Past CV disease, diabetes up trastuzumab cardiotoxicity risk in elderly with breast cancer

Nick Mulcahy

August 11, 2011

Barcelona, Spain - The risk of cardiotoxicity from trastuzumab (Herceptin, Genentech), already an issue for women receiving the drug for breast cancer, is even higher in elderly women who have a history of heart disease or diabetes, according to a small single-center study [1].

It's the first ever to carefully examine trastuzumab-related cardiotoxicity in elderly breast-cancer patients, in this case 70 years of age and older, according to the authors, led by Dr C é sar Serrano (Vall d'Hebron University Hospital, Barcelona, Spain). The pivotal clinical trials of trastuzumab were conducted in younger women, 65 years and younger, who had "optimal performance status," they write. Their study was published online August 9, 2011 in the Annals of Oncology.

In a chart review of 45 patients aged 70 years and older who had been treated with trastuzumab for early or advanced breast cancer at one center since 2005, the investigators found that 12 (26.7%) of the women developed heart problems, usually heart failure or asymptomatic systolic LV dysfunction. This rate of cardiotoxicity is slightly higher than what was seen in the pivotal clinical trials, note Serrano and colleagues.

Asymptomatic cardiotoxicity (about 18% of cases) was defined as an absolute drop of 10% or more in LVEF with a final LVEF below 50% or an absolute drop above 20%. The median duration of trastuzumab-based treatment was 49 weeks.

Most of the cases of cardiotoxicity (92%) resolved in a median of five weeks. "One of the main characteristics of trastuzumab cardiotoxicity is its reversibility. It is a well-known phenomenon that differs from other chemotherapeutic agents such as anthracyclines. Reversibility normally happens with treatment discontinuation but also can also occur spontaneously," explained Serrano, who is now at Brigham and Women's Hospital (Boston, MA), in a press statement [2]. "The decision to reintroduce trastuzumab or to continue with it must be taken case by case together with a cardiologist."

The investigators saw that 33% of women with a history of heart disease developed asymptomatic or symptomatic cardiotoxic effects as a result of receiving trastuzumab, compared with only 9.1% of women without such a history (p=0.01); 33.3% of women with diabetes developed such problems, compared with only 6.1% without diabetes (p=0.017).

In univariate analysis, development of trastuzumab-related cardiotoxicity was significantly associated with obesity (p=0.045), history of heart disease events—including heart failure, arrhythmias, myocardial ischemia, or valvular heart disease (p=0.047)—and diabetes (p=0.017). Not significantly related to cardiotoxicity were prior or current anthracycline exposure, prior treatment for hypertension, baseline LVEF, and smoking history.

But only a history of heart-disease events and diabetes were significant on multivariate analysis.

Despite its limitations, the new paper is a valuable addition to the literature about trastuzumab, according to an expert not involved in the study. "This paper starts to define what puts older women at increased risk for cardiotoxicity on this drug," Dr Ilene Browner (Johns Hopkins University, Baltimore, MD) said in an interview.

It also suggests that there is an "apparent similar tolerance" to trastuzumab in this older population when compared with the younger patients in the drug's pivotal trials, she said. "Most clinicians assume that older patients can't tolerate chemotherapeutic agents used in the treatment of cancer as well as younger patients do."

Patients with or without cardiovascular risk factors require "aggressive monitoring," according to Browner, who said that the standard of care is "frequent monitoring with echocardiograms," as indicated by the drug's package insert.

But, she said, "If a woman has cardiotoxicity risk factors, be even more vigilant." Clinicians may need to weigh the risks and benefits of trastuzumab for some of these patients, she advised.

The authors acknowledge the limited number of patients in their series and say that their findings need to be interpreted cautiously. But, they note, "The fact that the mortality rate at five years after diagnosis of congestive heart failure is about 50% in patients [older than] 65 years warrants close surveillance of early symptoms and cardiac function in the elderly breast-cancer population to be treated with trastuzumab."

The authors declare no conflict of interest.


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