failure or cardiomyopathy as a long-term effect.

Dr. Geiger concludes that there is a need to monitor women who have received trastuzumab on an ongoing basis, and calls for prudence in using trastuzumab outside of clinical trials.

She also highlights a role for observational studies. This study "illustrates how observational studies complement randomized controlled trials by capturing valuable information about treatment outcomes for the vast majority of women who are unable to access a trial."