Women with invasive breast cancer treated with two chemotherapy drugs had a sevenfold increase in the risk of heart failure (HF) or cardiomyopathy, according to results published online Sept. 4 in the Journal of the National Cancer Institute. The risk was higher than that found in clinical trials, suggesting that trials may have underestimated the cardiotoxicity risk.

Anthracycline or trastuzumab (Herceptin) are among drugs approved for treating patients with breast cancer. The regimen may include one drug or anthracycline followed by trastuzumab. Results from clinical trials indicated that both drugs had a cardiotoxic effect, with anthracycline associated with a 2 percent increase in HF or cadiomyopahy and anthracycline followed by trastuzumab associated with a 4 percent increase.

The clinical trials enrolled a select patient population that typically did not include women who were older or who had comorbidities, though. To better understand how these drugs affect patients in the community practice, Erin J. Aiello Bowles, MPH, of the Group Health Research Institute in Seattle, and colleagues designed a comparative safety study using data from the health maintenance organization Cancer Research Network.  

The population-based retrospective cohort study enrolled 12,500 women diagnosed with incident, invasive breast cancer from 1999 through 2007 at eight integrated Cancer Research Network health systems. The researchers identified anthracycline, trastuzumab and other chemotherapy use through administrative procedure and pharmacy codes.

They excluded women who were diagnosed with HF or cardiomyopathy before breast cancer diagnosis as well as those who did not receive chemotherapy but were diagnosed with either cardiac condition within 70 days of breast cancer diagnosis. The primary outcome was heart failure or cardiomyopathy after the breast cancer diagnosis.

Of the study cohort, 46.5 percent received no chemotherapy; 29.6 percent received anthracycline alone; 0.9 percent received trastuzumab alone; 3.5 percent received anthracycline plus trastuzumab; and 19.5 percent received other chemotherapy.

The HF or cardiomyopathy incidence among anthracycline recipients rose with increasing follow-up time, with a cumulative incidence of 1.2 percent at one year vs. 4.3 percent at five years. The cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2 percent vs. 20.1 percent. The risk of incident HF/ cardiomyopathy among all women was statistically significantly increased for anthracycline alone, trastuzumab without anthracycline, anthracycline plus trastuzumab and other chemotherapy, compared with no chemotherapy.

“The overall risk of incident HF/CM [cardiomyopathy] was statistically significantly increased among women who used anthracycline alone compared with no chemotherapy, but the overall risk of incident HF/CM was even greater among women who used trastuzumab,” Bowles and colleagues wrote. “Compared with women who received no chemotherapy, our hazard ratios suggest a fourfold increase in the risk of HF/CM among women who received trastuzumab alone and a sevenfold increase in the risk of HF/CM for those who received anthracycline plus trastuzumab.”

They noted that in their analysis the majority of older women did not receive chemotherapy, and of those who did, most received drugs other than anthracycline or trastuzumab. HF and cardiomyopathy risk results for women who were 65 years old or older who received anthracycline paralleled findings in clinical trials. “However, the risk of HF/CM among women who received trastuzumab with or without anthracycline in our study—especially among younger women—was unexpectedly higher than clinical trial estimates,” they wrote.

The researchers attributed that finding partly to detection bias because women given these drugs typically have cardiac function monitored during treatment. But they added that their findings suggested clinical trials underestimated the risk of anthracycline plus trastuzumab in a real-world setting.    

Observational studies may identify risk in community practice but they also have limitations, including misclassification and false-positive diagnoses in the administrative data. “Even in the presence of false-positive diagnoses and misclassification, our results suggest a greater risk of HF/CM than that previously estimated from clinical trials,” they wrote.