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Trastuzumab and the Risk of Congestive Heart Failure

December 1, 2012
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Abstract & Commentary

By Gary R. Shapiro, MD, Medical Director, Cancer Center of Western Wisconsin, New Richmond, Wisconsin. Dr. Shapiro reports no financial relationships relevant to this field of study.

Synopsis: This retrospective cohort study of 12,500 women with breast cancer, treated in the community, compared the incidence of congestive heart failure in those who received trastuzumab-containing adjuvant chemotherapy regimens with those who did not. There was a four-fold increase in the risk of heart failure in women who received trastuzumab alone and a seven-fold increase in those who received anthracycline plus trastuzumab.

Source: Bowles EJ, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: A retrospective cohort study. J Natl Cancer Inst 2012; 104:1293-1305.

The Cancer Research Network (CRN), a consortium of nonprofit research centers based in integrated health care delivery organizations, used administrative procedure and pharmacy codes to identify heart failure and/ or cardiomyopathy (HF/CM) in women with breast cancer at eight CRN sites who received adjuvant anthracycline, trastuzumab, and other chemotherapy. Of the 12,500 women (mean age, 60 years; range, 22-99 years) in this population-based, retrospective cohort study, 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy.

Compared to those who did not receive adjuvant chemotherapy, multivariable Cox proportional hazards regression analysis determined the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11-1.76), though this increased risk was similar to that of other chemotherapy (adjusted HR, 1.49; 95% CI, 1.25-1.77). On the other hand, the risk of HF/ CM was decidedly increased in patients treated with trastuzumab alone (adjusted HR, 4.12; 95% CI, 2.30-7.42) or anthracycline plus trastuzumab (adjusted HR, 7.19; 95% CI, 5.00-10.35).

Commentary

Although the relationship between trastuzumab-based adjuvant chemotherapy and HF/CM is well known, this is the first study to examine the “real world” of community-dwelling breast cancer patients. Older women and women with major comorbidities are underrepresented in formal clinical trials, and observational studies using Surveillance, Epidemiology, and End Results (SEER)-linked Medicare data do not include the broader group of women with breast cancer.1

As one might expect, women who received anthracycline alone or anthracycline plus trastuzumab in the CRN analysis were younger (age < 65 years, 86.4% and 89.6%, respectively) and had fewer comorbidities (Charlson score ≥ 2, 10.0% and 7.7%, respectively) than recipients of other or no adjuvant chemotherapy.

The median follow-up time for the analysis was 4.4 years, but it is important to note that the cumulative incidence of HF/CM in those who received anthracycline plus trastuzumab increased from 6.2% after 1 year of follow-up to 20.1% by 5 years. The 5-year cumulative incidence of HF/CM was 12.1% in those who got trastuzumab alone but only 4.3% in those who received anthracycline alone. These compare to a 5-year cumulative incidence of HF/CM of 4.5% in those who received other types of adjuvant chemotherapy and 3.1% in those who did not receive any adjuvant chemotherapy.

The 5-year cumulative incidence of trastuzumab-related HF/CM was most striking in the older age groups: 35.6% of those aged 65-74 and 40.7% of those 75 years of age and older who received anthracycline plus trastuzumab. These compare to 6.2% in those aged 65-74, and 10.6% in those 75 years and older who received anthracycline alone, and 8.7% of those age 65-74 years and 18.7% of those 75 years or older who received other forms of adjuvant chemotherapy.

Although the risk of anthracycline-associated HF/CM in younger women was similar to that reported from randomized clinical trials, the CRN analysis revealed a greater risk of trastuzumab-associated HF/ CM in both younger and older women than previously reported (whether the trastuzumab was administered alone or following anthracycline).2 The study’s median 4.4 years of follow-up is longer than that reported by other investigators, and it highlights the heretofore underappreciated ongoing long-term risk of trastuzumab-related HF/CM. Indeed, there appears to be no leveling off of this risk, and until more long-term data are accumulated, clinicians would be wise to provide ongoing surveillance for HF/CM in their patients who have received trastuzumab-containing adjuvant chemotherapy regimens.

References

1. Moja L, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012; 4:CD006243.

2. Procter M, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol 2010; 28:3422-3428.