Evidence Mounts on Heart Failure After Trastuzumab in Breast Cancer Survivors

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No Indication of a Plateau

The development of trastuzumab for the treatment of nonmetastatic invasive breast cancer tumors expressing human epidermal growth factor receptor 2 has been an important step in the field of personalized medicine.

Multiple trials have documented clinically and statistically significant improvements in overall and disease-free survival for women receiving adjuvant treatment including trastuzumab, compared with those receiving other chemotherapy agents. Unlike most new cancer chemotherapies, trastuzumab’s use in early-stage HER2-positive breast cancer also appears to be cost effective (Ann. Pharmacother. 2009;43:296-303).

This benefit, however, has been offset by safety concerns, with a pooled analysis of the early breast cancer trials suggesting a fivefold increase in risk of congestive heart failure for women who receive trastuzumab versus those who do not, with consistent results across varying treatment regimens (Cochrane Database Syst. Rev. 2012;4:CD006243).

The current study adds an additional year of follow-up to previous trials, during which the incidence of congestive heart failure continues to increase with no indication of a plateau. 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.

Although most previous randomized clinical trials have included anthracycline in both treatment and comparison arms, the current observational study found that, in real life, about 40% of women undergoing chemotherapy received regimens excluding anthracycline, probably due in part to the older age and higher comorbidity burden relative to participants in clinical trials.

Finally, this study raises concern in that roughly a quarter of the women who received adjuvant trastuzumab had been treated well before the publication of peer-reviewed results of relevant randomized controlled trials. Clinicians may have been basing their decision on findings from trials in women with metastatic breast cancer and preliminary data from the early breast cancer trials. The interim findings, however, were based on follow-up periods too short to account for the longer life expectancy of women with early breast cancer relative to women with metastatic disease.

There have been many instances in which new treatments disseminate based on preliminary reports of benefit, only to be withdrawn after additional safety data become available. Patients, clinicians, and researchers must temper their enthusiasm about the benefits of new cancer therapies with the recognition that estimates of the long-term risk of adverse events are based on short-term observations among carefully selected clinical trial participants.

Ann M. Geiger, Ph.D., is with the division of public health sciences at Wake Forest University, Winston Salem, N.C. She said that she has no conflicts of interest.



Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.

In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.

In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.

"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.

Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).

The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.

In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.

The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.

In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.

Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.

The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.

According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.

This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.

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