According to a large population-based, retrospective study of 12,500 women treated for invasive breast cancer, treatment with trastuzumab (Herceptin) increases the risk of congestive heart failure and cardiomyopathy. The research aimed to confirm the cardiac signals seen in trastuzumab clinical trials in a real-world, clinical setting. The results are published in the Journal of the National Cancer Institute.
The risk of either heart failure or cardiomyopathy was highest in those women who received either trastuzumab alone or in combination with anthracycline. Women given trastuzumab alone had a four-fold increased risk of heart failure or cardiomyopathy compared to those who received no chemotherapy (adjusted hazard ratio [HR] of 4.12). Those who were treated with a combination with anthracycline had a seven-fold higher risk of cardiomyopathy or heart failure (adjusted HR of 7.19). The relative risk of heart failure or cardiomyopathy in patients on chemotherapy was slightly higher for women taking chemotherapy compared to those who received no chemotherapy (adjusted HR of 1.4–1.49).
The cumulative incidence of heart failure or cardiomyopathy among patients given chemotherapy was 1.2%. In contrast, the cumulative incidence of cardiac events among those who received anthracycline with trastuzumab was 6.2% after a year of follow-up, increasing to 20.1% after 5 years.
The average age of the women in the study was 60 years. All of the assessed patients were diagnosed between 1999 and 2007. The data were from 14 nonprofit research centers within the health maintenance organization Cancer Research Network.
The study included patients who received anthracycline alone (29.6%), trastuzumab alone (0.9%), and patients who received both (3.5%). Another 19.5% of the patients studied received other forms of chemotherapy and 46.6% got no chemotherapy. In general, women who received trastuzumab tended to be younger and had less comorbidity compared to the women who were given other forms of chemotherapy or no chemotherapy at all.
Most of the women 65 years and older in the study did not receive chemotherapy. Of those that did, most received other agents besides anthracycline and trastuzumab. “These results suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice,” state the authors. The small proportion of older women who received trastuzumab alone had the highest prevalence of comorbidities. According to the authors, these results suggest that the exclusion of patients based on age and comorbidities for clinical trials occur in real-world settings but to a “lesser extent than in clinical trials.”
According to Erin J. Aiello Bowles, MPH, the Group Health Research Institute in Seattle, and coauthors, previous clinical trial analyses have shown a 2% increase in heart failure among women given anthracycline and an approximate 4% increase for those given anthracycline combined with trastuzumab. The authors note that these analyses had excluded women older than 70 years of age and those who had comorbidities.
In an accompanying editorial Ann M. Geiger, MPH, PhD, the division of public health sciences at Wake Forest School of Medicine in North Carolina, points out that despite limitations of observational studies, there is a strong association between trastuzumab and heart failure in the current study.
This study, according to Geiger, “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.”
Geiger is not surprised by the magnitude of increased congenital heart failure seen in the study. “It is not at all unusual to find that the long-term risks of treatments delivered on a more widespread basis in community settings are higher than identified in the more idealized setting of clinical trials,” said Geiger.
The editorial author would like to see even longer follow-up of patients taking trastuzumab to fully understand the risks of long-term exposure to the treatment. “It may be even more important to develop studies that will provide evidence to support an approach to early detection and management of congestive heart failure in these women,” said Geiger.
“My hope is that these results may give pause to clinicians when they recommend trastuzumab to women who are of a different age or health status than those included in clinical trials,” Geiger added.
As researchers learn more about the long-term risks of heart failure, studies to identify early biomarkers associated with increased risk for these cardiac effects should facilitate making educated choices about the best breast cancer treatment for patients.