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Trastuzumab linked to elevated risk for HF, cardiomyopathy
Patients with breast cancer treated with trastuzumab alone or after anthracycline exhibited a higher risk for heart failure and cardiomyopathy compared with patients who received no chemotherapy.
Previous studies have shown that patients with breast cancer treated with trastuzumab (Herceptin, Genentech) or anthracycline-based chemotherapy are at an increased risk for heart failure (HF)/cardiomyopathy. However, those clinical trials excluded older women (aged ≥70 years) and women with major comorbidities, making it difficult to distinguish the association between anthracycline and/or trastuzumab use and HF/cardiomyopathy in this population.
To determine the risk for HF/cardiomyopathy in this patient population, Erin J. Aiello Bowles, MPH, of Group Health Research Institute in Seattle, and colleagues reviewed 12,500 women diagnosed with invasive breast cancer from 1999 to 2007.
“We tried to take a broader look by estimating the risk of heart failure in a more general population,” Bowles said in a press release. “We looked at all the women in a population with breast cancer, not selected ones. Our study shows that people who are not generally eligible for clinical trials — older women and those with existing heart failure — do receive these drugs in real life.”
Using administrative procedure and pharmacy codes, the researchers identified anthracycline, trastuzumab and other chemotherapy use. The researchers also categorized incident HF/cardiomyopathy after chemotherapy initiation and assessed risk for HF/cardiomyopathy with time-varying chemotherapy exposures compared with no chemotherapy. Results were adjusted for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy and comorbidities.
According to study findings, 46.5% of the patients with breast cancer enrolled in the study received no chemotherapy, 29.6% received anthracycline alone, 19.5% received other chemotherapy, 3.5% received anthracycline plus trastuzumab and 0.9% received trastuzumab alone.
“These results suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice,” Bowles and colleagues wrote. “The overall risk of incident HF/[cardiomyopathy] was statistically significantly increased among women who used anthracycline alone compared with no chemotherapy, but the overall risk of incident HF/[cardiomyopathy] was even greater among women who used trastuzumab.”
Additionally, the risk for HF/cardiomyopathy was elevated in patients treated with anthracycline alone (adjusted HR=1.40; 95% CI, 1.11-1.76), although the increased risk was comparable to other chemotherapy (adjusted HR=1.49; 95% CI, 1.25-1.77). The risk was also observed to be highly 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, 5-10.35).
“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” Bowles and colleagues said. “The variability in predictive value of our HF/[cardiomyopathy] measure is a limitation, and studies with detailed data on [left ventricular ejection fraction] measures will be needed to confirm our findings.”
Disclosure: The researchers reported a grant from the NIH.
Perspective
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Trastuzumab-based therapies have dramatically changed the natural history of HER-2–positive breast cancer for the roughly 20% of women with invasive breast cancer that is HER-2–positive. Trastuzumab (Herceptin, Genentech) therapy for breast cancer is therefore correctly hailed as one of the foremost accomplishments in oncology over the past 20 years. With this success comes trade-offs: When anthracycline-based adjuvant therapy was combined with trastuzumab in clinical trials, rates of clinical congestive heart failure were as high as 4%. However, many of us were willing to consider this risk acceptable, given the tremendous advantages these regimens give our patients in terms of improved DFS, as well as OS.
Some of us were willing to continue to consider these risks acceptable even when phase 3 data in which non–anthracycline-based regimens containing trastuzumab gave statistically similar substantial benefits in terms of DFS and OS in women with early stage HER-2–positive breast cancer. This new "real world" data published in JNCI should perhaps give pause to those of us who continue to use anthracycline- trastuzumab combinations in the early breast cancer setting. Although several points of the article are debatable, in particular the exact definition of heart failure, an absolute cumulative rate of heart failure/cardiomyopathy in excess of 20% at 5 years in women receiving anthracycline- trastuzumab combinations should be a cause for concern. Perhaps this may give additional impetus for us to more strongly consider non–anthracycline-containing regimens such as TCH (trastuzumab /carboplatin/docetaxel), as this data is discussed and analyzed further by the wider oncology community.