The incidence of heart failure and cardiomyopathy were significantly increased in women with breast cancer treated with trastuzumab either alone or in combination with anthracycline-based chemotherapy, according to the results of a recent large, population-based, retrospective cohort study (Bowles EJ, et al. J Natl Cancer Inst. 2012;104:1293-1305). An adjusted analysis found that the risk of heart failure and/or cardiomyopathy was 4 times greater among women treated with trastuzumab alone and 7 times greater in women treated with trastuzumab plus anthracycline versus women who did not receive any chemotherapy.
The study was based on data from 8 integrated Cancer Research Network health maintenance systems. Overall, the risk of anthracycline-associated heart failure/cardiomyopathy in women under the age of 65 years was similar in this study as in previously reported randomized clinical trials, but the risk associated with trastuzumab alone or when combined with an anthracycline was higher than in previous reports.
Lead author Erin J. Aiello Bowles noted that this study shows that findings of clinical trials may not be generalizable to individual patients treated in real-world settings.
The study included 12,500 women, with a mean age of 60 years, diagnosed with invasive breast cancer from January 1, 1999, through December 31, 2007. Women with preexisting heart failure/cardiomyopathy were excluded.
At a median follow-up of 4.4 years, 46.5% had not been treated with chemotherapy, about 30% had received anthracycline-based chemotherapy alone, 0.9% had received trastuzumab with no anthracycline, 3.5% had received anthracycline plus trastuzumab, and about 20% had received other chemotherapy.
Baseline characteristics were different among the groups. Women who received anthracycline alone or in combination with trastuzumab were younger, had been diagnosed at later stages, had fewer comorbidities, and were slightly more likely to be treated with radiation therapy, compared with women who did not receive any chemotherapy or who received other chemotherapy.
With increasing follow-up, the incidence of heart failure/cardiomyopathy increased in all groups, but the greatest increase was seen in the trastuzumab-treated patients. In the group treated with anthracyclines, the cumulative incidence of heart failure/cardiomyopathy increased from 1.2% at year 1 to 4.3% at year 5; this increase was similar to that for patients treated with other chemotherapies (from 1.3% to 4.5%). Patients who did not receive any chemotherapy had a cumulative incidence of heart failure/cardiomyopathy of 0.9% at year 1 and 3.1% at year 5. The greatest increase was observed in patients treated with anthracycline plus trastuzumab: from 6.2% at year 1 to 20.1% by year 5.
At 5 years, the cumulative incidence of heart failure/cardiomyopathy was greater in older women for all treatment groups, but as women aged, the hazard ratio for heart failure/cardiomyopathy decreased.
The investigators noted that the study demonstrates the importance of observational comparative safety and effectiveness studies to complement data from clinical trials. These observational studies provide an estimate of risks and benefits in community practices that treat patients who often are not eligible for clinical trials but who still receive treatments based on clinical trial data.
In an accompanying editorial (Geiger AM. J Natl Cancer Inst. 2012;104:1269-1270), Ann Geiger, PhD, Wake Forest University, Winston-Salem, North Carolina, acknowledged the important survival benefits of trastuzumab in women with HER2-positive breast cancer, but she stated that there are still safety concerns related to risks of heart failure/cardiomyopathy. These risks, shown in the current study as well as in other studies, justify long-term surveillance for congestive heart failure in women treated with trastuzumab and for women enrolled in trials.
Also, Geiger expressed concern that about 25% of women in this study had received trastuzumab as adjuvant therapy before it was proven to be of benefit in randomized clinical trials in the adjuvant setting. This was probably based on data from the metastatic setting. She advocated longer follow-up on the risks of new treatments to justify their continued use.